John W. Day, MD, PhD

All Publications

• Long-term natural history in type II and III spinal muscular atrophy: a 4-year international study on the Hammersmith Functional Motor Scale Expanded. European journal of neurology Coratti, G., Bovis, F., Pera, M. C., Civitello, M., Rohwer, A., Salmin, F., Glanzman, A. M., Montes, J., Pasternak, A., De Sanctis, R., Dunaway Young, S., Duong, T., Mizzoni, I., Milev, E., Sframeli, M., Morando, S., Albamonte, E., D'Amico, A., Catteruccia, M., Brolatti, N., Pane, M., Scoto, M., Messina, S., Escudero, J. E., De Waele, L., Hirano, M., Zolkipli-Cunningham, Z., Darras, B. T., Bertini, E., Nascimiento Osorio, A., Bruno, C., Goemans, N., Sansone, V. A., Day, J., Baranello, G., Muntoni, F., Finkel, R., Mercuri, E., ISMAC/international SMA consortium, Cavallina, I., Rolle, E., Ricci, F., Mongini, T., Masson, R., Zanin, R., Arnoldi, M. T., Pini, A., Trabacca, A., Rodriguez-Torres, R. S., Forcina, N., Norcia, G., Stanca, G., Carnicella, S., Fanelli, L., Main, M., Bravetti, C., Longo, A., Nani, M., Antonaci, L., Catteruccia, M., Materia, R. 2024: e16517

  Abstract

  BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is a genetic disorder caused by SMN1 gene mutations. Although studies on available disease-modifying treatments have reported their efficacy and safety, long-term natural history data are lacking for comparison. The aim of this prospective study was to report 4-year changes on the Hammersmith Functional Motor Scale Expanded (HFMSE) in type II and III SMA in relation to several variables such as age, functional status and SMN2 copy number.METHODS: The study involves retrospective analysis of prospectively collected data from international datasets (Belgium, Italy, Spain, USA, UK). HFMSE longitudinal changes were analyzed using linear mixed effect models, examining annualized HFMSE change and its association with variables such as age at baseline, sex, motor function, SMN2 copy number.RESULTS: In SMA type II (n=226), the 4-year mean change was -2.20 points. The largest mean changes were observed in sitters aged 5-14years and the lowest in those who lost the ability to sit unsupported. In SMA type III (n=162), the 4-year mean change was -2.75 points. The largest mean changes were in those aged 7-15years, whilst the lowest were in those below 7 and in the SMA type IIIa subgroup over 15. Age and score at baseline were predictive of 4-year changes.CONCLUSIONS: Our findings provide natural history reference data for comparison with long-term follow-up of clinical trials or real-world data, highlighting the need to define patterns of changes in smaller SMA subgroups instead of reporting mean changes across an entire SMA cohort.

  View details for DOI 10.1111/ene.16517

  View details for PubMedID 39392101

• Exercise And Recovery Ventilatory Responses Between Individuals With Neuromuscular Disease And Healthy Adults Montalvo, S., Blumberg, Y., de Monts, C., Tang, W. J., Ataide, P., Young, S., Ghiollagain, N., Parker, D. M., Day, J. W., Myers, J. N., Wheeler, M. T., Duong, T., Christle, J. W. LIPPINCOTT WILLIAMS & WILKINS. 2024: 925-926

  View details for Web of Science ID 001315123204328

• Investigating Recovery From Maximal Exercise In Patients With Neuromuscular Disease Blumberg, Y., Patti, A., De Monts, C., Montalvo, S., Ataide, P., Tang, W., Young, S., Myers, J., Wheeler, M. T., Duong, T., Christle, J. W., Day, J. W. LIPPINCOTT WILLIAMS & WILKINS. 2024: 657

  View details for Web of Science ID 001315123203148

• Upper limb function changes over 12 months in untreated SMA II and III individuals: an item-level analysis using the Revised Upper Limb Module. Neuromuscular disorders : NMD Coratti, G., Civitello, M., Rohwer, A., Albamonte, E., Montes, J., Glanzman, A. M., Pasternak, A., De Sanctis, R., Young, S. D., Duong, T., Mizzoni, I., Milev, E., Sframeli, M., Morando, S., D'Amico, A., Catteruccia, M., Brolatti, N., Pane, M., Scoto, M., Messina, S., Hirano, M., Zolkipli-Cunningham, Z., Darras, B. T., Bertini, E., Bruno, C., Sansone, V. A., Salmin, F., Day, J., Baranello, G., Pera, M. C., Muntoni, F., Finkel, R. S., Mercuri, E. 2024: 104449

  Abstract

  The Revised upper limb module (RULM) has been increasingly used in clinical trials and in clinical settings. The aim of this study was to use the 'shift analysis' to assess the patterns of lost or gained abilities for each item on the RULM in an untreated cohort, stratified by SMA type, age, SMN2 copy number, and motor functional status. The analysis was performed on 222 12-month paired assessments from 129 individuals (115 assessment from type II and 107 from type III) who had at least two assessments at yearly intervals. There was a loss of one or more activities in 54% in type II and in 29% type III. A gain of one or more activities was found in 42% type II and in 22% type III. There were concomitant gains and losses in 27% in SMA II and in 9% in SMA III. Our results, measuring the number of abilities that are lost or gained, provide an additional method of detecting changes that can be used for the interpretation of the longitudinal data collected in treated SMA individuals.

  View details for DOI 10.1016/j.nmd.2024.08.006

  View details for PubMedID 39299818

• MINIMAL CLINICALLY IMPORTANT DIFFERENCE (MCID) FOR THE CMT PEDIATRIC SCALE (CMTPEDS) Cornett, K., Menezes, M., Donlevy, G., Estilow, T., McKay, M., Eichinger, K., Shy, R., Muntoni, F., Reilly, M., Yum, S., Moroni, I., Pareyson, D., Finkel, R., Herrmann, D., Acsadi, G., Day, J., Ramchandren, S., Shy, M. E., Burns, J., CMTPedS Study Grp WILEY. 2024: S192

  View details for Web of Science ID 001319566000386

• Therapeutic Role of Nusinersen on Respiratory Progression in Pediatric Patients With Spinal Muscular Atrophy Type 2 and Nonambulant Type 3. Neurology. Clinical practice Trucco, F., Ridout, D., Weststrate, H., Scoto, M., Rohwer, A., Coratti, G., Main, M. L., Mayhew, A. G., Montes, J., De Sanctis, R., Pane, M., Pera, M. C., Sansone, V. A., Albamonte, E., D'Amico, A., Bruno, C., Messina, S. S., Childs, A. M., Willis, T., Ong, M. T., Servais, L., Majumdar, A., Hughes, I., Marini-Bettolo, C., Parasuraman, D., Gowda, V. L., Baranello, G., Bertini, E. S., De Vivo, D. C., Darras, B. T., Day, J. W., Mayer, O., Zolkipli-Cunningham, Z., Finkel, R. S., Mercuri, E., Muntoni, F. 2024; 14 (3): e200298

  Abstract

  Nusinersen has shown significant functional motor benefit in the milder types of spinal muscular atrophy (SMA). Less is known on the respiratory outcomes in patients with nusinersen-treated SMA. The aim of this study was to describe changes in respiratory function in pediatric patients with SMA type 2 and 3 on regular treatment with nusinersen within the iSMAc international cohort and to compare their trajectory with the natural history (NH) data published by the consortium in 2020.This is a 5-year retrospective observational study of pediatric SMA type 2 and nonambulant type 3 (age ≤18 years) treated with nusinersen. The primary objective was to compare the slopes of decline in forced vital capacity % predicted (FVC% pred.), FVC, and age when FVC dropped below 60% between the treated patients and a control group from the natural history cohort. Data on peak cough flow and the use of noninvasive ventilation (NIV) and cough assist were collected.Data were available for 69 treated patients, 53 were SMA type 2 and 16 type 3. The mean (SD) age at first injection was 8.5 (3.2) and 9.7 (3.7) years, respectively. The median (interquartile range) treatment duration was 1 (0.7; 1.9) and 1.2 (0.9; 1.9) years, respectively. At the time of the first nusinersen injection, 24 of 52 (46%) patients with SMA type 2 and 2 of 16 (13%) patients with SMA type 3 were on NIV. Forty-three of 53 (81%) and 4 of 16 (25%) patients used cough device. FVC% pred. in treated patients with SMA type 2 declined annually by 2.3% vs 3.9% in NH (p = 0.08) and in treated patients with type 3 by 2.6% vs 3.4% NH (p = 0.59). Patients treated reached FVC <60% later than untreated (12.1 vs 10 years, p = 0.05). A higher percentage of treated vs untreated patients maintained FVC% pred. equal/above their baseline after 12 (65% vs 36%) and 24 (50% vs 24%) months, respectively. NIV use among treated did not significantly change throughout 1-year follow-up.This study included the largest real-world cohort of pediatric patients with milder SMA types. The results suggest a positive role of nusinersen in delaying the respiratory decline in patients treated longer than 1 year when compared with natural history. Larger cohorts and longer observation are planned.This study provided Class III evidence that nusinersen slows progression for patients with SMA types 2 and 3 compared with a natural history cohort.

  View details for DOI 10.1212/CPJ.0000000000200298

  View details for PubMedID 38932995

  View details for PubMedCentralID PMC11196214

• Changes in abilities over the initial 12 months of nusinersen treatment for type II SMA. Neuromuscular disorders : NMD Coratti, G., Civitello, M., Rohwer, A., Salmin, F., Glanzman, A. M., Montes, J., Pasternak, A., De Sanctis, R., Young, S. D., Duong, T., Mizzoni, I., Milev, E., Sframeli, M., Morando, S., Albamonte, E., D'Amico, A., Brolatti, N., Pane, M., Scoto, M., Messina, S., Hirano, M., Zolkipli-Cunningham, Z., Darras, B. T., Bertini, E., Bruno, C., Sansone, V. A., Day, J., Baranello, G., Pera, M. C., Muntoni, F., Finkel, R., Mercuri, E. 2024; 41: 42-50

  Abstract

  Several studies have shown the efficacy of new disease-modifying therapies in slowing down type II SMA progression using the Hammersmith Functional Motor Scale Expanded (HFMSE). This research aims to enhance understanding of activity changes across age groups post-nusinersen treatment using shift analysis, compared with untreated individuals. Retrospective data from the, international SMA consortium (iSMAc) dataset were analyzed, assessing individual item changes over 12 months. Shift analysis was used to determine the gain or loss of abilities, defining "gain" as a positive change between scores from 0 to either 1 or 2 and "loss" as a negative change from either 2 or 1 to 0. The cohort included 130 SMA II patients who underwent 12-month assessments from their first nusinersen dose, with age range between 0.6 and 49.6 years. One-third of the entire cohort experienced at least a loss in one activity, while 60% experienced a gain, particularly notable in children aged 2.5 to 5 years and 5 to 13 years. Overall, the study demonstrates a positive impact of nusinersen treatment on SMA II patients, showing a trend of increased activity gains and decreased probability of ability loss across different age groups.

  View details for DOI 10.1016/j.nmd.2024.05.003

  View details for PubMedID 38936290

• Beyond Contractures in Spinal Muscular Atrophy: Identifying Lower-Limb Joint Hypermobility. Journal of clinical medicine Harding, E. R., Kanner, C. H., Pasternak, A., Glanzman, A. M., Dunaway Young, S., Rao, A. K., McDermott, M. P., Zolkipli-Cunningham, Z., Day, J. W., Finkel, R. S., Darras, B. T., De Vivo, D. C., Montes, J. 2024; 13 (9)

  Abstract

  Background: The natural history of spinal muscular atrophy (SMA) is well understood, with progressive muscle weakness resulting in declines in function. The development of contractures is common and negatively impacts function. Clinically, joint hypermobility (JH) is observed but is poorly described, and its relationship with function is unknown. Methods: Lower-limb ROM (range of motion) assessments of extension and flexion at the hip, knee, and ankle were performed. ROMs exceeding the published norms were included in the analysis. The functional assessments performed included the six-minute walk test (6 MWT) and the Hammersmith Functional Motor Scale-Expanded (HFMSE). Results: Of the 143 participants, 86% (n = 123) had at least one ROM measure that was hypermobile, and 22% (n = 32) had three or more. The HFMSE scores were inversely correlated with hip extension JH (r = -0.60, p = 0.21; n = 6) and positively correlated with knee flexion JH (r = 0.24, p = 0.02, n = 89). There was a moderate, inverse relationship between the 6 MWT distance and ankle plantar flexion JH (r = -0.73, p = 0.002; n = 15). Conclusions: JH was identified in nearly all participants in at least one joint in this study. Hip extension, knee flexion and ankle plantar flexion JH was associated with function. A further understanding of the trajectory of lower-limb joint ROM is needed to improve future rehabilitation strategies.

  View details for DOI 10.3390/jcm13092634

  View details for PubMedID 38731167

  View details for PubMedCentralID PMC11084694

• Determining minimal clinically important differences in the Hammersmith Functional Motor Scale Expanded for untreated spinal muscular atrophy patients: An international study. European journal of neurology Coratti, G., Bovis, F., Pera, M. C., Scoto, M., Montes, J., Pasternak, A., Mayhew, A., Muni-Lofra, R., Duong, T., Rohwer, A., Dunaway Young, S., Civitello, M., Salmin, F., Mizzoni, I., Morando, S., Pane, M., Albamonte, E., D'Amico, A., Brolatti, N., Sframeli, M., Marini-Bettolo, C., Sansone, V. A., Bruno, C., Messina, S., Bertini, E., Baranello, G., Day, J., Darras, B. T., De Vivo, D. C., Hirano, M., Muntoni, F., Finkel, R., Mercuri, E. 2024: e16309

  Abstract

  Spinal muscular atrophy (SMA) is a rare and progressive neuromuscular disorder with varying severity levels. The aim of the study was to calculate minimal clinically important difference (MCID), minimal detectable change (MDC), and values for the Hammersmith Functional Motor Scale Expanded (HFMSE) in an untreated international SMA cohort.The study employed two distinct methods. MDC was calculated using distribution-based approaches to consider standard error of measurement and effect size change in a population of 321 patients (176 SMA II and 145 SMA III), allowing for stratification based on age and function. MCID was assessed using anchor-based methods (receiver operating characteristic [ROC] curve analysis and standard error) on 76 patients (52 SMA II and 24 SMA III) for whom the 12-month HFMSE could be anchored to a caregiver-reported clinical perception questionnaire.With both approaches, SMA type II and type III patients had different profiles. The MCID, using ROC analysis, identified optimal cutoff points of -2 for type II and -4 for type III patients, whereas using the standard error we found the optimal cutoff points to be 1.5 for improvement and -3.2 for deterioration. Furthermore, distribution-based methods uncovered varying values across age and functional status subgroups within each SMA type.These results emphasize that the interpretation of a single MCID or MDC value obtained in large cohorts with different functional status needs to be made with caution, especially when these may be used to assess possible responses to new therapies.

  View details for DOI 10.1111/ene.16309

  View details for PubMedID 38656662

• From Review to Readiness: CMT4J and the Road to Clinical Trials Cooper, S., Gottlieb, K., Messahel, S., Thomas, R., Duff, J., Pirovolakis, T., Shy, M., Bonnemann, C. G., Day, J., Iannaccone, S. CELL PRESS. 2024: 321-322

  View details for Web of Science ID 001332783401223

• A Strategy to Select Minimally Immunogenic Candidate AAV Vectors to Treat GNE Myopathy Hamilton, B. A., Patil, R., Ruland, B., Day, J., Wright, J. CELL PRESS. 2024: 726-727

  View details for Web of Science ID 001332783402481

• Safety and Efficacy of Apitegromab in Patients With Spinal Muscular Atrophy Types 2 and 3: The Phase 2 TOPAZ Study. Neurology Crawford, T. O., Darras, B. T., Day, J. W., Dunaway Young, S., Duong, T., Nelson, L. L., Barrett, D., Song, G., Bilic, S., Cote, S., Sadanowicz, M., Iarrobino, R., Xu, T. J., O'Neil, J., Rossello, J., Place, A., Kertesz, N., Nomikos, G., Chyung, Y. 2024; 102 (5): e209151

  Abstract

  Currently approved therapies for spinal muscular atrophy (SMA) reverse the degenerative course, leading to better functional outcome, but they do not address the impairment arising from preexisting neurodegeneration. Apitegromab, an investigational, fully human monoclonal antibody, inhibits activation of myostatin (a negative regulator of skeletal muscle growth), thereby preserving muscle mass. The phase 2 TOPAZ trial assessed the safety and efficacy of apitegromab in individuals with later-onset type 2 and type 3 SMA.In this study, designed to investigate potential meaningful combinations of eligibility and treatment regimen for future studies, participants aged 2-21 years received IV apitegromab infusions every 4 weeks for 12 months in 1 of 3 cohorts. Cohort 1 stratified ambulatory participants aged 5-21 years into 2 arms (apitegromab 20 mg/kg alone or in combination with nusinersen); cohort 2 evaluated apitegromab 20 mg/kg combined with nusinersen in nonambulatory participants aged 5-21 years; and cohort 3 blindly evaluated 2 randomized apitegromab doses (2 and 20 mg/kg) combined with nusinersen in younger participants ≥2 years of age. The primary efficacy measure was mean change from baseline using the Hammersmith Functional Motor Scale version appropriate for each cohort. Data were analyzed using a paired t test with 2-sided 5% type 1 error for the mean change from baseline for predefined cohort-specific primary efficacy end points.Fifty-eight participants (mean age 9.4 years) were enrolled at 16 trial sites in the United States and Europe. Participants had been treated with nusinersen for a mean of 25.9 months before enrollment in any of the 3 trial cohorts. At month 12, the mean change from baseline in Hammersmith scale score was -0.3 points (95% CI -2.1 to 1.4) in cohort 1 (n = 23), 0.6 points (-1.4 to 2.7) in cohort 2 (n = 15), and in cohort 3 (n = 20), the mean scores were 5.3 (-1.5 to 12.2) and 7.1 (1.8 to 12.5) for the 2-mg/kg (n = 8) and 20-mg/kg (n = 9) arms, respectively. The 5 most frequently reported treatment-emergent adverse events were headache (24.1%), pyrexia (22.4%), upper respiratory tract infection (22.4%), cough (22.4%), and nasopharyngitis (20.7%). No deaths or serious adverse reactions were reported.Apitegromab led to improved motor function in participants with later-onset types 2 and 3 SMA. These results support a randomized, placebo-controlled phase 3 trial of apitegromab in participants with SMA.This trial is registered with ClinicalTrials.gov (NCT03921528).This study provides Class III evidence that apitegromab improves motor function in later-onset types 2 and 3 spinal muscular atrophy.

  View details for DOI 10.1212/WNL.0000000000209151

  View details for PubMedID 38330285

• Disease Trajectories in the Revised Hammersmith Scale in a Cohort of Untreated Patients with Spinal Muscular Atrophy types 2 and 3. Journal of neuromuscular diseases Wolfe, A., Stimpson, G., Ramsey, D., Coratti, G., Dunaway Young, S., Mayhew, A., Pane, M., Rohwer, A., Muni Lofra, R., Duong, T., O'Reilly, E., Milev, E., Civitello, M., Sansone, V. A., D'Amico, A., Bertini, E., Messina, S., Bruno, C., Albamonte, E., Mazzone, E., Main, M., Montes, J., Glanzman, A. M., Zolkipli-Cunningham, Z., Pasternak, A., Marini-Bettolo, C., Day, J. W., Darras, B. T., De Vivo, D. C., Baranello, G., Scoto, M., Finkel, R. S., Mercuri, E., Muntoni, F. 2024

  Abstract

  Spinal muscular atrophy (SMA) is a neuromuscular disorder characterised by progressive motor function decline. Motor function is assessed using several functional outcome measures including the Revised Hammersmith Scale (RHS).In this study, we present longitudinal trajectories for the RHS in an international cohort of 149 untreated paediatric SMA 2 and 3 patients (across 531 assessments collected between March 2015 and July 2019).We contextualise these trajectories using both the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). At baseline, this cohort included 50% females and 15% of patients had undergone spinal fusion surgery. Patient trajectories were modelled using a natural cubic spline with age, sex, and random effects for each patient.RHS and HFMSE scores show similar trends over time in this cohort not receiving disease modifying therapies. The results confirm the strong correlation between the RHS and RULM previously observed in SMA types 2 and 3a. Scoliosis surgery is associated with a reduction of 3 points in the RHS, 4.5 points in the HFMSE for the SMA 2 population, and a reduction of 11.8 points in the RHS, and 13.4 points in the HFMSE for the SMA 3a populations. When comparing the RHS and RULM, there is a lower correlation in the type 3a's than the type 2 patients. In the SMA 2 population, there is no significant difference between the sexes in either the RHS or HFMSE trajectories. There is no significant difference in the RULM trajectory in the SMA 2 or 3a participants by sex.This study demonstrates that the RHS could be used in conjunction with other functional measures such as the RULM to holistically detect SMA disease progression. This will assist with fully understanding changes that occur with treatments, further defining trajectories and therapy outcomes.

  View details for DOI 10.3233/JND-230211

  View details for PubMedID 38427497

• Real-World Outcomes in Patients with Spinal Muscular Atrophy Treated with Onasemnogene Abeparvovec Monotherapy: Findings from the RESTORE Registry. Journal of neuromuscular diseases Servais, L., Day, J. W., De Vivo, D. C., Kirschner, J., Mercuri, E., Muntoni, F., Proud, C. M., Shieh, P. B., Tizzano, E. F., Quijano-Roy, S., Desguerre, I., Saito, K., Faulkner, E., Benguerba, K. M., Raju, D., LaMarca, N., Sun, R., Anderson, F. A., Finkel, R. S. 2024

  Abstract

  BACKGROUND: Long-term, real-world effectiveness and safety data of disease-modifying treatments for spinal muscular atrophy (SMA) are important for assessing outcomes and providing information for a larger number and broader range of SMA patients than included in clinical trials.OBJECTIVE: We sought to describe patients with SMA treated with onasemnogene abeparvovec monotherapy in the real-world setting.METHODS: RESTORE is a prospective, multicenter, multinational, observational registry that captures data from a variety of sources.RESULTS: Recruitment started in September 2018. As of May 23, 2022, data were available for 168 patients treated with onasemnogene abeparvovec monotherapy. Median (IQR) age at initial SMA diagnosis was 1 (0-6) month and at onasemnogene abeparvovec infusion was 3 (1-10) months. Eighty patients (47.6%) had two and 70 (41.7%) had three copies of SMN2, and 98 (58.3%) were identified by newborn screening. Infants identified by newborn screening had a lower age at final assessment (mean age 11.5 months) and greater mean final (SD) CHOP INTEND score (57.0 [10.0] points) compared with clinically diagnosed patients (23.1 months; 52.1 [8.0] points). All patients maintained/achieved motor milestones. 48.5% (n = 81/167) experienced at least one treatment-emergent adverse event (AE), and 31/167 patients (18.6%) experienced at least one serious AE, of which 8/31 were considered treatment-related.CONCLUSION: These real-world outcomes support findings from the interventional trial program and demonstrate effectiveness of onasemnogene abeparvovec over a large patient population, which was consistent with initial clinical data and published 5-year follow-up data. Observed AEs were consistent with the established safety profile of onasemnogene abeparvovec.

  View details for DOI 10.3233/JND-230122

  View details for PubMedID 38250783

• Long-term efficacy, safety, and patient-reported outcomes of apitegromab in patients with spinal muscular atrophy: results from the 36-month TOPAZ study. Frontiers in neurology Crawford, T. O., Day, J. W., De Vivo, D. C., Krueger, J. M., Mercuri, E., Nascimento, A., Pasternak, A., Mazzone, E. S., Duong, T., Song, G., Marantz, J. L., Baver, S., Yu, D., Liu, L., Darras, B. T. 2024; 15: 1419791

  Abstract

  Background and purpose: At 12months in the phase 2 TOPAZ study, treatment with apitegromab was associated with both an improved motor function in patients with Type 2 or 3 spinal muscular atrophy (SMA) and with a favorable safety profile. This manuscript reports the extended efficacy and safety in the nonambulatory group of the TOPAZ study at 36months.Methods: Patients who completed the primary study (NCT03921528) could enroll in an open-label extension, during which patients received apitegromab 20mg/kg by intravenous infusion every 4weeks. Patients were assessed periodically via the Hammersmith Functional Motor Scale-Expanded (HFMSE), Revised Upper Limb Module (RULM), World Health Organization (WHO) motor development milestones, Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) Daily Activities and Mobility domains, and Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue questionnaire.Results: Of the 58 patients enrolled in TOPAZ, 35 were nonambulatory (mean age 7.3years). The mean change at 36months in HFMSE score from baseline was +4.0 (standard deviation [SD]: 7.54), and+2.4 (3.24) for RULM score (excluding n=7 after scoliosis surgery). Caregiver-reported outcomes (PEDI-CAT and PROMIS Fatigue) showed improvements from baseline over 36months. In addition, most patients (28/32) improved or maintained WHO motor milestones achieved at baseline. The most frequently reported treatment-emergent adverse events were pyrexia (48.6%), nasopharyngitis (45.7%), COVID-19 infection (40.0%), vomiting (40.0%), and upper respiratory tract infection (31.4%).Conclusion: The benefit of apitegromab treatment observed at 12months was sustained at 36months with no new safety findings.

  View details for DOI 10.3389/fneur.2024.1419791

  View details for PubMedID 39105058

• Adeno-associated virus serotype 9 antibody seroprevalence for patients in the United States with spinal muscular atrophy. Molecular therapy. Methods & clinical development Day, J. W., Mendell, J. R., Burghes, A. H., van Olden, R. W., Adhikary, R. R., Dilly, K. W. 2023; 31: 101117

  Abstract

  Onasemnogene abeparvovec is a recombinant adeno-associated virus serotype 9 (AAV9) vector-based gene therapy for spinal muscular atrophy (SMA). Patients with elevated titers of anti-AAV9 antibodies (AAV9-Ab) should not receive onasemnogene abeparvovec because of potential safety and efficacy implications. We conducted a retrospective study to describe the seroprevalence of anti-AAV9 binding antibodies for pediatric patients with SMA in the United States. At initial testing, 13.0% (115 of 882) of patients (mean [SD] age, 26.29 [33.66] weeks) had elevated AAV9-Ab titers. The prevalence of elevated titers decreased as age increased, with 18.2% (92 of 507) of patients ≤3 months old but only 1.1% (1 of 92) of patients ≥21 months old having elevated titers. This suggests transplacental maternal transfer of antibodies. No patterns of geographic variations in AAV9-Ab prevalence were confirmed. Elevated AAV9-Ab titers in children <6 weeks old decreased in all circumstances. Lower magnitudes of elevated titers declined more rapidly than greater magnitudes. Retesting was completed at the discretion of the treating clinician, so age at testing and time between tests varied. AAV9-Ab retesting should be considered when patients have elevated titers, and elevations at a young age are not a deterrent to eventual onasemnogene abeparvovec administration. Early disease-modifying treatment for SMA leads to optimal outcomes.

  View details for DOI 10.1016/j.omtm.2023.101117

  View details for PubMedID 37822718

  View details for PubMedCentralID PMC10562739

• Assessing the Assisted Six-Minute Cycling Test as a Measure of Endurance in Non-Ambulatory Patients with Spinal Muscular Atrophy (SMA). Journal of clinical medicine Tang, W. J., Gu, B., Montalvo, S., Dunaway Young, S., Parker, D. M., de Monts, C., Ataide, P., Ni Ghiollagain, N., Wheeler, M. T., Tesi Rocha, C., Christle, J. W., He, Z., Day, J. W., Duong, T. 2023; 12 (24)

  Abstract

  Assessing endurance in non-ambulatory individuals with Spinal Muscular Atrophy (SMA) has been challenging due to limited evaluation tools. The Assisted 6-Minute Cycling Test (A6MCT) is an upper limb ergometer assessment used in other neurologic disorders to measure endurance. To study the performance of the A6MCT in the non-ambulatory SMA population, prospective data was collected on 38 individuals with SMA (13 sitters; 25 non-sitters), aged 5 to 74 years (mean = 30.3; SD = 14.1). The clinical measures used were A6MCT, Revised Upper Limb Module (RULM), Adapted Test of Neuromuscular Disorders (ATEND), and Egen Klassifikation Scale 2 (EK2). Perceived fatigue was assessed using the Fatigue Severity Scale (FSS), and effort was assessed using the Rate of Perceived Exertion (RPE). Data were analyzed for: (1) Feasibility, (2) Clinical discrimination, and (3) Associations between A6MCT with clinical characteristics and outcomes. Results showed the A6MCT was feasible for 95% of the tested subjects, discriminated between functional groups (p = 0.0086), and was significantly associated with results obtained from RULM, ATEND, EK2, and Brooke (p < 0.0001; p = 0.029; p < 0.001; p = 0.005). These findings indicate the A6MCT's potential to evaluate muscular endurance in non-ambulatory SMA individuals, complementing clinician-rated assessments. Nevertheless, further validation with a larger dataset is needed for broader application.

  View details for DOI 10.3390/jcm12247582

  View details for PubMedID 38137651

  View details for PubMedCentralID PMC10743820

• Sunfish parts 1 and 2: 4-year efficacy and safety data of risdiplam in types 2 and 3 spinal muscular atrophy (SMA) Oskoui, M., Deconinck, N., Mazzone, E. S., Nascimento, A., Day, J. W., Saito, K., Vuillerot, C., Baranello, G., Boespflug-Tanguy, O., Goemans, N., Kirschnero, J., Kostera-Pruszczyk, A., Servais, L., Braid, J., Gerber, M., Gorni, K., Martin, C., Yeung, W., Scalco, R. S., Mercuri, E. ELSEVIER. 2023

  View details for DOI 10.1016/j.jns.2023.121096

  View details for Web of Science ID 001163199100226

• Cerebrospinal Fluid Proteomic Changes after Nusinersen in Patients with Spinal Muscular Atrophy. Journal of clinical medicine Beaudin, M., Kamali, T., Tang, W., Hagerman, K. A., Dunaway Young, S., Ghiglieri, L., Parker, D. M., Lehallier, B., Tesi-Rocha, C., Sampson, J. B., Duong, T., Day, J. W. 2023; 12 (20)

  Abstract

  Disease-modifying treatments have transformed the natural history of spinal muscular atrophy (SMA), but the cellular pathways altered by SMN restoration remain undefined and biomarkers cannot yet precisely predict treatment response. We performed an exploratory cerebrospinal fluid (CSF) proteomic study in a diverse sample of SMA patients treated with nusinersen to elucidate therapeutic pathways and identify predictors of motor improvement. Proteomic analyses were performed on CSF samples collected before treatment (T0) and at 6 months (T6) using an Olink panel to quantify 1113 peptides. A supervised machine learning approach was used to identify proteins that discriminated patients who improved functionally from those who did not after 2 years of treatment. A total of 49 SMA patients were included (10 type 1, 18 type 2, and 21 type 3), ranging in age from 3 months to 65 years. Most proteins showed a decrease in CSF concentration at T6. The machine learning algorithm identified ARSB, ENTPD2, NEFL, and IFI30 as the proteins most predictive of improvement. The machine learning model was able to predict motor improvement at 2 years with 79.6% accuracy. The results highlight the potential application of CSF biomarkers to predict motor improvement following SMA treatment. Validation in larger datasets is needed.

  View details for DOI 10.3390/jcm12206696

  View details for PubMedID 37892834

• Intravenous and intrathecal onasemnogene abeparvovec gene therapy in symptomatic and presymptomatic spinal muscular atrophy (SMA): long-term follow-up study Darras, B., Mercuri, E., Strauss, K., Day, J., Chien, Y., Masson, R., Wigderson, M., Alecu, I., Ballarini, N., Mehl, L., Marra, J., Connolly, A. PERGAMON-ELSEVIER SCIENCE LTD. 2023: S87

  View details for DOI 10.1016/j.nmd.2023.07.093

  View details for Web of Science ID 001087070800083

• Assisted Six Minute Cycle Test (A6MCT): A Feasible and Valid Measurement of Functional and Fatigue Changes in Individuals with Spinal Muscular Atrophy Tang, W., Montalvo, S., De Monts, C., Young, S., Ataide, P., Ghiollagain, N., Stevens, V., Parker, D., He, Z., Rocha, C., Day, J., Duong, T. PERGAMON-ELSEVIER SCIENCE LTD. 2023: S135

  View details for DOI 10.1016/j.nmd.2023.07.276

  View details for Web of Science ID 001087070800265

• Quality of life in adults with dysferlinopathy: international clinical outcome study of dysferlinopathy Hilsden, H., James, M., Dressman, H., Day, J., Mendell, J., Torron, R., Harms, M., Pestronk, A., Vissing, J., Desai, U., Yoshimura, M., Shin, J., Mozaffar, T., Stojkovic, T., Pegoraro, E., Raivas, J., Olive, M., Paradas, C., Straub, V., Mayhew, A. PERGAMON-ELSEVIER SCIENCE LTD. 2023: S113

  View details for DOI 10.1016/j.nmd.2023.07.191

  View details for Web of Science ID 001087070800180

• Topline data analysis of the phase 1/2 clinical trial evaluating AOC 1001 in adult patients with myotonic dystrophy type 1: MARINA Johnson, N., Day, J., Hamel, J., Thornton, C., Subramony, S., Soltanzadeh, P., Statland, J., Wicklund, M., Arnold, W., Freimer, M., DiTrapani, K., Heusner, C., Chen, C., Cho, H., McEvoy, B., Zhu, Y., Tai, L., Ackermann, E. PERGAMON-ELSEVIER SCIENCE LTD. 2023: S72

  View details for DOI 10.1016/j.nmd.2023.07.036

  View details for Web of Science ID 001087070800026

• Topline safety and efficacy data analysis of phase 1/2 clinical trial evaluating AOC 1001 in adults with myotonic dystrophy type 1: MARINA ™ Johnson, N., Day, J., Hamel, J., Thornton, C., Subramony, S., Soltanzadeh, P., Statland, J., Wicklund, M., Arnold, W., Freimer, M., DiTrapani, K., Heusner, C., Chen, C., McEvoy, B., Zhu, Y., Tai, L., Ackermann, E. PERGAMON-ELSEVIER SCIENCE LTD. 2023: S190-S191

  View details for DOI 10.1016/j.nmd.2023.07.487

  View details for Web of Science ID 001087070800476

• Safety update: Risdiplam clinical trial program for spinal muscular atrophy (SMA) Baranello, G., Chiriboga, C., Servais, L., Darras, B., Day, J., Deconinck, N., Farrar, M., Finkel, R., Bertini, E., Kirschner, J., Rasson, M., Mazurkiewicz-Beldzinska, M., Vlodavets, D., Bader-Weder, S., Gorni, K., Jaber, B., Yeung, W., Papp, G., Scalco, R., Mercuri, E., FIREFISH SUNFISH JEWELFISH RAINBOW PERGAMON-ELSEVIER SCIENCE LTD. 2023: S92-S93

  View details for DOI 10.1016/j.nmd.2023.07.112

  View details for Web of Science ID 001087070800102

• Effect of Apitegromab on pedi-cat and promis-fatigue questionnaire at 36-months in patients with spinal muscular atrophy Crawford, T., Darras, B., Day, J., Krueger, J., Mercuri, E., Nascimento, A., Pasternak, A., Duong, T., Liu, L., Sadanowicz, M., Baver, S., Topaz Study Team PERGAMON-ELSEVIER SCIENCE LTD. 2023: S93-S94

  View details for DOI 10.1016/j.nmd.2023.07.116

  View details for Web of Science ID 001087070800106

• More prevalent comorbidities, healthcare costs, and service utilization in male Myotonic Dystrophy (DM) patients and female patients Day, J., Munoz, K., Chen, C., Brook, R., Kleinman, N., Cho, H., McEvoy, B., Stahl, M., Tai, L. PERGAMON-ELSEVIER SCIENCE LTD. 2023: S157

  View details for DOI 10.1016/j.nmd.2023.07.360

  View details for Web of Science ID 001087070800349

• Effect of apitegromab on motor function at 36 months in patients with nonambulatory spinal muscular atrophy aged 2-12 years old Crawford, T., Darras, B., Day, J., De Vivo, D., Mercuri, E., Nascimento, A., Mazzone, E., Waugh, A., Song, G., Evans, R., Marantz, J., TOPAZ Study Team PERGAMON-ELSEVIER SCIENCE LTD. 2023: S91

  View details for DOI 10.1016/j.nmd.2023.07.106

  View details for Web of Science ID 001087070800096

• Assessment of maximal effort for weaker individuals with NMD during the assisted six-minute cycling test Blumberg, Y., De Monts, C., Tang, W., Montalvo, S., Ataide, P., Young, S., Wheeler, M., Ashley, E., Myers, J., Day, J., Christle, J., Duong, T. PERGAMON-ELSEVIER SCIENCE LTD. 2023: S187

  View details for DOI 10.1016/j.nmd.2023.07.473

  View details for Web of Science ID 001087070800462

• Generation of two induced pluripotent stem cell lines from Duchenne muscular dystrophy patients. Stem cell research Liu, W., Zeng, W., Kong, X., Htet, M., Yu, R., Wheeler, M., Day, J. W., Wu, J. C. 2023; 72: 103207

  Abstract

  Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder that leads to death in early adulthood. Patients with DMD have null mutations leading to loss of functional dystrophin protein. Here we generated two DMD induced pluripotent stem cell (iPSC) lines, one with deletion of exon 51 and the other with a single nucleotide nonsense mutation (c.10171C > T). Both lines expressed high levels of pluripotency markers, had the capability of differentiating into derivatives of the three germ layers, and possessed normal karyotypes. These iPSC lines can serve as powerful tools to model DMD in vitro and as a platform for therapeutic development.

  View details for DOI 10.1016/j.scr.2023.103207

  View details for PubMedID 37740996

• Nusinersen Treatment of Children with Later-Onset Spinal Muscular Atrophy and Scoliosis Is Associated with Improvements or Stabilization of Motor Function. Journal of clinical medicine Dunaway Young, S., Montes, J., Glanzman, A. M., Gee, R., Day, J. W., Finkel, R. S., Darras, B. T., De Vivo, D. C., Gambino, G., Foster, R., Wong, J., Garafalo, S., Berger, Z. 2023; 12 (15)

  Abstract

  Nusinersen has been shown to improve or stabilize motor function in individuals with spinal muscular atrophy (SMA). We evaluated baseline scoliosis severity and motor function in nusinersen-treated non-ambulatory children with later-onset SMA. Post hoc analyses were conducted on 95 children initiating nusinersen treatment in the CHERISH study or SHINE long-term extension trial. Participants were categorized by baseline Cobb angle (first nusinersen dose): ≤10°, >10° to ≤20°, and >20° to <40° (no/mild/moderate scoliosis, respectively). Outcome measures included the Hammersmith Functional Motor Score-Expanded (HFMSE) and the Revised Upper Limb Module (RULM). Regression analysis determined the relationships between baseline scoliosis severity and later motor function. For children with no, mild, and moderate scoliosis, the mean increase in HFMSE from baseline to Day 930 was 6.0, 3.9, and 0.7 points, and in RULM was 6.1, 4.6, and 2.3 points. In the linear model, a 10° increase in baseline Cobb angle was significantly associated with a -1.4 (95% CI -2.6, -0.2) point decrease in HFMSE (p = 0.02) and a -1.2 (95% CI -2.1, -0.4) point decrease in RULM (p = 0.006) at Day 930. Treatment with nusinersen was associated with improvements/stabilization in motor function in all groups, with greater response in those with no/mild scoliosis at baseline.

  View details for DOI 10.3390/jcm12154901

  View details for PubMedID 37568304

• ADAPTations to low load blood flow restriction exercise versus conventional heavier load resistance exercise in UK military personnel with persistent knee pain: protocol for the ADAPT study, a multi-centre randomized controlled trial BMC MUSCULOSKELETAL DISORDERS Cassidy, R. P., Lunt, K. M., Coppack, R. J., Bennett, A. N., Bilzon, J. J., Mcguigan, M., Egginton, N., Sellon, E., Day, J., Ladlow, P. 2023; 24 (1): 580

  Abstract

  Muscle atrophy, muscle weakness and localised pain are commonly reported following musculoskeletal injury (MSKI). To mitigate this risk and prepare individuals to return to sport or physically demanding occupations, resistance training (RT) is considered a vital component of rehabilitation. However, to elicit adaptations in muscle strength, exercise guidelines recommend lifting loads ≥ 70% of an individual's one repetition maximum (1-RM). Unfortunately, individuals with persistent knee pain are often unable to tolerate such high loads and this may negatively impact the duration and extent of their recovery. Low load blood flow restriction (LL-BFR) is an alternative RT technique that has demonstrated improvements in muscle strength, hypertrophy, and pain in the absence of high mechanical loading. However, the effectiveness of high-frequency LL-BFR in a residential rehabilitation environment remains unclear. This study will compare the efficacy of high frequency LL-BFR to 'conventional' heavier load resistance training (HL-RT) on measures of physical function and pain in adults with persistent knee pain.This is a multicentre randomised controlled trial (RCT) of 150 UK service personnel (aged 18-55) admitted for a 3-week residential rehabilitation course with persistent knee pain. Participants will be randomised to receive: a) LL-BFR delivered twice daily at 20% 1-RM or b) HL-RT three-times per week at 70% 1-RM. Outcomes will be recorded at baseline (T1), course discharge (T2) and at three-months following course (T3). The primary outcome will be the lower extremity functional scale (LEFS) at T2. Secondary outcomes will include patient reported perceptions of pain, physical and occupational function and objective measures of muscle strength and neuromuscular performance. Additional biomechanical and physiological mechanisms underpinning both RT interventions will also be investigated as part of a nested mechanistic study.LL-BFR is a rehabilitation modality that has the potential to induce positive clinical adaptations in the absence of high mechanical loads and therefore could be considered a treatment option for patients suffering significant functional deficits who are unable to tolerate heavy load RT. Consequently, results from this study will have a direct clinical application to healthcare service providers and patients involved in the rehabilitation of physically active adults suffering MSKI.ClinicalTrials.org reference number, NCT05719922.

  View details for DOI 10.1186/s12891-023-06693-3

  View details for Web of Science ID 001032457700001

  View details for PubMedID 37461024

  View details for PubMedCentralID PMC10351180

• Correction to: Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study. Neurology and therapy Chiriboga, C. A., Bruno, C., Duong, T., Fischer, D., Mercuri, E., Kirschner, J., Kostera-Pruszczyk, A., Jaber, B., Gorni, K., Kletzl, H., Carruthers, I., Martin, C., Warren, F., Scalco, R. S., Wagner, K. R., Muntoni, F., JEWELFISH Study Group, Deconinck, N., Balikova, I., Joniau, I., Tahon, V., Wittevrongel, S., Goemans, N., Cassiman, C., Prove, L., Vancampenhout, L., van den Hauwe, M., Van Impe, A., Cances, C., Soler, V., De La Morandais, L. M., Vovan, D., Cintas, P., Auriol, F., Mus, M., Alphonsa, G., Bellio, V., Gil Mato, O., Flamein, F., Evrard, C., Ziouche, A., Bouacha-Allou, I., Debruyne, P., Derlyn, G., Defoort, S., Leroy, F., Danjoux, L., Desguerre, I., Bremond-Gignac, D., Rateuax, M., Deladriere, E., Vuillerot, C., Veillerot, Q., Sibille-Dabadi, B., Barriere, A., Tinat, M., Saidi, M., Fontaine, S., De Montferrand, C., Le-Goff, L., Portefaix, A., Louvier, U. W., Duval, P., Caradec, P., Touati, S., Herranz, A. Z., Kirschner, J., Bollig, J., Molnar, F., Vogt, S., Pechmann, A., Schorling, D., Wider, S., Kolbel, H., Schara, U., Braun, F., Gangfuss, A., Hagenacker, T., Eckstein, A., Dekowski, D., Oeverhaus, M., Stoehr, M., Andres, B., Smuda, K., Bertini, E., D'Amico, A., Petroni, S., Valente, P., Bonetti, A. M., Carlesi, A., Mizzoni, I., Bruno, C., Pedemonte, M., Brolatti, N., Priolo, E., Rao, G., Sposetti, L., Morando, S., Comi, G., Osnaghi, S., Minorini, V., Abbati, F., Fassini, F., Foa, M., Lopopolo, M. A., Magri, F., Govoni, A., Meneri, M., Parente, V., Mercuri, E., Antonaci, L., Pera, M. C., Pane, M., Amorelli, G. M., Barresi, C., D'Amico, G., Orazi, L., Coratti, G., De Sanctis, R., Vita, G., Sframeli, M., Vita, G. L., Aragona, P., Inferrera, L., Postorino, E. I., Montanini, D., Di Bella, V., Donato, C., Cala, E., Van der Pol, L., Aalbers, J., de Boer, J., Imhof, S., Cooijmans, P., Ruyten, T., Van Der Woude, D., Kostera-Pruszczyk, A., Klimaszewska, B., Romanczak, D., Gierlak-Wojcicka, Z., Kepa, M., Sikorski, A., Sobieraj, M., Lusakowska, A., Kierdaszuk, B., Czeczko, K., Fischer, D., Henzi, B., Gugleta, K., Kusnyerik, A., Siems, P., Akos, S., Frei, N., Seppi, C., Haschke, C. W., Guglieri, M., Straub, V., Bell, R., Nassar, M., Page, S., Clarke, M. P., Regan, A., Mayhew, A., Lofra, R. M., Parasuraman, D., Bruschi, S., Ghauri, A., Castle, A., Naqvi, S., Patt, N., Scoto, M., Trucco, F., Henderson, R. H., Kukadia, R., Moore, W., Milev, E., Rye, C., Selby, V., Wolfe, A., Darras, B., Baglieri, A. M., Fulton, A., Lucken, C., Maczek, E., Pasternak, A., Chiriboga, C. A., Kane, S., Bautista, M. E., Frommer, E., Pensec, N., Salazar, R., Yochai, C., Rodrigues-Torres, R., Chawla, M., Day, J., Beres, S., Gee, R., Young, S. D., Finkel, R., Nazario, A. N., Fasiuddin, A., Wells, J. A., Wilson, J., Berry, D., Rizzo, V., Duke, J., Monduy, M., Collado, J. 2023

  View details for DOI 10.1007/s40120-023-00503-7

  View details for PubMedID 37395990

• Learning Spectral Fractional Anisotropy and Mean Diffusivity Features as Neuroimaging Biomarkers for Tracking White Matter Integrity Changes in Myotonic Dystrophy Type 1 Patients using Deep Convolutional Neural Networks. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference Kamali, T., Day, J. W., Deutsch, G. K., Sampson, J. B., Murad, A., Chaufty, J., Parker, D., Wozniak, J. R. 2023; 2023: 1-4

  Abstract

  Myotonic dystrophy type 1 (DM1) is a genetic neuromuscular progressive multisystem disease that results in a broad spectrum of clinical central nervous system (CNS) involvement, including problems with memory, attention, executive functioning, and social cognition. Fractional anisotropy and mean diffusivity along-tract data calculated using diffusion tensor imaging techniques play a vital role in assessing white matter microstructural changes associated with neurodegeneration caused by DM1. In this work, a novel spectrogram-based deep learning method is proposed to characterize white matter network alterations in DM1 with the goal of building a deep learning model as neuroimaging biomarkers of DM1. The proposed method is evaluated on fractional anisotropies and mean diffusivities along-tract data calculated for 25 major white matter tracts of 46 DM1 patients and 96 unaffected controls. The evaluation data consists of a total of 7100 spectrogram images. The model achieved 91% accuracy in identifying DM1, a significant improvement compared to previous methods.Clinical relevance- Clinical care of DM1 is particularly challenging due to DM1 multisystem involvement and the disease variability. Patients with DM1 often experience neurological and psychological symptoms, such as excessive sleepiness and apathy, that greatly impact their quality of life. Some of DM1 CNS symptoms may be responsive to treatment. The goal of this research is to gain a deeper understanding of the impact of DM1 on the CNS and to develop a deep learning model that can serve as a biomarker for the disease, with the potential to be used in future clinical trials as an outcome measure.

  View details for DOI 10.1109/EMBC40787.2023.10340468

  View details for PubMedID 38083393

• DEVOTE Study Exploring Higher Dose of Nusinersen in Spinal Muscular Atrophy: Study Design and Part A Results. Journal of neuromuscular diseases Finkel, R. S., Day, J. W., Pascual, S. I., Ryan, M. M., Mercuri, E., De Vivo, D. C., Montes, J., Gurgel-Giannetti, J., Monine, M., Gambino, G., Makepeace, C., Foster, R., Berger, Z., DEVOTE Study Group 2023

  Abstract

  BACKGROUND: Pharmacokinetic/pharmacodynamic modeling indicates that the higher dose of nusinersen may be associated with a clinically meaningful increase in efficacy above that seen with the 12-mg approved dose.OBJECTIVE: Here we describe both the design of DEVOTE (NCT04089566), a 3-part clinical study evaluating safety, tolerability, and efficacy of higher dose of nusinersen, and results from the initial Part A.METHODS: DEVOTE Part A evaluates safety and tolerability of a higher nusinersen dose; Part B assesses efficacy in a randomized, double-blind design; and Part C assesses safety and tolerability of participants transitioning from the 12-mg dose to higher doses.RESULTS: In the completed Part A of DEVOTE, all 6 enrolled participants aged 6.1-12.6 years have completed the study. Four participants experienced treatment-emergent adverse events (TEAEs), the majority of which were mild. Common TEAEs of headache, pain, chills, vomiting, and paresthesia were considered related to the lumbar puncture procedure. There were no safety concerns regarding clinical or laboratory parameters. Nusinersen levels in the cerebrospinal fluid were within the range of modeled predictions for higher dose of nusinersen. While Part A was not designed for assessing efficacy, most participants showed stabilization or improvement in motor function. Parts B and C of DEVOTE are ongoing.CONCLUSIONS: The findings from Part A of the DEVOTE study support further development of higher dose of nusinersen.

  View details for DOI 10.3233/JND-221667

  View details for PubMedID 37393513

• Genetic analysis and natural history of Charcot-Marie-Tooth disease CMTX1 due to GJB1 variants. Brain : a journal of neurology Record, C. J., Skorupinska, M., Laura, M., Rossor, A. M., Pareyson, D., Pisciotta, C., Feely, S. M., Lloyd, T. E., Horvath, R., Sadjadi, R., Herrmann, D. N., Li, J., Walk, D., Yum, S. W., Lewis, R. A., Day, J., Burns, J., Finkel, R. S., Saporta, M. A., Ramchandren, S., Weiss, M. D., Acsadi, G., Fridman, V., Muntoni, F., Poh, R., Polke, J. M., Zuchner, S., Shy, M. E., Scherer, S. S., Reilly, M. M., Inherited Neuropathies Consortium - Rare Disease Clinical Research Network, Abreu, L., Anderson, K. A., Baratta, S., Berry, D., Blake, J., Cavalca, E., Cornett, K., Cortese, A., Donlevy, G., Dragon, A., Dudziec, M., Estilow, K. E., Ferment, V., Grant, N., Grider, T., Hyslop, E., Jones, T., Kressin, N., Leon, W., Magri, S., McCray, B., Menezes, M., Milev, E., Parrott, L., Patel, P., Pires, C. B., Prada, V., Ramdharry, G., Saveri, P., Schirinzi, G., Shy, R., Siskind, C., Sowden, J., Stork, S., Sumner, C. J., Taroni, F., Thomas, S., Twachtman-Bassett, J., Villalpando, N., Vujovic, D., Wells, J., Wood, E., Zuccarino, R. 2023

  Abstract

  Charcot-Marie-Tooth disease (CMT) due to GJB1 variants (CMTX1) is the second most common form of CMT. It is an X-linked disorder characterised by progressive sensory and motor neuropathy with males affected more severely than females. Many reported GJB1 variants remain classified as variants of uncertain significance (VUS). In this large, international, multicentre study we prospectively collected demographic, clinical and genetic data on patients with CMT associated with GJB1 variants. Pathogenicity for each variant was defined using adapted American College of Medical Genetics criteria. Baseline and longitudinal analyses were conducted to study genotype-phenotype correlations, to calculate longitudinal change using the CMT Examination Score (CMTES), to compare males versus females, and pathogenic/likely pathogenic (P/LP) variants versus VUS. We present 387 patients from 295 families harbouring 154 variants in GJB1. Of these, 319 patients (82.4%) were deemed to have P/LP variants, 65 had VUS (16.8%) and 3 benign variants (0.8%; excluded from analysis); an increased proportion of patients with P/LP variants compared with using ClinVar's classification (74.6%). Male patients (166/319, 52.0%, P/LP only) were more severely affected at baseline. Baseline measures in patients with P/LP variants and VUS showed no significant differences, and regression analysis suggested the disease groups were near identical at baseline. Genotype-phenotype analysis suggested c.-17G>A produces the most severe phenotype of the five most common variants, and missense variants in the intracellular domain are less severe than other domains. Progression of disease was seen with increasing CMTES over time up to 8 years follow-up. Standard response mean (SRM), a measure of outcome responsiveness, peaked at 3 years with moderate responsiveness (change in CMTES (DeltaCMTES) = 1.3 ± 2.6, p = 0.00016, SRM = 0.50). Males and females progressed similarly up to 8 years, but baseline regression analysis suggested that over a longer period, females progress more slowly. Progression was most pronounced for mild phenotypes (CMTES = 0-7; 3-year DeltaCMTES = 2.3 ± 2.5, p = 0.001, SRM = 0.90). Enhanced variant interpretation has yielded an increased proportion of GJB1 variants classified as P/LP and will aid future variant interpretation in this gene. Baseline and longitudinal analysis of this large cohort of CMTX1 patients describes the natural history of the disease including the rate of progression; CMTES showed moderate responsiveness for the whole group at 3 years and higher responsiveness for the mild group at 3, 4 and 5 years. These results have implications for patient selection for upcoming clinical trials.

  View details for DOI 10.1093/brain/awad187

  View details for PubMedID 37284795

• COMPARATIVE REAL-WORLD RETROSPECTIVE DATA ANALYSIS OF COMORBID CONDITIONS AND HEALTHCARE UTILIZATION FOR PATIENTS WITH MYOTONIC DYSTROPHY OVER A 5-YEAR TIMEFRAME Day, J. W., Chen, C. Y., Munoz, K., Brook, R. A., Kleinman, N. L., McEvoy, B., Cho, H., Stahl, M., Tai, L. J. ELSEVIER SCIENCE INC. 2023: S393

  View details for Web of Science ID 001031473302457

• FIREFISH Parts 1 and 2: 4-year efficacy and safety of risdiplam in Type 1 spinal muscular atrophy (SMA) Mazurkiewicz-Beldzinska, M., Baranello, G., Boespflug-Tanguy, O., Day, J., Deconinck, N., Klein, A., Masson, R., Mercuri, E., Rose, K., Servais, L., Vlodavets, D., Xiong, H., Zanoteli, E., El-Khairi, M., Gerber, M., Gorni, K., Kletzl, H., Palfreeman, L., Dodman, A., Darras, B. WILEY. 2023: 196

  View details for Web of Science ID 001058307000263

• COMET: Patient-reported outcome measures in patients with late-onset Pompe disease after 145 weeks' avalglucosidase alfa Toscano, A., Kishnani, P., Diaz-Manera, J., Kushlaf, H., Ladha, S., Mozaffar, T., Straub, V., Van der Ploeg, A., Clemens, P., Day, J., Illarioshkin, S., Roberts, M., Attarian, S., Carvalho, G., Erdem-Ozdamar, S., Goker-Alpan, O., Kostera-Pruszczyk, A., Haack, K., Huynh-Ba, O., Tammireddy, S., Thibault, N., Zhou, T., Dimachkie, M., Schoser, B., Comet Invest Grp WILEY. 2023: 209-210

  View details for Web of Science ID 001058307000282

• Apitegromab in SMA: An Analysis of Additional Efficacy Endpoints in the TOPAZ Study at 36 Months Crawford, T., Darras, B., Day, J., Mercuri, E., Nascimento, A., Mazzone, E., Waugh, A., Song, G., Bilic, S., Marantz, J., Topaz Study Team WILEY. 2023: 192

  View details for Web of Science ID 001058307000258

• SUNFISH Parts 1 and 2: 4-year efficacy and safety data of risdiplam in Types 2 and 3 spinal muscular atrophy (SMA) Kostera-Pruszczyk, A., Day, J., Deconinck, N., Mazzone, E., Nascimento, A., Oskoui, M., Saito, K., Vuillerot, C., Baranello, G., Boespflug-Tanguy, O., Goemans, N., Kirschner, J., Servais, L., Braid, J., Gerber, M., Gorni, K., Martin, C., Yeung, W., Scalco, R., Mercuri, E. WILEY. 2023: 194

  View details for Web of Science ID 001058307000261

• Choroid plexus mis-splicing and altered cerebrospinal fluid composition in myotonic dystrophy type 1. Brain : a journal of neurology Nutter, C. A., Kidd, B. M., Carter, H. A., Hamel, J. I., Mackie, P. M., Kumbkarni, N., Davenport, M. L., Tuyn, D. M., Gopinath, A., Creigh, P. D., Sznajder, Ł. J., Wang, E. T., Ranum, L. P., Khoshbouei, H., Day, J. W., Sampson, J. B., Prokop, S., Swanson, M. S. 2023

  Abstract

  Myotonic dystrophy type 1 is a dominantly inherited multisystemic disease caused by CTG tandem repeat expansions in the DMPK 3' untranslated region. These expanded repeats are transcribed and produce toxic CUG RNAs that sequester and inhibit activities of the MBNL family of developmental RNA processing factors. Although myotonic dystrophy is classified as a muscular dystrophy, the brain is also severely affected by an unusual cohort of symptoms, including hypersomnia, executive dysfunction, as well as early onsets of tau/MAPT pathology and cerebral atrophy. To address the molecular and cellular events that lead to these pathological outcomes, we recently generated a mouse Dmpk CTG expansion knockin model and identified choroid plexus epithelial cells as particularly affected by the expression of toxic CUG expansion RNAs. To determine if toxic CUG RNAs perturb choroid plexus functions, alternative splicing analysis was performed on lateral and hindbrain choroid plexi from Dmpk CTG knockin mice. Choroid plexus transcriptome-wide changes were evaluated in Mbnl2 knockout mice, a developmental-onset model of myotonic dystrophy brain dysfunction. To determine if transcriptome changes also occurred in the human disease, we obtained post-mortem choroid plexus for RNA-seq from donors without neurologically unaffected (two females, three males; ages 50-70) and myotonic dystrophy type 1 donors (one female, three males; ages 50-70). To test that choroid plexus transcriptome alterations resulted in altered CSF composition, we obtained CSF via lumbar puncture from patients with myotonic dystrophy type 1 (five females, five males; ages 35-55) and non-myotonic dystrophy patients (three females, four males; ages 26-51) and Western blot and osmolarity analyses were used to test CSF alterations predicted by choroid plexus transcriptome analysis. We determined that CUG RNA induced toxicity was more robust in the lateral choroid plexus of Dmpk CTG knockin mice due to comparatively higher Dmpk and lower Mbnl RNA levels. Impaired transitions to adult splicing patterns during choroid plexus development were identified in Mbnl2 knockout mice, including mis-splicing previously found in Dmpk CTG knockin mice. Whole transcriptome analysis of myotonic dystrophy type 1 choroid plexus revealed disease-associated RNA expression and mis-splicing events. Based on these RNA changes, predicted alterations in ion homeostasis, secretory output, and CSF composition were confirmed by analysis of myotonic dystrophy type 1 CSF. Our results implicate choroid plexus spliceopathy and concomitant alterations in CSF homeostasis as an unappreciated contributor to myotonic dystrophy type 1 CNS pathogenesis.

  View details for DOI 10.1093/brain/awad148

  View details for PubMedID 37143315

• A Human PBMC Assay of Type 1 Interferon Responses to Closely Related AAV Vectors Hamilton, B. A., Patil, R., Kim, S., Day, J. W., Wright, J. CELL PRESS. 2023: 76

  View details for Web of Science ID 001045144200141

• Integrated Analyses of Data from Clinical Trials of Delandistrogene Moxeparvovec (SRP-9001) in Duchenne Muscular Dystrophy (DMD) Proud, C., Zaidman, C., Shieh, P., McDonald, C., Day, J., Mason, S., Guridi, M., Han, L., Yu, L., Reid, C., Darton, E., Wandel, C., Richardson, J., Malhotra, J., Singh, T., Rodino-Klapac, L., Mendell, J. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for DOI 10.1212/WNL.0000000000203470

  View details for Web of Science ID 001053672108049

• FIREFISH Parts 1 and 2: 36-month safety and efficacy of risdiplam in Type 1 spinal muscular atrophy (SMA) Darras, B., Baranello, G., Boespflug-Tanguy, O., Day, J., Deconinck, N., Klein, A., Masson, R., Mazurkiewicz-Beldzinska, M., Mercuri, E., Rose, K., Vlodavets, D., Xiong, H., Zanoteli, E., El-Khairi, M., Gerber, M., Gorni, K., Kletzl, H., Palfreeman, L., Dodman, A., Servais, L. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for DOI 10.1212/WNL.0000000000203624

  View details for Web of Science ID 001053672105263

• A Multimodal Neuroimaging Feature Extraction Framework for Biomarker Discovery in Myotonic Dystrophies Kamali, T., Day, J., Sampson, J., Murad, A., Chaufty, J. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for DOI 10.1212/WNL.0000000000203814

  View details for Web of Science ID 001053672106058

• Intravenous and Intrathecal Onasemnogene Abeparvovec Gene Therapy in Symptomatic and Presymptomatic Spinal Muscular Atrophy: Long-Term Follow-Up Study Darras, B., Mercuri, E., Strauss, K., Day, J., Chien, Y., Masson, R., Wigderson, M., Alecu, I., Ballarini, N., Mehl, L., Marra, J., Connolly, A. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for DOI 10.1212/WNL.0000000000202555

  View details for Web of Science ID 001053672107192

• Preliminary Assessment of the Phase 1/2 Clinical Trial Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AOC 1001 Administered Intravenously to Adult Patients with Myotonic Dystrophy Type 1 (DM1) (MARINA) Johnson, N., Day, J., Hamel, J., Thornton, C., Subramony, S., Soltanzadeh, P., Statland, J., Arnold, W., Wicklund, M., Ditrapani, K., Heusner, C., Chen, C., McEvoy, B., Zhu, Y., Tai, L., Ackermann, E. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for DOI 10.1212/WNL.0000000000202529

  View details for Web of Science ID 001053672108045

• Motor Outcomes to Validate Evaluations in Facioscapulohumeral muscular dystrophy (MOVE FSHD): Preliminary Baseline Characteristics Walker, M., Butterfield, R., Day, J., Eichinger, K., Elsheikh, B., Friedman, S., Genge, A., Higgs, K., Johnson, N., Jones, P., Leung, D., Lewis, L., Lochmuller, H., O'Ferrall, E., Martens, W., Shaw, D., Shieh, P., Subramony, S., Trivedi, J., Wang, L., Wicklund, M., Tawil, A., Statland, J. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for DOI 10.1212/WNL.0000000000203663

  View details for Web of Science ID 001053672108104

• SUNFISH Parts 1 and 2: 4-year Efficacy and Safety Data of Risdiplam in Types 2 and 3 Spinal Muscular Atrophy (SMA) Servais, L., Oskoui, M., Day, J., Deconinck, N., Mazzone, E., Nascimento, A., Saito, K., Vuillerot, C., Baranello, G., Boespflug-Tanguy, O., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Braid, J., Papp, G., Gorni, K., Martin, C., Scalco, R., Yeung, W., Mercuri, E. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for DOI 10.1212/WNL.0000000000203570

  View details for Web of Science ID 001053672107199

• Correction to: Two‑year efficacy and safety of risdiplam in patients with type 2 or non‑ambulant type 3 spinal muscular atrophy (SMA). Journal of neurology Oskoui, M., Day, J. W., Deconinck, N., Mazzone, E. S., Nascimento, A., Saito, K., Vuillerot, C., Baranello, G., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Papp, G., Gorni, K., Kletzl, H., Martin, C., McIver, T., Scalco, R. S., Staunton, H., Yeung, W. Y., Fontoura, P., Mercuri, E., SUNFISH Working Group 2023

  View details for DOI 10.1007/s00415-023-11658-6

  View details for PubMedID 37071150

• Generation of two induced pluripotent stem cell lines from spinal muscular atrophy type 1 patients carrying no functional copies of SMN1 gene. Stem cell research Zeng, W., Kong, X., Alamana, C., Liu, Y., Guzman, J., Pang, P. D., Day, J. W., Wu, J. C. 2023; 69: 103095

  Abstract

  Spinal muscular atrophy (SMA) is a severe neurodegenerative muscular disease caused by the homozygous loss of survival of motor neuron 1 (SMN1) genes. SMA patients exhibit marked skeletal muscle (SKM) loss, eventually leading to death. Here we generated two iPSC lines from two SMA type I patients with homozygous SMN1 mutations and validated the pluripotency and the ability to differentiate into three germ layers. The iPSC lines can be applied to generate skeletal muscles to model muscle atrophy of SMA that persists after treatment of motor neurons and will serve as a complementary platform for drug screening in vitro.

  View details for DOI 10.1016/j.scr.2023.103095

  View details for PubMedID 37087898

• Efficacy and Safety of Avalglucosidase Alfa in Patients With Late-Onset Pompe Disease After 97 Weeks: A Phase 3 Randomized Clinical Trial. JAMA neurology Kishnani, P. S., Diaz-Manera, J., Toscano, A., Clemens, P. R., Ladha, S., Berger, K. I., Kushlaf, H., Straub, V., Carvalho, G., Mozaffar, T., Roberts, M., Attarian, S., Chien, Y. H., Choi, Y. C., Day, J. W., Erdem-Ozdamar, S., Illarioshkin, S., Goker-Alpan, O., Kostera-Pruszczyk, A., van der Ploeg, A. T., An Haack, K., Huynh-Ba, O., Tammireddy, S., Thibault, N., Zhou, T., Dimachkie, M. M., Schoser, B. 2023

  Abstract

  In the previously reported Comparative Enzyme Replacement Trial With neoGAA Versus rhGAA (COMET) trial, avalglucosidase alfa treatment for 49 weeks showed clinically meaningful improvements in upright forced vital capacity (FVC) percent predicted and 6-minute walk test (6MWT) compared with alglucosidase alfa.To report avalglucosidase alfa treatment outcomes during the COMET trial extension.This phase 3 double-blind randomized clinical trial with crossover in the extension period enrolled patients 3 years and older with previously untreated late-onset Pompe disease (LOPD) between November 2, 2016, and February 10, 2021, with primary analysis after 49 weeks. Patients were treated at 55 referral centers in 20 countries. Efficacy outcomes were assessed at 97 weeks and safety outcomes to last follow-up, with data cutoff at February 10, 2021. Data were analyzed from May to June 2021.Random assignment (1:1) to receive 20 mg/kg of avalglucosidase alfa or alglucosidase alfa by intravenous infusion every other week for 49 weeks; thereafter, all patients received 20 mg/kg of avalglucosidase alfa every other week.The primary outcome was the least squares (LS) mean change from baseline in FVC percent predicted. Secondary outcomes included the LS mean change from baseline in 6MWT, muscle strength, motor function, quality of life, and disease biomarkers. Safety and tolerability were also assessed.Of 100 participants from the double-blind treatment period, 95 entered the extension period. Of these, 51 (54%) were men, and the mean (range) age was 48.3 (10-79) years. At the start of this study, mean upright FVC percent predicted was similar between treatment arms, and 6MWT distance was greater in the avalglucosidase alfa arm. From baseline to week 97, LS mean (SE) FVC percent predicted increased by 2.65 (1.05) for those who continued avalglucosidase alfa and 0.36 (1.12) for those who switched to avalglucosidase alfa. The LS mean (SE) 6MWT distance increased by 18.60 (12.01) m and 4.56 (12.44) m, respectively. For participants who switched to avalglucosidase alfa, FVC percent predicted remained stable (LS mean [SE] change from week 49 to 97, 0.09 [0.88]) and 6MWT distance improved (LS mean [SE] change from week 49 to 97, 5.33 [10.81] m). Potentially treatment-related adverse events were reported in 29 patients (56.9%) who continued avalglucosidase alfa and in 25 patients (56.8%) who switched.In this randomized clinical trial extension, maintenance of positive clinical outcomes was demonstrated for patients continuing avalglucosidase alfa treatment and, to a lesser extent, patients who switched from alglucosidase alfa. No new safety concerns were observed.ClinicalTrials.gov Identifier: NCT02782741.

  View details for DOI 10.1001/jamaneurol.2023.0552

  View details for PubMedID 37036722

  View details for PubMedCentralID PMC10087094

• Intrathecal Onasemnogene Abeparvovec for Sitting, Nonambulatory Patients with Spinal Muscular Atrophy: Phase I Ascending-Dose Study (STRONG). Journal of neuromuscular diseases Finkel, R. S., Darras, B. T., Mendell, J. R., Day, J. W., Kuntz, N. L., Connolly, A. M., Zaidman, C., Crawford, T. O., Butterfield, R. J., Shieh, P. B., Tennekoon, G., Brandsema, J. F., Iannaccone, S. T., Shoffner, J., Kavanagh, S., Macek, T. A., Tauscher-Wisniewski, S. 2023

  Abstract

  Spinal muscular atrophy (SMA) is a neuromuscular disorder arising from biallelic non-functional survival motor neuron 1 (SMN1) genes with variable copies of partially functional SMN2 gene. Intrathecal onasemnogene abeparvovec administration, at fixed, low doses, may enable treatment of heavier patients ineligible for weight-based intravenous dosing.STRONG (NCT03381729) assessed the safety/tolerability and efficacy of intrathecal onasemnogene abeparvovec for sitting, nonambulatory SMA patients.Sitting, nonambulatory SMA patients (biallelic SMN1 loss, three SMN2 copies, aged 6-<60 months) received a single dose of intrathecal onasemnogene abeparvovec. Patients were enrolled sequentially into one of three (low, medium, and high) dose cohorts and stratified into two groups by age at dosing: younger (6-<24 months) and older (24-<60 months). Primary endpoints included safety/tolerability, independent standing ≥3 seconds (younger group), and change in Hammersmith Functional Motor Scale Expanded (HFMSE) from baseline (older group) compared with historic controls.Thirty-two patients were enrolled and completed the study (medium dose, n = 25). All patients had one or more treatment-emergent adverse events, with one serious and related to treatment (transaminase elevations). No deaths were reported. One of 13 patients (7.7%) in the younger group treated with the medium dose achieved independent standing. At Month 12 for the older group receiving the medium dose, change from baseline in HFMSE was significantly improved compared with the SMA historic control population (P <  0.01).Intrathecal onasemnogene abeparvovec was safe and well-tolerated. Older patients treated with the medium dose demonstrated increases in HFMSE score greater than commonly observed in natural history.

  View details for DOI 10.3233/JND-221560

  View details for PubMedID 36911944

• Expanding the muscle imaging spectrum in dysferlinopathy: description of an outlier population from the classical MRI pattern. Neuromuscular disorders : NMD Llansó, L., Moore, U., Bolano-Diaz, C., James, M., Blamire, A. M., Carlier, P. G., Rufibach, L., Gordish-Dressman, H., Boyle, G., Hilsden, H., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Pestronk, A., Walter, M. C., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Pegoraro, E., Mendell, J. R., Straub, V., Díaz-Manera, J. 2023; 33 (4): 349-357

  Abstract

  Dysferlinopathy is a muscle disease characterized by a variable clinical presentation and is caused by mutations in the DYSF gene. The Jain Clinical Outcome Study for Dysferlinopathy (COS) followed the largest cohort of patients (n=187) with genetically confirmed dysferlinopathy throughout a three-year natural history study, in which the patients underwent muscle function tests and muscle magnetic resonance imaging (MRI). We previously described the pattern of muscle pathology in this population and established a series of imaging criteria for diagnosis. In this paper, we describe the muscle imaging and clinical features of a subgroup of COS participants whose muscle imaging results did not completely meet the diagnostic criteria. We reviewed 184 T1-weighted (T1w) muscle MRI scans obtained at the baseline visit of the COS study, of which 106 were pelvic and lower limb only and 78 were whole-body scans. We identified 116 of the 184 patients (63%) who did not meet at least one of the established imaging criteria. The highest number found of unmet criteria was four per patient. We identified 24 patients (13%) who did not meet three or more of the nine established criteria and considered them as "outliers". The most common unmet criterion (27.3% of cases) was the adductor magnus being equally or more affected than the adductor longus. We compared the genetic, demographic, clinical and muscle function data of the outlier patients with those who met the established criteria and observed that the outlier patients had an age of disease onset that was significantly older than the whole group (29.3 vs 20.5 years, p=0.0001). This study expands the phenotypic muscle imaging spectrum of patients with dysferlinopathy and can help to guide the diagnostic process in patients with limb girdle weakness of unknown origin.

  View details for DOI 10.1016/j.nmd.2023.02.007

  View details for PubMedID 36972667

• Antisense oligonucleotide targeting DMPK in patients with myotonic dystrophy type 1: a multicentre, randomised, dose-escalation, placebo-controlled, phase 1/2a trial LANCET NEUROLOGY Thornton, C. A., Iii, R., Eichinger, K., Heatwole, C., Mignon, L., Arnold, W., Ashizawa, T., Day, J. W., Dent, G., Tanner, M. K., Duong, T., Greene, E. P., Herbelin, L., Johnson, N. E., King, W., Kissel, J., Leung, D. G., Lott, D. J., Norris, D. A., Pucillo, E. M., Schell, W., Statland, J. M., Stinson, N., Subramony, S. H., Xia, S., Bishop, K. M., Bennett, C. 2023; 22 (3): 218-228

  View details for Web of Science ID 000996507100001

• Antisense oligonucleotide targeting DMPK in patients with myotonic dystrophy type 1: a multicentre, randomised, dose-escalation, placebo-controlled, phase 1/2a trial. The Lancet. Neurology Thornton, C. A., Moxley, R. T., Eichinger, K., Heatwole, C., Mignon, L., Arnold, W. D., Ashizawa, T., Day, J. W., Dent, G., Tanner, M. K., Duong, T., Greene, E. P., Herbelin, L., Johnson, N. E., King, W., Kissel, J. T., Leung, D. G., Lott, D. J., Norris, D. A., Pucillo, E. M., Schell, W., Statland, J. M., Stinson, N., Subramony, S. H., Xia, S., Bishop, K. M., Bennett, C. F. 2023; 22 (3): 218-228

  Abstract

  Myotonic dystrophy type 1 results from an RNA gain-of-function mutation, in which DM1 protein kinase (DMPK) transcripts carrying expanded trinucleotide repeats exert deleterious effects. Antisense oligonucleotides (ASOs) provide a promising approach to treatment of myotonic dystrophy type 1 because they reduce toxic RNA levels. We aimed to investigate the safety of baliforsen (ISIS 598769), an ASO targeting DMPK mRNA.In this dose-escalation phase 1/2a trial, adults aged 20-55 years with myotonic dystrophy type 1 were enrolled at seven tertiary referral centres in the USA and randomly assigned via an interactive web or phone response system to subcutaneous injections of baliforsen 100 mg, 200 mg, or 300 mg, or placebo (6:2 randomisation at each dose level), or to baliforsen 400 mg or 600 mg, or placebo (10:2 randomisation at each dose level), on days 1, 3, 5, 8, 15, 22, 29, and 36. Sponsor personnel directly involved with the trial, participants, and all study personnel were masked to treatment assignments. The primary outcome measure was safety in all participants who received at least one dose of study drug up to day 134. This trial is registered with ClinicalTrials.gov (NCT02312011), and is complete.Between Dec 12, 2014, and Feb 22, 2016, 49 participants were enrolled and randomly assigned to baliforsen 100 mg (n=7, one patient not dosed), 200 mg (n=6), 300 mg (n=6), 400 mg (n=10), 600 mg (n=10), or placebo (n=10). The safety population comprised 48 participants who received at least one dose of study drug. Treatment-emergent adverse events were reported for 36 (95%) of 38 participants assigned to baliforsen and nine (90%) of ten participants assigned to placebo. Aside from injection-site reactions, common treatment-emergent adverse events were headache (baliforsen: ten [26%] of 38 participants; placebo: four [40%] of ten participants), contusion (baliforsen: seven [18%] of 38; placebo: one [10%] of ten), and nausea (baliforsen: six [16%] of 38; placebo: two [20%] of ten). Most adverse events (baliforsen: 425 [86%] of 494; placebo: 62 [85%] of 73) were mild in severity. One participant (baliforsen 600 mg) developed transient thrombocytopenia considered potentially treatment related. Baliforsen concentrations in skeletal muscle increased with dose.Baliforsen was generally well tolerated. However, skeletal muscle drug concentrations were below levels predicted to achieve substantial target reduction. These results support the further investigation of ASOs as a therapeutic approach for myotonic dystrophy type 1, but suggest improved drug delivery to muscle is needed.Ionis Pharmaceuticals, Biogen.

  View details for DOI 10.1016/S1474-4422(23)00001-7

  View details for PubMedID 36804094

• 2-Year Change in Revised Hammersmith Scale Scores in a Large Cohort of Untreated Paediatric Type 2 and 3 SMA Participants. Journal of clinical medicine Stimpson, G., Ramsey, D., Wolfe, A., Mayhew, A., Scoto, M., Baranello, G., Muni Lofra, R., Main, M., Milev, E., Coratti, G., Pane, M., Sansone, V., D'Amico, A., Bertini, E., Messina, S., Bruno, C., Albamonte, E., Mazzone, E. S., Montes, J., Glanzman, A. M., Zolkipli-Cunningham, Z., Pasternak, A., Duong, T., Dunaway Young, S., Civitello, M., Marini-Bettolo, C., Day, J. W., Darras, B. T., De Vivo, D. C., Finkel, R. S., Mercuri, E., Muntoni, F. 2023; 12 (5)

  Abstract

  The Revised Hammersmith Scale (RHS) is a 36-item ordinal scale developed using clinical expertise and sound psychometrics to investigate motor function in participants with Spinal Muscular Atrophy (SMA). In this study, we investigate median change in the RHS score up to two years in paediatric SMA 2 and 3 participants and contextualise it to the Hammersmith Functional Motor Scale-Expanded (HFMSE). These change scores were considered by SMA type, motor function, and baseline RHS score. We consider a new transitional group, spanning crawlers, standers, and walkers-with-assistance, and analyse that alongside non-sitters, sitters, and walkers. The transitional group exhibit the most definitive change score trend, with an average 1-year decline of 3 points. In the weakest patients, we are most able to detect positive change in the RHS in the under-5 age group, whereas in the stronger patients, we are most able to detect decline in the RHS in the 8-13 age group. The RHS has a reduced floor effect compared to the HFMSE, although we show that the RHS should be used in conjunction with the RULM for participants scoring less than 20 points on the RHS. The timed items in the RHS have high between-participant variability, so participants with the same RHS total can be differentiated by their timed test items.

  View details for DOI 10.3390/jcm12051920

  View details for PubMedID 36902710

• Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study. Neurology and therapy Chiriboga, C. A., Bruno, C., Duong, T., Fischer, D., Mercuri, E., Kirschner, J., Kostera-Pruszczyk, A., Jaber, B., Gorni, K., Kletzl, H., Carruthers, I., Martin, C., Warren, F., Scalco, R. S., Wagner, K. R., Muntoni, F. 2023

  Abstract

  Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier for the treatment of patients with spinal muscular atrophy (SMA). The JEWELFISH study (NCT03032172) was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of risdiplam in previously treated pediatric and adult patients with types 1-3 SMA. Here, an analysis was performed after all patients had received at least 1 year of treatment with risdiplam.Patients with a confirmed diagnosis of 5q-autosomal recessive SMA between the ages of 6 months and 60 years were eligible for enrollment. Patients were previously enrolled in the MOONFISH study (NCT02240355) with splicing modifier RG7800 or treated with olesoxime, nusinersen, or onasemnogene abeparvovec. The primary objectives of the JEWELFISH study were to evaluate the safety and tolerability of risdiplam and investigate the PK after 2 years of treatment.A total of 174 patients enrolled: MOONFISH study (n = 13), olesoxime (n = 71 patients), nusinersen (n = 76), onasemnogene abeparvovec (n = 14). Most patients (78%) had three SMN2 copies. The median age and weight of patients at enrollment was 14.0 years (1-60 years) and 39.1 kg (9.2-108.9 kg), respectively. About 63% of patients aged 2-60 years had a baseline total score of less than 10 on the Hammersmith Functional Motor Scale-Expanded and 83% had scoliosis. The most common adverse event (AE) was upper respiratory tract infection and pyrexia (30 patients each; 17%). Pneumonia (four patients; 2%) was the most frequently reported serious AE (SAE). The rates of AEs and SAEs per 100 patient-years were lower in the second 6-month period compared with the first. An increase in SMN protein was observed in blood after risdiplam treatment and was comparable across all ages and body weight quartiles.The safety and PD of risdiplam in patients who were previously treated were consistent with those of treatment-naïve patients.

  View details for DOI 10.1007/s40120-023-00444-1

  View details for PubMedID 36780114

• Validation of the Parent-Proxy Pediatric Charcot-Marie-Tooth Disease Quality of Life Outcome Measure. Journal of the peripheral nervous system : JPNS Wu, T. T., Finkel, R. S., Siskind, C. E., Feely, S. M., Burns, J., Reilly, M. M., Muntoni, F., Estilow, T., Shy, M. E., Ramchandren, S., Childhood CMT Study Group of the Inherited Neuropathy Consortium, Bacon, C. J., Shy, R. R., Cornett, K., Laura, M., Milev, E., Day, J. W., Lloyd, T., Sumner, C. J., Herrmann, D. N., Kirk, C., Yum, S. W. 2023

  Abstract

  OBJECTIVE: Charcot-Marie-Tooth disease (CMT) reduces health-related quality of life (QOL) in children. We have previously developed and validated the English and Italian versions of the pediatric CMT-specific QOL outcome measure (pCMT-QOL) for children aged 8-18. There is currently no parent-proxy CMT QOL outcome measure for use in clinical trials, which could provide complementary information in these children and adolescents. This study describes the validation studies conducted to develop the parent-proxy version of the pCMT-QOL outcome measure for children aged 8-18years old.METHODS: Development and validation of the parent-proxy version of the pCMT-QOL outcome measure for children aged 8-18years old was iterative, involving identifying relevant domains, item pool generation, prospective pilot testing and clinical assessments, structured focus-group interviews, and psychometric testing, conducted on parents of children with CMT seen at participating sites from the USA, United Kingdom, and Australia.RESULTS: We utilized previously described methods to develop a working parent-proxy version of the pCMT-QOL measure. From 2010-2016, the parent-proxy pCMT-QOL working version was administered to 358 parents of children with CMT aged 8-18, seen at the participating study sites of the Inherited Neuropathies Consortium. The resulting data underwent rigorous psychometric analysis, including factor analysis, test-retest reliability, internal consistency, convergent validity, IRT analysis, and longitudinal analysis, to develop the final parent-proxy version of the pCMT-QOL outcome measure for children aged 8-18years old.INTERPRETATION: The parent-proxy version of the pCMT-QOL outcome measure is a reliable, valid, and sensitive proxy measure of health-related QOL for children aged 8-18 with CMT.

  View details for DOI 10.1111/jns.12538

  View details for PubMedID 36748295

• Assessing Bulbar Function in Spinal Muscular Atrophy Using Patient-Reported Outcomes. Journal of neuromuscular diseases Young, S. D., Pasternak, A., Duong, T., McGrattan, K. E., Stranberg, S., Maczek, E., Dias, C., Tang, W., Parker, D., Levine, A., Rohan, A., Wolford, C., Martens, W., McDermott, M. P., Darras, B. T., Day, J. W. 2023

  Abstract

  Novel Spinal Muscular Atrophy (SMA) treatments have demonstrated improvements on motor measures that are clearly distinct from the natural history of progressive decline. Comparable measures are needed to monitor bulbar function, which is affected in severe SMA.To assess bulbar function with patient-reported outcome measures (PROs) and determine their relationships with clinical characteristics.We recruited 47 non-ambulatory participants (mean (SD) age = 29.8 (13.7) years, range = 10.3-73.2) with SMA. PROs including Voice Handicap Index (VHI) and Eating Assessment Tool-10 (EAT-10) were collected alongside clinical characteristics and standardized motor assessments. Associations were assessed using Spearman correlation coefficients and group comparisons were performed using Wilcoxon rank sum tests.A majority of the 47 participants were SMA type 2 (70.2%), non-sitters (78.7%), 3 copies of SMN2 (77.5%), and using respiratory support (66.0%). A majority (94%) reported voice issues primarily in 8/30 VHI questions. Problems included: difficulty understanding me in a noisy room (87.2%); difficult for people to hear me (74.5%); and people ask me to repeat when speaking face-to-face (72.3%). A majority (85.1%) reported swallowing issues primarily in 3/10 EAT-10 questions: swallowing pills (68.1%); food sticks to my throat (66.0%); and swallowing solids (61.7%). The two PROs were moderately associated (rs = 0.66).Weaker individuals with SMA experience bulbar problems including difficulties with voice and swallowing. Further refinement and assessment of functional bulbar scales will help determine their relevance and responsiveness to changes in SMA. Additional study is needed to quantify bulbar changes caused by SMA and their response to disease-modifying treatments.

  View details for DOI 10.3233/JND-221573

  View details for PubMedID 36776075

• Two-year efficacy and safety of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy (SMA). Journal of neurology Oskoui, M., Day, J. W., Deconinck, N., Mazzone, E. S., Nascimento, A., Saito, K., Vuillerot, C., Baranello, G., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Papp, G., Gorni, K., Kletzl, H., Martin, C., McIver, T., Scalco, R. S., Staunton, H., Yeung, W. Y., Fontoura, P., Mercuri, E., SUNFISH Working Group 2023

  Abstract

  Risdiplam is an oral, survival of motor neuron2 (SMN2) pre-mRNA splicing modifier approved for the treatment of spinal muscular atrophy (SMA). SUNFISH (NCT02908685) Part 2, a Phase 3, randomized, double-blind, placebo-controlled study, investigated the efficacy and safety of risdiplam in type 2 and non‑ambulant type 3 SMA. The primary endpoint was met: a significantly greater change from baseline in 32-item Motor Function Measure (MFM32) total score was observed with risdiplam compared with placebo at month 12. After 12months, all participants received risdiplam while preserving initial treatment blinding. We report 24-month efficacy and safety results in this population. Month 24 exploratory endpoints included change from baseline in MFM32 and safety. MFM‑derived results were compared with an external comparator. At month 24 of risdiplam treatment, 32% of patients demonstrated improvement (a change of≥3) from baseline in MFM32 total score; 58% showed stabilization (a change of≥0). Compared with an external comparator, a treatment difference of 3.12 (95% confidence interval [CI] 1.67-4.57) in favor of risdiplam was observed in MFM-derived scores. Overall, gains in motor function at month 12 were maintained or improved upon at month 24. In patients initially receiving placebo, MFM32 remained stable compared with baseline (0.31 [95% CI - 0.65 to 1.28]) after 12months of risdiplam; 16% of patients improved their score and 59% exhibited stabilization. The safety profile after 24months was consistent with that observed after 12months. Risdiplam over 24months resulted in further improvement or stabilization in motor function, confirming the benefit of longer-term treatment.

  View details for DOI 10.1007/s00415-023-11560-1

  View details for PubMedID 36735057

• AT845 gene replacement therapy for late onset Pompe disease: An update on safety and preliminary efficacy data from FORTIS, a phase I/II open-label clinical study Manera, J., Mozaffar, T., Day, J. W., Longo, N., Straub, V., Varfaj, F., Chou, H., Maruoka, M., Han, C., Coats, J., Maziere, J. A., Walzer, M., Smith, A. R. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2023: 34-35

  View details for DOI 10.1016/j.ymgme.2022.107078

  View details for Web of Science ID 001013039500096

• Efficacy and safety of avalglucosidase alfa in participants with late-onset Pompe disease after 145 weeks of treatment during the COMET trial Kishnani, P. S., Diaz-Manera, J., Kushlaf, H., Ladha, S., Mozaffar, T., Straub, V., Toscano, A., van der Ploeg, A. T., Clemens, P. R., Day, J. W., Illarioshkin, S., Roberts, M. E., Attarian, S., Carvalho, G., Erdem-Ozdamar, S., Goker-Alpan, O., Kostera-Pruszczyk, A., Haack, K., Huynh-Ba, O., Tammireddy, S., Thibault, N., Zhou, T., Dimachkie, M. M., Schoser, B., COMET Investigator Grp ACADEMIC PRESS INC ELSEVIER SCIENCE. 2023: 74

  View details for DOI 10.1016/j.ymgme.2022.107185

  View details for Web of Science ID 001013039500203

• Myostatin and follistatin as monitoring and prognostic biomarkers in dysferlinopathy. Neuromuscular disorders : NMD Moore, U., Fernandez-Simon, E., Schiava, M., Cox, D., Gordish-Dressman, H., James, M. K., Mayhew, A., Wilson, I., Guglieri, M., Rufibach, L., Blamire, A., Carlier, P. G., Mori-Yoshimura, M., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Pestronk, A., Walter, M. C., Paradas, C., Stojkovic, T., Bravver, E., Pegoraro, E., Mendell, J. R., Bushby, K., Diaz-Manera, J., Straub, V., Jain COS Consortium 2023; 33 (2): 199-207

  Abstract

  Myostatin is a myokine which acts upon skeletal muscle to inhibit growth and regeneration. Myostatin is endogenously antagonised by follistatin. This study assessed serum myostatin and follistatin concentrations as monitoring or prognostic biomarkers in dysferlinopathy, an autosomal recessively inherited muscular dystrophy. Myostatin was quantified twice with a three-year interval in 76 patients with dysferlinopathy and 38 controls. Follistatin was quantified in 62 of these patients at the same timepoints, and in 31 controls. Correlations with motor function, muscle fat fraction and contractile cross-sectional area were performed. A regression model was used to account for confounding variables. Baseline myostatin, but not follistatin, correlated with baseline function and MRI measures. However, in individual patients, three-year change in myostatin did not correlate with functional or MRI changes. Linear modelling demonstrated that function, serum creatine kinase and C-reactive protein, but not age, were independently related to myostatin concentration. Baseline myostatin concentration predicted loss of ambulation but not rate of change of functional or MRI measures, even when relative inhibition with follistatin was considered. With adjustment for extra-muscular causes of variation, myostatin could form a surrogate measure of functional ability or muscle mass, however myostatin inhibition does not form a promising treatment target in dysferlinopathy.

  View details for DOI 10.1016/j.nmd.2023.01.001

  View details for PubMedID 36689846

• Advances and limitations for the treatment of spinal muscular atrophy. BMC pediatrics Day, J. W., Howell, K., Place, A., Long, K., Rossello, J., Kertesz, N., Nomikos, G. 2022; 22 (1): 632

  Abstract

  Spinal muscular atrophy (5q-SMA; SMA), a genetic neuromuscular condition affecting spinal motor neurons, is caused by defects in both copies of the SMN1 gene that produces survival motor neuron (SMN) protein. The highly homologous SMN2 gene primarily expresses a rapidly degraded isoform of SMN protein that causes anterior horn cell degeneration, progressive motor neuron loss, skeletal muscle atrophy and weakness. Severe cases result in limited mobility and ventilatory insufficiency. Untreated SMA is the leading genetic cause of death in young children. Recently, three therapeutics that increase SMN protein levels in patients with SMA have provided incremental improvements in motor function and developmental milestones and prevented the worsening of SMA symptoms. While the therapeutic approaches with Spinraza®, Zolgensma®, and Evrysdi® have a clinically significant impact, they are not curative. For many patients, there remains a significant disease burden. A potential combination therapy under development for SMA targets myostatin, a negative regulator of muscle mass and strength. Myostatin inhibition in animal models increases muscle mass and function. Apitegromab is an investigational, fully human, monoclonal antibody that specifically binds to proforms of myostatin, promyostatin and latent myostatin, thereby inhibiting myostatin activation. A recently completed phase 2 trial demonstrated the potential clinical benefit of apitegromab by improving or stabilizing motor function in patients with Type 2 and Type 3 SMA and providing positive proof-of-concept for myostatin inhibition as a target for managing SMA. The primary goal of this manuscript is to orient physicians to the evolving landscape of SMA treatment.

  View details for DOI 10.1186/s12887-022-03671-x

  View details for PubMedID 36329412

• Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial. The Lancet. Neurology Masson, R., Mazurkiewicz-Beldzinska, M., Rose, K., Servais, L., Xiong, H., Zanoteli, E., Baranello, G., Bruno, C., Day, J. W., Deconinck, N., Klein, A., Mercuri, E., Vlodavets, D., Wang, Y., Dodman, A., El-Khairi, M., Gorni, K., Jaber, B., Kletzl, H., Gaki, E., Fontoura, P., Darras, B. T., FIREFISH Study Group, Volpe, J. J., Posner, J., Kellner, U., Quinlivan, R., Gerber, M., Khwaja, O., Scalco, R. S., Seabrook, T., Koch, A., Balikova, I., Joniau, I., Accou, G., Tahon, V., Wittevrongel, S., De Vos, E., de Holanda Mendonca, R., Matsui, C. J., Fornazieri Darcie, A. L., Machado, C., Kiyoko Oyamada, M., Martini, J., Polido, G., Rodrigues Iannicelli, J., Caires de Oliveira Achili Ferreira, J., Hu, C., Zhu, X., Qian, C., Shen, L., Li, H., Shi, Y., Zhou, S., Xiao, Y., Zhou, Z., Wang, S., Sang, T., Wei, C., Dong, H., Cao, Y., Wen, J., Li, W., Qin, L., Barisic, N., Celovec, I., Galiot Delic, M., Ivkic, P. K., Vukojevic, N., Kern, I., Najdanovic, B., Skugor, M., Tomas, J., Boespflug-Tanguy, O., De Lucia, S., Seferian, A., Barreau, E., Mnafek, N., Peche, H., Grange, A., Trang Nguyen, D., Milascevic, D., Tachibana, S., Pagliano, E., Bianchi Marzoli, S., Santarsiero, D., Garcia Sierra, M., Tremolada, G., Arnoldi, M. T., Vigano, M., Dosi, C., Zanin, R., Schembri, V., Brolatti, N., Rao, G., Tassara, E., Morando, S., Tacchetti, P., Pedemonte, M., Priolo, E., Sposetti, L., Comi, G. P., Govoni, A., Osnaghi, S. G., Minorini, V., Abbati, F., Fassini, F., Foa, M., Lopopolo, A., Pane, M., Palermo, C., Pera, M. C., Amorelli, G. M., Barresi, C., D'Amico, G., Orazi, L., Coratti, G., Leone, D., Laura, A., De Sanctis, R., Berti, B., Kimura, N., Takeshima, Y., Shimomura, H., Lee, T., Gomi, F., Morimatsu, T., Furukawa, T., Stodolska-Koberda, U., Waskowska, A., Kolendo, J., Sobierajska-Rek, A., Modrzejewska, S., Lemska, A., Melnik, E., Artemyeva, S., Leppenen, N., Yupatova, N., Monakhova, A., Papina, Y., Shidlovsckaia, O., Litvinova, E., Enzmann, C., Galiart, E., Gugleta, K., Wondrusch Haschke, C., Topaloglu, H., Oncel, I., Ertugrul, N. E., Konuskan, B., Eldem, B., Kadayifcilar, S., Alemdaroglu, I., Sari, S., Bilgin, N., Karaduman, A. A., Sarikaya, F. G., Graham, R. J., Ghosh, P., Casavant, D., Levine, A., Titus, R., Engelbrekt, A., Ambrosio, L., Fulton, A., Baglieri, A. M., Dias, C., Maczek, E., Pasternak, A., Beres, S., Duong, T., Gee, R., Young, S. 2022

  Abstract

  BACKGROUND: Risdiplam is an orally administered therapy that modifies pre-mRNA splicing of the survival of motor neuron 2 (SMN2) gene and is approved for the treatment of spinal muscular atrophy. The FIREFISH study is investigating the safety and efficacy of risdiplam in treated infants with type 1 spinal muscular atrophy versus historical controls. The primary endpoint of part 2 of the FIREFISH study showed that infants with type 1 spinal muscular atrophy attained the ability to sit without support for at least 5 s after 12 months of treatment. Here, we report on the safety and efficacy of risdiplam in FIREFISH part 2 over 24 months of treatment.METHODS: FIREFISH is an ongoing, multicentre, open-label, two-part study. In FIREFISH part 2, eligible infants (aged 1-7 months at enrolment, with a genetically confirmed diagnosis of spinal muscular atrophy, and two SMN2 gene copies) were enrolled in 14 hospitals in ten countries across Europe, North America, South America, and Asia. Risdiplam was orally administered once daily at 0·2 mg/kg for infants between 5 months and 2 years of age; once an infant reached 2 years of age, the dose was increased to 0·25 mg/kg. Infants younger than 5 months started at 0·04 mg/kg (infants between 1 month and 3 months old) or 0·08 mg/kg (infants between 3 months and 5 months old), and this starting dose was adjusted to 0·2 mg/kg once pharmacokinetic data were available for each infant. The primary and secondary endpoints included in the statistical hierarchy and assessed at month 12 have been reported previously. Here we present the remainder of the secondary efficacy endpoints that were included in the statistical hierarchy at month 24: the ability to sit without support for at least 30 s, to stand alone, and to walk alone, as assessed by the Bayley Scales of Infant and Toddler Development, third edition gross motor subscale. These three endpoints were compared with a performance criterion of 5% that was defined based on the natural history of type 1 spinal muscular atrophy; the results were considered statistically significant if the lower limit of the two-sided 90% CI was above the 5% threshold. FIREFISH is registered with ClinicalTrials.gov, NCT02913482. Recruitment is closed; the 36-month extension period of the study is ongoing.FINDINGS: Between March 13 and Nov 19, 2018, 41 infants were enrolled in FIREFISH part 2. After 24 months of treatment, 38 infants were ongoing in the study and 18 infants (44% [90% CI 31-58]) were able to sit without support for at least 30 s (p<0·0001 compared with the performance criterion derived from the natural history of untreated infants with type 1 spinal muscular atrophy). No infants could stand alone (0 [90% CI 0-7]) or walk alone (0 [0-7]) after 24 months of treatment. The most frequently reported adverse event was upper respiratory tract infection, in 22 infants (54%); the most common serious adverse events were pneumonia in 16 infants (39%) and respiratory distress in three infants (7%).INTERPRETATION: Treatment with risdiplam over 24 months resulted in continual improvements in motor function and achievement of developmental motor milestones. The FIREFISH open-label extension phase will provide additional evidence regarding long-term safety and efficacy of risdiplam.FUNDING: F Hoffmann-La Roche.

  View details for DOI 10.1016/S1474-4422(22)00339-8

  View details for PubMedID 36244364

• Disease Progression in CMT related to MPZ Mutations: A Longitudinal Study. Annals of neurology Fridman, V., Sillau, S., Bockhorst, J., Smith, K., Moroni, I., Pagliano, E., Pisciotta, C., Piscosquito, G., Laura, M., Muntoni, F., Bacon, C., Feely, S., Grider, T., Gutmann, L., Shy, R., Wilcox, J., Herrmann, D. N., Li, J., Ramchandren, S., Sumner, C. J., Lloyd, T. E., Day, J., Siskind, C. E., Yum, S. W., Sadjadi, R., Finkel, R. S., Scherer, S. S., Pareyson, D., Reilly, M. M., Shy, M. E., Inherited Neuropathies Consortium-Rare Diseases Clinical Research Network (INC-RDCRN), Fridman, V., Sillau, S., Acsadi, G., Bacon, C., Dooley, K., Burns, J., Day, J., Feely, S., Finkel, R. S., Grider, T., Gutmann, L., Herrmann, D. N., Volpenhein, C., Bockhorst, J., Laura, M., Lewis, R. A., Li, J., Lloyd, T. E., Moroni, I., Muntoni, F., Pagliano, E., Pareyson, D., Pisciotta, C., Piscosquito, G., Ramchandren, S., Saporta, M., Sadjadi, R., Shy, R. R., Siskind, C. E., Sumner, C. J., Walk, D., Yum, S. W., Zuchner, S., Scherer, S. S., Reilly, M. M., Shy, M. E. 2022

  Abstract

  OBJECTIVE: The paucity of longitudinal natural history studies in MPZ-neuropathy remains a barrier to clinical trials. We have completed a longitudinal natural history study in patients with MPZ-neuropathies across 13 sites of the Inherited Neuropathy Consortium.METHODS: Change in Charcot Marie Tooth Examination scores (CMTES) and Rasch modified CMTES (CMTES-R) scores were evaluated using longitudinal regression over a 5-year period in subjects with MPZ-neuropathy. Data from 139 patients with MPZ-neuropathy were examined.RESULTS: The average baseline CMTES and CMTES-R scores were 10.84 (SD 6.0, range 0 - 28) and 14.60 (SD=7.56, range 0 - 32), respectively. A mixed regression model showed significant change in CMTES at years 2-5 [mean change from baseline of 0.87 points at 2years (p=0.008)]. Subgroup analysis revealed greater change in CMTES at 2years in subjects with axonal as compared to demyelinating neuropathy [mean change of 1.30 points, (p=0.016) versus 0.06 points, (p=0.889)]. Patients with a moderate baseline neuropathy severity also showed more notable change, by estimate, than those with mild or severe neuropathy [mean 2 year change of 1.14 for baseline CMTES 8-14 (p=0.025), versus -0.03 for baseline CMTES 0-7 (p=0.958) and 0.25 for baseline CMTES ≥15 (p=0.6897)]. The progression in patients harboring specific MPZ mutations was highly variable.INTERPRETATION: CMTES scores are sensitive to change over time in adult patients with axonal but not demyelinating forms of MPZ-neuropathy. Change in CMTES was greatest in patients with moderate baseline disease severity. These findings will inform future clinical trials of MPZ-neuropathies. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ana.26518

  View details for PubMedID 36203352

• Motor Responses in Pediatric Pompe Disease in the ADVANCE Participant Cohort. Journal of neuromuscular diseases Duong, T., Kishnani, P. S., An Haack, K., Foster, M. C., Gibson, J. B., Wilson, C., Hahn, S. H., Hillman, R., Kronn, D., Leslie, N. D., Peña, L. D., Sparks, S. E., Stockton, D. W., Tanpaiboon, P., Day, J. W. 2022

  Abstract

  ADVANCE (NCT01526785) presented an opportunity to obtain a more nuanced understanding of motor function changes in treatment-experienced children with Pompe disease receiving 4000L-production-scale alglucosidase alfa for 52 weeks.To estimate minimal detectable change (MDC) and effect size on Gross Motor Function Measure-88 (GMFM-88) after 52 weeks of 4000L alglucosidase alfa (complete data N =  90).The GMFM-88 mean total % score changes, MDC, and effect size were analyzed post hoc by Pompe Motor Function Level at enrollment, age groups at enrollment, and fraction of life on pre-study 160L-production-scale alglucosidase alfa.Overall, participants aged <  2 years surpassed MDC at Week 52 (change [mean±standard deviation] 21.1±14.1, MDC range 5.7-13.3, effect size 1.1), whereas participants aged≥2 years did not attain this (change -0.9±15.3, MDC range 10.8-25.2, effect size -0.03). In participants aged <  2 years, improvements surpassed the MDC for walkers (change 17.1±13.3, MDC range 3.0-6.9, effect size 1.7), supported standers (change 35.2±18.0, MDC range 5.9-13.7, effect size 1.8) and sitters (change 24.1±12.1, MDC range 2.6-6.2, effect size 2.7). Age-independent MDC ranges were only attained by walkers (change 7.7±12.3, MDC range 6.4-15.0, effect size 0.4) and sitters (change 9.9±17.2, MDC range 3.3-7.7, effect size 0.9).These first GMFM-88 minimal-detectable-change estimates for alglucosidase alfa-treated Pompe disease offer utility for monitoring motor skills.ClinicalTrials.gov; NCT01526785; Registered 6 February 2012; https://clinicaltrials.gov/ct2/show/NCT01526785.

  View details for DOI 10.3233/JND-210784

  View details for PubMedID 36214004

• Adaptive test for neuromuscular disorders: Design of a wheelchair-based assessment Duong, T., Tang, W., Nelson, L., Parker, D., Pasternak, A., Young, S., Muni-Lofra, R., Maczek, E., Michell-Sodhi, J., Moat, D., Chatfield, S., Appleton, P., Day, J., Glanzman, A., Mayhew, A. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S61

  View details for DOI 10.1016/j.nmd.2022.07.083

  View details for Web of Science ID 000873062200081

• Results from the end of Part A of the ongoing 3-part DEVOTE study to explore higher doses of nusinersen in SMA Day, J., Finkel, R., Pascual, S., Ryan, M., Mercuri, E., De Vivo, D., Montes, J., Gurgel-Giannetti, J., Gambino, G., Makepeace, C., Foster, R., Irzhevsky, V., Berger, Z. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S85

  View details for DOI 10.1016/j.nmd.2022.07.181

  View details for Web of Science ID 000873062200177

• Evaluating 2-3 year responses to disease modifying treatment in adults with spinal muscular atrophy Duong, T., Tang, W., Young, S., Parker, D., Wolford, C., Sampson, J., Day, J. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S90

  View details for DOI 10.1016/j.nmd.2022.07.201

  View details for Web of Science ID 000873062200196

• A phase 1/2 clinical trial evaluating the safety and pharmacokinetics of AOC 1001 in adults with myotonic dystrophy type 1: MARINA study design Johnson, N., Day, J., Hamel, J., Statland, J., Subramony, S., Arnold, W., Thornton, C., Wicklund, M., Soltanzadeh, P., Knisely, B., Goel, V., DiTrapani, K., Chen, C., Clark, K., Peters, A., Heusner, C., Younis, H., Tai, L., Ackermann, E. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S131

  View details for DOI 10.1016/j.nmd.2022.07.372

  View details for Web of Science ID 000873062200365

• Myostatin concentration is unreliable as a biomarker of disease progression in dysferlinopathy Moore, U., Simon, E., Day, J., Jones, K., Bharucha-Goebel, D., Pestronk, A., Walter, M., Paradas, C., Stojkovic, T., Bravver, E., Pegoraro, E., Mendell, J., Guglieri, M., Straub, V., Diaz-Manera, J. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S113

  View details for DOI 10.1016/j.nmd.2022.07.295

  View details for Web of Science ID 000873062200291

• Safety update: Risdiplam clinical trial development program Chiriboga, C., Servais, L., Baranello, G., Darras, B., Day, J., Deconinck, N., Farrar, M., Finkel, R., Bertini, E., Kirschner, J., Masson, R., Mazurkiewicz-Beldzinska, M., Vlodavets, D., Bader-Weder, S., Gorni, K., Jaber, B., McIver, T., Papp, G., Scalco, R., Mercuri, E. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S89

  View details for DOI 10.1016/j.nmd.2022.07.198

  View details for Web of Science ID 000873062200193

• Multimodal fusion of neuroimaging and neuropsych data: A machine learning approach to study brain alterations linked with cognitive domains in DM1 Kamali, T., Parker, D., Deutsch, G., Sampson, J., Day, J., Wozniak, J. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S132

  View details for DOI 10.1016/j.nmd.2022.07.376

  View details for Web of Science ID 000873062200369

• Efficacy and safety of Avalglucosidase Alfa in participants with late-onset Pompe Disease after 145 weeks' treatment during the COMET trial Schoser, B., Kishnani, P., Kushlaf, H., Ladha, S., Mozaffar, T., Straub, Toscano, A., van der Ploeg, A., Clemens, P., Day, J., Illarioshkin, S., Roberts, M., Attarian, S., Carvalho, G., Erdem-Ozdamar, S., Goker-Alpan, O., Kostera-Pruszczyk, A., Diaz-Manera, J., Dimachkie, M., COMET Investigator Grp PERGAMON-ELSEVIER SCIENCE LTD. 2022

  View details for Web of Science ID 000873062200397

• Real-world outcomes of exon skipping therapy use in patients with Duchenne muscular dystrophy: Experience at a single, large tertiary care center Yaworski, A., Duong, T., Low, J., Gee, R., Watson, K., Buu, M., Kaufman, B., Klotz, J., Day, J., Guzman, J., Rocha, C. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S102

  View details for DOI 10.1016/j.nmd.2022.07.250

  View details for Web of Science ID 000873062200246

• Clinical outcome study of dysferlinopathy 2: Characterising involvement of the intrinsic muscles of the hand in LGMDR2 James, M., Mayhew, A., Gordish-Dressman, H., Rufibach, L., Wong, K., Roper, W., Holsten, S., Lowes, L., Duong, T., Yochai, C., Zabala Pardo, A., Ogasawara, Y., Rudolph, K., Alarcon, S., Weber, J., Montiel Morillo, E., Pedrosa-Hernandez, I., Birnbaum, S., Rojas Rojas, J., Day, J., Straub, V. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S115

  View details for DOI 10.1016/j.nmd.2022.07.302

  View details for Web of Science ID 000873062200298

• FIREFISH Parts 1 and 2: 36-month safety and efficacy of risdiplam in Type 1 spinal muscular atrophy (SMA) Servais, L., Baranello, G., Boespflug-Tanguy, O., Day, J., Deconinck, N., Klein, A., Masson, R., Mazurkiewicz-Beldzinska, M., Mercuri, E., Rose, K., Vlodavets, D., Xiong, H., Zanoteli, E., El-Khairi, M., Gerber, M., Gorni, K., Kletzl, H., Palfreeman, L., Dodman, A., Gaki, E., Darras, B. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S88

  View details for DOI 10.1016/j.nmd.2022.07.194

  View details for Web of Science ID 000873062200189

• Prevalence of healthcare conditions and services used by patients with myotonic dystrophy (DM) pre- and post-diagnosis: A real-world data analysis Day, J., Munoz, K., Brook, R., McEvoy, B., Tai, L., DiTrapani, K., Kleinman, N., Chen, C., Stahl, M. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S131

  View details for DOI 10.1016/j.nmd.2022.07.371

  View details for Web of Science ID 000873062200364

• Impact of nusinersen on respiratory progression in paediatric patients with spinal muscular atrophy type 2 and non-ambulant type 3 Trucco, F., Weststrate, H., Ridout, D., Scoto, M., Rohwer, A., Coratti, G., Main, M., Pane, M., Messina, S., D'Amico, A., Bruno, C., De Vivo, D., Darras, B., Day, J., Baranello, G., Sansona, V., Bertini, E., Finkel, R., Mercuri, E., Muntoni, F. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S89

  View details for DOI 10.1016/j.nmd.2022.07.197

  View details for Web of Science ID 000873062200192

• SUNFISH parts 1 and 2: 3-year efficacy and safety of risdiplam in types 2 and 3 spinal muscular atrophy (SMA) Day, J., Deconinck, N., Mazzone, E., Nascimento, A., Oskoui, M., Saito, K., Vuillerot, C., Baranello, G., Boespflug-Tanguy, O., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Braid, J., Gerber, M., Gorni, K., Martin, C., Scalco, R., Yeung, W., Mercuri, E. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S89-S90

  View details for DOI 10.1016/j.nmd.2022.07.199

  View details for Web of Science ID 000873062200194

• Apitegromab in SMA: An analysis of multiple efficacy endpoints in the TOPAZ extension study Crawford, T., Darras, B., Day, J., Barrett, D., Song, G., O'Neil, J., Kertesz, N., Bilic, S., Patel, J., Nomikos, G., Chyung, Y. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S86-S87

  View details for DOI 10.1016/j.nmd.2022.07.187

  View details for Web of Science ID 000873062200183

• Integrated analyses of data from clinical trials of delandistrogene moxeparvovec in DMD Zaidman, C., Shieh, P., Proud, C., McDonald, C., Day, J., Mason, S., Guridi, M., Hu, L., Yu, L., Reid, C., Darton, E., Wandel, C., Richardson, J., Malhotra, J., Singh, T., Rodino-Klapac, L., Mendell, J. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S101

  View details for DOI 10.1016/j.nmd.2022.07.244

  View details for Web of Science ID 000873062200240

• Water T2 could predict functional decline in patients with dysferlinopathy. Journal of cachexia, sarcopenia and muscle Moore, U., Caldas de Almeida Araújo, E., Reyngoudt, H., Gordish-Dressman, H., Smith, F. E., Wilson, I., James, M., Mayhew, A., Rufibach, L., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Pestronk, A., Walter, M. C., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Pegoraro, E., Mendell, J. R., Bushby, K., Blamire, A. M., Straub, V., Carlier, P. G., Diaz-Manera, J. 2022

  Abstract

  Water T2 (T2H2O ) mapping is increasingly being used in muscular dystrophies to assess active muscle damage. It has been suggested as a surrogate outcome measure for clinical trials. Here, we investigated the prognostic utility of T2H2O to identify changes in muscle function over time in limb girdle muscular dystrophies.Patients with genetically confirmed dysferlinopathy were assessed as part of the Jain Foundation Clinical Outcomes Study in dysferlinopathy. The cohort included 18 patients from two sites, both equipped with 3-tesla magnetic resonance imaging (MRI) systems from the same vendor. T2H2O value was defined as higher or lower than the median in each muscle bilaterally. The degree of deterioration on four functional tests over 3 years was assessed in a linear model against covariates of high or low T2H2O at baseline, age, disease duration, and baseline function.A higher T2H2O at baseline significantly correlated with a greater decline on functional tests in 21 out of 35 muscles and was never associated with slower decline. Higher baseline T2H2O in adductor magnus, vastus intermedius, vastus lateralis, and vastus medialis were the most sensitive, being associated bilaterally with greater decline in multiple timed tests. Patients with a higher than median baseline T2H2O (>40.6 ms) in the right vastus medialis deteriorated 11 points more on the North Star Ambulatory Assessment for Dysferlinopathy and lost an additional 86 m on the 6-min walk than those with a lower T2H2O (<40.6 ms). Optimum sensitivity and specificity thresholds for predicting decline were 39.0 ms in adductor magnus and vastus intermedius, 40.0 ms in vastus medialis, and 40.5 ms in vastus lateralis from different sites equipped with different MRI systems.In dysferlinopathy, T2H2O did not correlate with current functional ability. However, T2H2O at baseline was higher in patients who worsened more rapidly on functional tests. This suggests that inter-patient differences in functional decline over time may be, in part, explained by different severities of the active muscle damage, assessed by T2H2O measure at baseline. Significant challenges remain in standardizing T2H2O values across sites to allow determining globally applicable thresholds. The results from the present work are encouraging and suggest that T2H2O could be used to improve prognostication, patient selection, and disease modelling for clinical trials.

  View details for DOI 10.1002/jcsm.13063

  View details for PubMedID 36058852

• Large Fenestrations Versus Scallops for the SMA During Fenestrated EVAR: Does it Matter? Annals of vascular surgery Sorondo, S. M., Ss, D., K, T., Vt, H., Jr, S., J, L. 2022

  Abstract

  FEVAR is an established customized treatment for aortic aneurysms with three current commercially available configurations for the superior mesenteric artery (SMA) - a single-wide scallop, large fenestration, or small fenestration, with the scallop or large fenestration most utilized. Outcomes comparing SMA single-wide scallops to large fenestrations with the ZFEN device are scarce. As large fenestrations have the benefit of extending the proximal seal zone compared to scalloped configurations, we sought to determine the differences in seal zone and sac regression outcomes between the two SMA configurations.We retrospectively reviewed our prospectively maintained complex EVAR database and included all patients treated with the Cook ZFEN device with an SMA scallop or large fenestration configuration at its most proximal build. All first post-operative CT scans (1-30 days) were analyzed on TeraRecon to determine precise proximal seal zone lengths, and standard follow-up anatomic and clinical metrics were tabulated.A total of 234 consecutive ZFEN patients from 2012-2021 were reviewed, and 137 had either a scallop or large fenestration for the SMA as the proximal-most configuration (72 scallops and 65 large fenestrations) with imaging available for analysis. Mean follow-up was 35 months. Mean proximal seal zone length was 19.5±7.9 mm for scallop vs 41.7±14.4 mm for large fenestration groups (P<.001). There was no difference in sac regression between scallop and large fenestration at one year (10.1±10.9 mm vs 11.0±12.1, P = 0.63). Overall, 30-day mortality (1.3% vs 2.5%, P=.51) and all-cause three-year mortality (72.5% vs 81.7%, P=.77) were not significantly different. Reinterventions within 30 days were primarily secondary to renal artery branch occlusions, with only one patient in the scallop group requiring reintervention for an SMA branch occlusion.Despite attaining longer proximal seal lengths, large SMA fenestrations were not associated with a difference in sac regression compared to scalloped SMA configurations at one-year follow up. There were no significant differences in reinterventions or overall long-term survival between the two SMA strategies.

  View details for DOI 10.1016/j.avsg.2022.07.013

  View details for PubMedID 36058451

• SUNFISH 3-YEAR EFFICACY AND SAFETY OF RISDIPLAM IN TYPES 2 AND 3 SMA Servais, L., Day, J. W., Mazzone, E. S., Oskoui, M., Baranello, G., Gerber, M., Martin, C., McIver, T., Yeung, W., Mercuri, E. BMJ PUBLISHING GROUP. 2022

  View details for DOI 10.1136/jnnp-2022-abn2.232

  View details for Web of Science ID 000841239400136

• SUNFISH PART 2: 24-MONTH EFFICACY OF RISDIPLAM COMPARED WITH EXTERNAL CONTROL COMPARATORS Servais, L., Day, J. W., Mazzone, E. S., Oskoui, M., Baranello, G., Gerber, M., Martin, C., McIver, T., Yeung, W., Mercuri, E. BMJ PUBLISHING GROUP. 2022

  View details for DOI 10.1136/jnnp-2022-abn2.231

  View details for Web of Science ID 000841239400131

• PREVALENCE OF HEALTHCARE CONDITIONS AND SERVICES USED BY PATIENTS WITH MYOTONIC DYSTROPHY PRE-AND POST-DIAGNOSIS, A REAL-WORLD DATA ANALYSIS Day, J. W., Munoz, K., Brook, R. A., McEvoy, B., Tai, L. J., DiTrapani, K., Kleinman, N. L., Chen, C. Y., Stahl, M. ELSEVIER SCIENCE INC. 2022: S596

  View details for Web of Science ID 000828757302154

• Cognitive Impairment Analysis of Myotonic Dystrophy via Weakly Supervised Classification of Neuropsychological Features. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference Kamali, T., Deutsch, G. K., Hagerman, K. A., Parker, D., Day, J. W., Sampson, J. B., Wozniak, J. R. 2022; 2022: 4377-4382

  Abstract

  The myotonic dystrophies (DM1 and DM2) are dominantly inherited disorders that cause pathological changes throughout the body. Many individuals with DM experience cognitive, behavioral and other functional central nervous system effects that impact their quality of life. The extent of psychological impairment that will develop in each patient is variable and unpredictable. Hence, it is difficult to get strong supervision information like fully ground truth labels for all cognitive involvement patterns. This study is to assess cognitive involvement among healthy controls and patients with DM. The DM cognitive impairment pattern observation is modeled in a weakly supervised setting and supervision information is used to transform the input feature space to a more discriminative representation suitable for pattern observation. This study incorporated results from 59 adults with DM and 92 control subjects. The developed system categorized the neuropsychological testing data into five cognitive clusters. The quality of the obtained clustering solution was assessed using an internal validity metric. The experimental results show that the proposed algorithm can discover interesting patterns and useful information from neuropsychological data, which will be be crucial in planning clinical trials and monitoring clinical performance. The proposed system resulted in an average classification accuracy of 88%, which is very promising considering the unique challenges present in this population.

  View details for DOI 10.1109/EMBC48229.2022.9871626

  View details for PubMedID 36086274

• Spinal Muscular Atrophy Type 1: Fetal Diagnosis, Prenatal Coordination, and Postnatal Management in the Era of Novel Therapies. NeoReviews Chitkara, R., Chock, V., Davis, A., Rocha, C. T., Day, J. W., Fluharty, B., Hintz, S. 2022; 23 (7): e520-e526

  View details for DOI 10.1542/neo.23-7-e520

  View details for PubMedID 35773512

• SUNFISH: 3-year efficacy and safety of risdiplam in Types 2 and 3 spinal muscular atrophy Goemans, N., Day, J., Deconinck, N., Mazzone, E., Nascimento, A., Oskoui, M., Saito, K., Vuillerot, C., Baranello, G., Boespflug-Tanguy, O., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Braid, J., Gerber, M., Gorni, K., Martin, C., Scalco, R., Yeung, W., Mercuri, E., SUNFISH Working Grp WILEY. 2022: 278

  View details for Web of Science ID 000815254001142

• FIREFISH Parts 1 and 2: 36-month safety and efficacy of risdiplam in Type 1 spinal muscular atrophy Deconinck, N., Baranello, G., Boespflug-Tanguy, O., Day, J., Klein, A., Masson, R., Mazurkiewicz-Beldzinska, M., Mercuri, E., Rose, K., Servais, L., Vlodavets, D., Xiong, H., Zanoteli, E., El-Khairi, M., Gerber, M., Gorni, K., Kletzl, H., Dodman, A., Gaki, E., Darras, B., FIREFISH Working Grp WILEY. 2022: 279

  View details for Web of Science ID 000815254001143

• COMET: Efficacy and safety of avalglucosidase alfa in late-onset Pompe disease participants after 97 weeks of treatment Schoser, B., Kishnani, P., Diaz-Manera, J., Kushlaf, H., Ladha, S., Mozaffar, T., Straub, V., Toscano, A., Van der Ploeg, A., Berger, K., Clemens, P., Chien, Y., Day, J., Ilarioshkin, S., Roberts, M., Attarian, S., Carvalho, G., Choi, Y., Erdem-Ozdamar, S., Goker-Alpan, O., Kostera-Pruszczyk, A., Haack, K., Thibault, N., Zhou, T., Dimachkie, M., COMET Investigator Grp WILEY. 2022: 59-60

  View details for Web of Science ID 000815254000098

• MECP2-related pathways are dysregulated in a cortical organoid model of myotonic dystrophy. Science translational medicine Morelli, K. H., Jin, W., Shathe, S., Madrigal, A. A., Jones, K. L., Schwartz, J. L., Bridges, T., Mueller, J. R., Shankar, A., Chaim, I. A., Day, J. W., Yeo, G. W. 2022; 14 (651): eabn2375

  Abstract

  Myotonic dystrophy type 1 (DM1) is a multisystem, autosomal-dominant inherited disorder caused by CTG microsatellite repeat expansions (MREs) in the 3' untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene. Despite its prominence as the most common adult-onset muscular dystrophy, patients with congenital to juvenile-onset forms of DM1 can present with debilitating neurocognitive symptoms along the autism spectrum, characteristic of possible in utero cortical defects. However, the molecular mechanism by which CTG MREs lead to these developmental central nervous system (CNS) manifestations is unknown. Here, we showed that CUG foci found early in the maturation of three-dimensional (3D) cortical organoids from DM1 patient-derived induced pluripotent stem cells (iPSCs) cause hyperphosphorylation of CUGBP Elav-like family member 2 (CELF2) protein. Integrative single-cell RNA sequencing and enhanced cross-linking and immunoprecipitation (eCLIP) analysis revealed that reduced CELF2 protein-RNA substrate interactions results in misregulation of genes critical for excitatory synaptic signaling in glutamatergic neurons, including key components of the methyl-CpG binding protein 2 (MECP2) pathway. Comparisons to MECP2(y/-) cortical organoids revealed convergent molecular and cellular defects such as glutamate toxicity and neuronal loss. Our findings provide evidence suggesting that early-onset DM1 might involve neurodevelopmental disorder-associated pathways and identify N-methyl-d-aspartic acid (NMDA) antagonists as potential treatment avenues for neuronal defects in DM1.

  View details for DOI 10.1126/scitranslmed.abn2375

  View details for PubMedID 35767654

• Scientific rationale for a higher dose of nusinersen. Annals of clinical and translational neurology Finkel, R. S., Ryan, M. M., Pascual Pascual, S. I., Day, J. W., Mercuri, E., De Vivo, D. C., Foster, R., Montes, J., Gurgel-Giannetti, J., MacCannell, D., Berger, Z. 2022

  Abstract

  OBJECTIVE: The long-term favorable safety profile of nusinersen provides an opportunity to consider a higher dose. We report on the relationships between nusinersen cerebrospinal fluid (CSF) exposure, biomarker levels, and clinical efficacy.METHODS: The analyses used data from the CS3A and ENDEAR studies of nusinersen in participants with infantile-onset spinal muscular atrophy (SMA). Steady-state CSF trough (Ctrough ) levels, plasma phosphorylated neurofilament heavy chain (pNF-H) levels, body weight, and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scores were selected as parameters of interest. A validated population pharmacokinetic (PK) model was applied to predict the nusinersen CSF Ctrough . PK/pharmacodynamic (PK/PD) models used nusinersen CSF Ctrough measurements, which were time-matched with CHOP INTEND scores.RESULTS: Higher nusinersen CSF exposure was associated with a greater decrease in pNF-H levels and greater efficacy, as measured by change in the CHOP INTEND score from baseline. These findings indicate a dose-response relationship between CSF nusinersen levels and treatment response. The higher dose is predicted to lead to approximately a 2.4-fold increase in nusinersen CSF levels with fewer loading doses. PK/PD modeling indicates that a higher concentration of nusinersen may predict an additional 5-point increase in CHOP INTEND score beyond that observed with 12mg.INTERPRETATION: Our data indicate that a higher dose of nusinersen may lead to additional clinically meaningful improvement in efficacy when compared with the currently approved 12-mg dose. The efficacy, safety, and PK of a higher nusinersen dose are currently under investigation in the ongoing phase 2/3 DEVOTE study (NCT04089566).

  View details for DOI 10.1002/acn3.51562

  View details for PubMedID 35567345

• Mesial Temporal Enlargement in Adult-Onset Myotonic Dystrophy Type 1 Fecto, F., Parker, D., Sampson, J., Mueller, B., Lim, K., Wozniak, J., Hagerman, K., Day, J. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000894020500810

• The RESTORE Registry: Real -World Assessments of Interventions and Long -Term Outcomes in Patients with Spinal Muscular Atrophy (SMA) Finkel, R., Day, J., De Vivo, D., Mercuri, E., Muntoni, F., Shieh, P., Tizzano, E., Desguerre, I., Saito, K., Menier, M., LaMarca, N., Anderson, F., Dabbous, O., Servais, L. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000894020500059

• FIREFISH Parts 1 and 2: 24-month Safety and Efficacy of Risdiplam in Type 1 SMA Darras, B. T., Boespflug-Tanguy, O., Day, J. W., Deconinck, N., Klein, A., Masson, R., Mazurkiewicz-Beldzinska, M., Mercuri, E., Rose, K., Servais, L., Vlodavets, D., Xiong, H., Zanoteli, E., Dodman, A., El-Khairi, M., Gaki, E., Gerber, M., Gorni, K., Kletzl, H., Baranello, G. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000894020500384

• Mesial Temporal Enlargement in Adult-Onset Myotonic Dystrophy Type 1 Fecto, F., Parker, D., Sampson, J., Mueller, B., Lim, K., Wozniak, J., Hagerman, K., Day, J. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000894020500814

• Pooled Safety Data from the Risdiplam Clinical Trial Development Program Darras, B. T., Chiriboga, C. A., Servais, L., Baranello, G., Bertini, E., Day, J. W., Deconinck, N., Fischer, D., Goemans, N., Kirschner, J., Klein, A., Masson, R., Mazurkiewicz-Beldzinska, M., Wang, Y., Bader-Weder, S., Gorni, K., Jaber, B., McIver, T., Scalco, R., Mercuri, E. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000894020500313

• Apitegromab in Spinal Muscular Atrophy (SMA): An Analysis of Multiple Efficacy Endpoints in the TOPAZ Trial Crawford, T., Darras, B., Day, J., Song, G., Nomikos, G., Place, A., Barrett, D., Bilic, S., O'Neil, J., Kertesz, N., Cote, S., Patel, J., Chyung, Y. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000894020500062

• SUNFISH: 3-year Efficacy and Safety of Risdiplam in Types 2 and 3 SMA Day, J. W., Deconinck, N., Kirschner, J., Mazzone, E. S., Nascimento, A., Oskoui, M., Saito, K., Vuillerot, C., Baranello, G., Boespflug-Tanguy, O., Goemans, N., Kostera-Pruszczyk, A., Servais, L., Braid, J., Gerber, M., Gorni, K., Martin, C., Scala, R. S., Yeung, W., Mercuri, E. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000894020500382

• Exploring Protein Changes in Cerebrospinal Fluid of Spinal Muscular Atrophy Patients Pre-Nusinersen vs. Post-Nusinersen Treatment using Bayesian Machine Learning Algorithms Kamali, T., Hagerman, K., Duong, T., Parker, D., Young, S., Tang, W., Sampson, J., Day, J. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000894020500808

• Major Adverse Dystrophinopathy Event Score as Marker of Cumulative Morbidity and Risk for Mortality in Boys with Duchenne Muscular Dystrophy Kaufman, B. D., Garcia, A., He, Z., Buu, M., Tesi-Rocha, C., Day, J. W., Rosenthal, D. N., Gordish-Dressman, H., Almond, C., Duong, T. ELSEVIER SCIENCE INC. 2022: S95

  View details for Web of Science ID 000780119700198

• Cardiac and pulmonary findings in dysferlinopathy: a 3-year, longitudinal study. Muscle & nerve Moore, U., Fernandez-Torron, R., Jacobs, M., Gordish, H., Diaz-Manera, J., James, M. K., Mayhew, A. G., Harris, E., Guglieri, M., Rufibach, L. E., Feng, J., Blamire, A. M., Carlier, P. G., Spuler, S., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Pestronk, A., Walter, M. C., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Pegoraro, E., Lowes, L. P., Mendell, J. R., Bushby, K., Jain COS Consortium, Bourke, J., Straub, V. 2022

  Abstract

  INTRODUCTION/AIMS: There is debate about whether and to what extent either respiratory or cardiac dysfunction occur in patients with dysferlinopathy. This study aimed to establish definitively whether dysfunction in either system is part of the dysferlinopathy phenotype.METHODS: As part of the Jain Foundation's International Clinical Outcome Study (COS) for dysferlinopathy, objective measures of respiratory and cardiac function were collected twice, with a three-year interval between tests, in 188 genetically confirmed patients aged 11-86years (53% female). Measures included forced vital capacity (FVC), electrocardiogram (ECG) and echocardiogram (echo).RESULTS: Mean FVC was 90% predicted at baseline, decreasing to 88% at year three. FVC was less than 80% predicted in 44 patients (24%) at baseline and 48 patients (30%) by year three, including ambulant participants. ECGs showed P-wave abnormalities indicative of delayed trans-atrial conduction in 58% of patients at baseline, representing a risk for developing atrial flutter or fibrillation. The prevalence of impaired left ventricular function or hypertrophy was comparable to that in the general population.DISCUSSION: These results demonstrate clinically significant respiratory impairment and abnormal atrial conduction in some patients with dysferlinopathy. Therefore, we recommend that annual or biannual follow-up should include FVC measurement, enquiry about arrhythmia symptoms and peripheral pulse palpation to assess cardiac rhythm. However, periodic specialist cardiac review is probably not warranted unless prompted by symptoms or abnormal pulse findings.

  View details for DOI 10.1002/mus.27524

  View details for PubMedID 35179231

• Intron Mutations and Early Transcription Termination in Duchenne and Becker muscular dystrophy. Human mutation Waldrop, M. A., Moore, S. A., Mathews, K. D., Darbro, B. W., Medne, L., Finkel, R., Connolly, A. M., Crawford, T. O., Drachman, D., Wein, N., Habib, A. A., Krzesniak-Swinarska, M. A., Zaidman, C. M., Collins, J. J., Jokela, M., Udd, B., Day, J. W., Ortiz-Guerrero, G., Statland, J., Butterfield, R. J., Dunn, D. M., Weiss, R. B., Flanigan, K. M. 2022

  Abstract

  DMD pathogenic variants for Duchenne and Becker muscular dystrophy are detectable with high sensitivity by standard clinical exome analyses of genomic DNA. However, up to 7% of DMD mutations are deep intronic and analysis of muscle-derived RNA is an important diagnostic step for patients who have negative genomic testing but abnormal dystrophin expression in muscle. In this study, muscle biopsies were evaluated from 19 patients with clinical features of a dystrophinopathy, but negative clinical DMD mutation analysis. Reverse transcription PCR (RT-PCR) or high-throughput RNA sequencing (RNA-Seq) methods identified 19 mutations with one of three pathogenic pseudoexon types: deep intronic point mutations, deletions or insertions, and translocations. In association with point mutations creating intronic splice acceptor sites, we observed the first examples of DMD pseudo 3'-terminal exon mutations causing high efficiency transcription termination within introns. This connection between splicing and premature transcription termination is reminiscent of U1 snRNP-mediating telescripting in sustaining RNA polymerase II elongation across large genes, such as DMD. We propose a novel classification of three distinct types of mutations identifiable by muscle RNA analysis, each of which differ in potential treatment approaches. Recognition and appropriate characterization may lead to therapies directed toward full-length dystrophin expression for some patients. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/humu.24343

  View details for PubMedID 35165973

• AT845 gene replacement therapy for late onset Pompe disease: Overview of clinical data from FORTIS, a phase 1/2 open-label clinical study Mozaffar, T., Day, J. W., Longo, N., Manera, J., Straub, V., Maruoka, M., Han, C., Foo, C., Smith, A. R., Bachtell, N. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2022: S85-S86

  View details for DOI 10.1016/j.ymgme.2021.11.221

  View details for Web of Science ID 000803066100208

• The avalglucosidase alfa phase 3 COMET trial in late-onset Pompe disease patients: Efficacy and safety results after 97 weeks Kishnani, P., Diaz-Manera, J., Kushlaf, H., Ladha, S., Mozaffar, T., Straub, V., Toscano, A., van der Ploeg, A. T., Berger, K. I., Clemens, P. R., Chien, Y., Day, J. W., Illarioshkin, S., Roberts, M., Attarian, S., Carvalho, G., Choi, Y., Erdem-Ozdamar, S., Goker-Alpan, O., Kostera-Pruszczyk, A., Haack, K., Thibault, N., Zhou, T., Dimachkie, M. M., Schoser, B. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2022: S66-S67

  View details for DOI 10.1016/j.ymgme.2021.11.168

  View details for Web of Science ID 000803066100155

• Brief assessment of cognitive function in myotonic dystrophy: multicenter longitudinal study using computer-assisted evaluation. Muscle & nerve Deutsch, G. K., Hagerman, K. A., Sampson, J., Dent, G., Dekdebrun, J., Parker, D. M., Thornton, C. A., Heatwole, C. R., Subramony, S. H., Mankodi, A. K., Ashizawa, T., Statland, J. M., Arnold, W. D., Moxley, R. T., Day, J. W. 2022

  Abstract

  Myotonic dystrophy type 1 (DM1) is known to affect cognitive function, but the best methods to assess CNS involvement in multicenter studies have not been determined. This study's primary aim was to evaluate the potential of computerized cognitive tests to assess cognition in DM1.We conducted a prospective, longitudinal, observational study of 113 adults with DM1 at 6 sites. Psychomotor speed, attention, working memory, and executive functioning were assessed at baseline, 3-months and 12-months using computerized cognitive tests. Results were compared with assessments of muscle function and patient reported outcomes (PROs), including the Myotonic Dystrophy Health Index (MDHI) and EQ-5D-5L.Based on intra-class correlation coefficients (ICCs), computerized cognitive tests had moderate to good reliability for psychomotor speed (0.76), attention (0.82), working memory speed (0.79), working memory accuracy (0.65), and executive functioning (0.87). Performance at baseline was lowest for working memory accuracy (p < 0.0001). Executive function performance improved from baseline to 3-months (p < 0.0001), without further changes over one year. There was a moderate correlation between poorer executive function and larger CTG repeat size (r = -0.433). There were some weak associations between PROs and cognitive performance.Computerized tests of cognition are feasible in multicenter studies of DM1. Poor performance was exhibited in working memory, which may be a useful variable in clinical trials. Learning effects may have contributed to the improvement in executive functioning. The relationship between PROs and cognitive impairment in DM1 requires further study. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/mus.27520

  View details for PubMedID 35179228

• Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial. The Lancet. Neurology Mercuri, E., Deconinck, N., Mazzone, E. S., Nascimento, A., Oskoui, M., Saito, K., Vuillerot, C., Baranello, G., Boespflug-Tanguy, O., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Gerber, M., Gorni, K., Khwaja, O., Kletzl, H., Scalco, R. S., Staunton, H., Yeung, W. Y., Martin, C., Fontoura, P., Day, J. W., SUNFISH Study Group, Volpe, J. J., Posner, J., Kellner, U., Quinlivan, R., Fuerst-Recktenwald, S., Marquet, A., Mulhardt, N., Trundell, D., Daron, A., Delstanche, S., Romain, B., Dal Farra, F., Schneider, O., Deconinck, N., Balikova, I., Delbeke, P., Joniau, I., Tahon, V., Wittevrongel, S., De Vos, E., Goemans, N., Casteels, I., De Waele, L., Balikova, I., Cassiman, C., Prove, L., Kinoo, D., Vancampenhout, L., Van Den Hauwe, M., Van Impe, A., Prufer de Queiroz Campos Araujo, A., Chacon Pereira, A., Nardes, F., Haefeli, L., Rossetto, J., Almeida Pereira, J., Ferreira Rebel, M., Campbell, C., Sharan, S., McDonald, W., Scholtes, C., Mah, J., Sframeli, M., Chiu, A., Hagel, J., Oskoui, M., Beneish, R., Pham, C., Toffoli, D., Arpin, S., Turgeon Desilets, S., Wang, Y., Hu, C., Huang, J., Qian, C., Shen, L., Xiao, Y., Zhou, Z., Li, H., Wang, S., Xiong, H., Chang, X., Dong, H., Liu, Y., Sang, T., Wei, C., Wen, J., Cao, Y., Lv, X., Wen, J., Zhao, J., Li, W., Qin, L., Barisic, N., Galiot Delic, M., Ivkic, P. K., Vukojevic, N., Kern, I., Najdanovic, B., Skugor, M., Servais, L., Boespflug-Tanguy, O., Gidaro, T., Seferian, A., De Lucia, S., Barreau, E., Mnafek, N., Momtchilova, M. M., Peche, H., Valherie, C., Grange, A., Lilien, C., Milascevic, D., Tachibana, S., Ravelli, C., Cardas, R., Vanden Brande, L., Davion, J., Coopman, S., Bouacha, I., Debruyne, P., Defoort, S., Derlyn, G., Leroy, F., Danjoux, L., Guilbaud, J., Desguerre, I., Barnerias, C., Semeraro, M., Bremond-Gignac, D., Bruere, L., Rateaux, M., Deladriere, E., Germa, V., Pereon, Y., Magot, A., Mercie, S., Billaud, F., Le Goff, L., Letellier, G., Vuillerot, C., Portefaix, A., Fontaine, S., De-Montferrand, C., Le-Goff, L., Saidi, M., Bouzid, N., Barriere, A., Tinat, M., Saidi, M., Kirschner, J., Dreesbach, M., Lagreze, W., Michaelis, B., Molnar, F., Seger, D., Vogt, S., Bertini, E., D'Amico, A., Petroni, S., Bonetti, A. M., Carlesi, A., Mizzoni, I., Bruno, C., Priolo, E., Rao, G., Morando, S., Tacchetti, P., Zuffi, A., Comi, G. P., Brusa, R., Corti, S., Daniele, V., Govoni, A., Magri, F., Minorini, V., Osnaghi, S. G., Abbati, F., Fassini, F., Foa, M., Lopopolo, A., Meneri, M., Zoppas, F., Parente, V., Baranello, G., Masson, R., Bianchi Marzoli, S., Santarsiero, D., Garcia Sierra, M., Tremolada, G., Arnoldi, M. T., Vigano, M., Zanin, R., Mercuri, E., Amorelli, G. M., Barresi, C., D'Amico, G., Orazi, L., Coratti, G., Haginoya, K., Kato, A., Morishita, Y., Kira, R., Akiyama, K., Goto, M., Mori, Y., Okamoto, M., Tsutsui, S., Takatsuji, Y., Tanaka, A., Komaki, H., Suzuki, I., Takeuchi, M., Todoroki, D., Watanabe, S., Omori, M., Matsubayashi, T., Inakazu, E., Nagura, H., Suzuki, A., Osaka, H., Ohashi, M., Ishikawa, N., Harada, Y., Fudeyasu, K., Hirata, K., Michiue, K., Ueda, K., Saito, K., Yashiro, S., Seki, M., Sano, N., Uemura, A., Fukuyama, K., Matsumoto, Y., Miyazaki, H., Shibata, M., Kobayashi, K., Nakamura, Y., Takeshima, Y., Kuma, M., Kostera-Pruszczyk, A., Fraczek, A., Jedrzejowska, M., Lusakowska, A., Czeszyk-Piotrowicz, A., Hautz, W., Rakusiewicz, K., Burlewicz, M., Gierlak-Wojcicka, Z., Kepa, M., Sikorski, A., Sobieraj, M., Mazurkiewicz-Beldzinska, M., Lemska, A., Modrzejewska, S., Koberda, M., Stodolska-Koberda, U., Waskowska, A., Kolendo, J., Sobierajska-Rek, A., Steinborn, B., Dalz, M., Grabowska, J., Hajduk, W., Janasiewicz-Karachitos, J., Klimas, M., Stopa, M., Gajewska, E., Pusz, B., Vlodavets, D., Melnik, E., Leppenen, N., Yupatova, N., Monakhova, A., Papina, Y., Shidlovsckaia, O., Milic Rasic, V., Brankovic, V., Kosac, A., Djokic, O., Jaksic, V., Pepic, A., Martinovic, J., Munell Casadesus, F., Tizzano, E., Martin Begue, N., Wolley Dod, C., Subira, O., Planas Pascual, B., Toro Tamargo, E., Madruga Garrido, M., Medina Romero, J. D., Salinas, M. P., Nascimento Osorio, A., Diaz Cortes, A., Jimenez Ganan, E., Suh, S. D., Medina Cantillo, J., Moya, O., Padros, N., Roca Urraca, S., Gonzalez Valdivia, H., Pascual Pascual, S., de Manuel, S., Noval Martin, S., Burnham, P., Espinosa Garcia, S., Martinez Moreno, M., Topaloglu, H., Oncel, I., Eroglu Ertugrul, N., Konuskan, B., Eldem, B., Kadayifcilar, S., Alemdaroglu, I., Ayse Karaduman, A., Tunca Yilmaz, O., Bilgin, N., Sari, S., Chiriboga, C., Kane, S., Lee, J., Rome-Martin, D., Day, J. W., Beres, S., Duong, T., Gee, R., Dunaway Young, S. 1800; 21 (1): 42-52

  Abstract

  BACKGROUND: Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy.METHODS: In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2-25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing ≥20 kg) or 0·25 mg/kg (for individuals weighing <20 kg), or daily oral placebo (matched to risdiplam in colour and taste). Randomisation was conducted by permutated block randomisation with a computerised system run by an external party. Patients, investigators, and all individuals in direct contact with patients were masked to treatment assignment. The primary endpoint was the change from baseline in the 32-item Motor Function Measure total score at month 12. All individuals who were randomly assigned to risdiplam or placebo, and who did not meet the prespecified missing item criteria for exclusion, were included in the primary efficacy analysis. Individuals who received at least one dose of risdiplam or placebo were included in the safety analysis. SUNFISH is registered with ClinicalTrials.gov, NCT02908685. Recruitment is closed; the study is ongoing.FINDINGS: Between Oct 9, 2017, and Sept 4, 2018, 180 patients were randomly assigned to receive risdiplam (n=120) or placebo (n=60). For analysis of the primary endpoint, 115 patients from the risdiplam group and 59 patients from the placebo group were included. At month 12, the least squares mean change from baseline in 32-item Motor Function Measure was 1·36 (95% CI 0·61 to 2·11) in the risdiplam group and -0·19 (-1·22 to 0·84) in the placebo group, with a treatment difference of 1·55 (0·30 to 2·81, p=0·016) in favour of risdiplam. 120 patients who received risdiplam and 60 who received placebo were included in safety analyses. Adverse events that were reported in at least 5% more patients who received risdiplam than those who received placebo were pyrexia (25 [21%] of 120 patients who received risdiplam vs ten [17%] of 60 patients who received placebo), diarrhoea (20 [17%] vs five [8%]), rash (20 [17%] vs one [2%]), mouth and aphthous ulcers (eight [7%] vs 0), urinary tract infection (eight [7%] vs 0), and arthralgias (six [5%] vs 0). The incidence of serious adverse events was similar between treatment groups (24 [20%] of 120 patients in the risdiplam group; 11 [18%] of 60 patients in the placebo group), with the exception of pneumonia (nine [8%] in the risdiplam group; one [2%] in the placebo group).INTERPRETATION: Risdiplam resulted in a significant improvement in motor function compared with placebo in patients aged 2-25 years with type 2 or non-ambulant type 3 spinal muscular atrophy. Our exploratory subgroup analyses showed that motor function was generally improved in younger individuals and stabilised in older individuals, which requires confirmation in further studies. SUNFISH part 2 is ongoing and will provide additional evidence regarding the long-term safety and efficacy of risdiplam.FUNDING: F Hoffmann-La Roche.

  View details for DOI 10.1016/S1474-4422(21)00367-7

  View details for PubMedID 34942136

• Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2) : a phase 3, double-blind, randomised, placebo-controlled trial LANCET NEUROLOGY Mercuri, E., Deconinck, N., Mazzone, E. S., Nascimento, A., Oskoui, M., Saito, K., Vuillerot, C., Baranello, G., Boespflug-Tanguy, O., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Gerber, M., Gorni, K., Khwaja, O., Kletzl, H., Scalco, R. S., Staunton, H., Yeung, W., Martin, C., Fontoura, P., Day, J. W., SUNFISH Study Grp 2022; 21 (1): 42-52

  View details for Web of Science ID 000734663200021

• Assessing the Relationship of Patient Reported Outcome Measures With Functional Status in Dysferlinopathy: A Rasch Analysis Approach. Frontiers in neurology Mayhew, A. G., James, M. K., Moore, U., Sutherland, H., Jacobs, M., Feng, J., Lowes, L. P., Alfano, L. N., Muni Lofra, R., Rufibach, L. E., Rose, K., Duong, T., Bello, L., Pedrosa-Hernandez, I., Holsten, S., Sakamoto, C., Canal, A., Sanchez-Aguilera Praxedes, N., Thiele, S., Siener, C., Vandevelde, B., DeWolf, B., Maron, E., Gordish-Dressman, H., Hilsden, H., Guglieri, M., Hogrel, J., Blamire, A. M., Carlier, P. G., Spuler, S., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Pestronk, A., Walter, M. C., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Diaz-Manera, J., Pegoraro, E., Mendell, J. R., Straub, V. 2022; 13: 828525

  Abstract

  Dysferlinopathy is a muscular dystrophy with a highly variable functional disease progression in which the relationship of function to some patient reported outcome measures (PROMs) has not been previously reported. This analysis aims to identify the suitability of PROMs and their association with motor performance.Two-hundred and four patients with dysferlinopathy were identified in the Jain Foundation's Clinical Outcome Study in Dysferlinopathy from 14 sites in 8 countries. All patients completed the following PROMs: Individualized Neuromuscular Quality of Life Questionnaire (INQoL), International Physical Activity Questionnaire (IPAQ), and activity limitations for patients with upper and/or lower limb impairments (ACTIVLIMs). In addition, nonambulant patients completed the Egen Klassifikation Scale (EK). Assessments were conducted annually at baseline, years 1, 2, 3, and 4. Data were also collected on the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) and Performance of Upper Limb (PUL) at these time points from year 2. Data were analyzed using descriptive statistics and Rasch analysis was conducted on ACTIVLIM, EK, INQoL. For associations, graphs (NSAD with ACTIVLIM, IPAQ and INQoL and EK with PUL) were generated from generalized estimating equations (GEE). The ACTIVLIM appeared robust psychometrically and was strongly associated with the NSAD total score (Pseudo R 2 0.68). The INQoL performed less well and was poorly associated with the NSAD total score (Pseudo R 2 0.18). EK scores were strongly associated with PUL (Pseudo R 2 0.69). IPAQ was poorly associated with NSAD scores (Pseudo R 2 0.09). This study showed that several of the chosen PROMs demonstrated change over time and a good association with functional outcomes. An alternative quality of life measure and method of collecting data on physical activity may need to be selected for assessing dysferlinopathy.

  View details for DOI 10.3389/fneur.2022.828525

  View details for PubMedID 35359643

• Correction to: Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy. Drug safety Day, J. W., Mendell, J. R., Mercuri, E., Finkel, R. S., Strauss, K. A., Kleyn, A., Tauscher-Wisniewski, S., Tukov, F. F., Reyna, S. P., Chand, D. H. 1800

  View details for DOI 10.1007/s40264-021-01130-7

  View details for PubMedID 34940960

• Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial LANCET NEUROLOGY Diaz-Manera, J., Kishnani, P. S., Kushlaf, H., Ladha, S., Mozaffar, T., Straub, V., Toscano, A., Van der Ploeg, A. T., Berger, K. I., Clemens, P. R., Chien, Y., Day, J. W., Illarioshkin, S., Roberts, M., Attarian, S., Borges, J., Bouhour, F., Choi, Y., Erdem-Ozdamar, S., Goker-Alpan, O., Kostera-Pruszczyk, A., Haack, K., Hug, C., Huynh-Ba, O., Johnson, J., Thibault, N., Zhou, T., Dimachkie, M. M., Schoser, B., The Comet 2021; 20 (12): 1012-1026

  View details for Web of Science ID 000755602800026

• Revised upper limb module in type II and III spinal muscular atrophy: 24-month changes. Neuromuscular disorders : NMD Coratti, G., Carmela Pera, M., Montes, J., Scoto, M., Pasternak, A., Bovis, F., Sframeli, M., D'Amico, A., Pane, M., Albamonte, E., Antonaci, L., Lia Frongia, A., Mizzoni, I., Sansone, V. A., Russo, M., Bruno, C., Baranello, G., Messina, S., Dunaway Young, S., Glanzman, A. M., Duong, T., de Sanctis, R., Stacy Mazzone, E., Milev, E., Rohwer, A., Civitello, M., Darras, B. T., Bertini, E., Day, J., Muntoni, F., De Vivo, D. C., Finkel, R. S., Mercuri, E. 1800

  Abstract

  The aim of the study was to establish 24-month changes in a large cohort of type II and III spinal muscular atrophy (SMA) patients assessed with the Revised Upper Limb Module (RULM), a tool specifically developed to assess upper limb function in SMA. We included 107 patients (54 type II and 53 type III) with at least 24-months follow up. The overall RULM 24-month changes showed a mean decline of -0.79 points. The difference between baseline and 24 months was significant in type II but not in type III patients. There was also a difference among functional subgroups but not in relation to age. Most patients had 24-month mean changes within 2 points, with 23% decreasing more than 2 points and 7% improving by >2 points. Our results suggest an overall progressive decline in upper limb function over 24 months. The negative changes were most notable in type II, in non-ambulant type III and with a different pattern of progression, also in non-sitter type II. In contrast, ambulant type III showed relative stability within the 24-month follow up. These findings will help in the interpretation of the real world data collected following the availability of new therapeutic approaches.

  View details for DOI 10.1016/j.nmd.2021.10.009

  View details for PubMedID 34980538

• Correction to: Reldesemtiv in Patients with Spinal Muscular Atrophy: a Phase 2 Hypothesis-Generating Study. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics Rudnicki, S. A., Andrews, J. A., Duong, T., Cockroft, B. M., Malik, F. I., Meng, L., Wei, J., Wolff, A. A., Genge, A., Johnson, N. E., Tesi-Rocha, C., Connolly, A. M., Darras, B. T., Felice, K., Finkel, R. S., Shieh, P. B., Mah, J. K., Statland, J., Campbell, C., Habib, A. A., Kuntz, N. L., Oskoui, M., Day, J. W. 2021

  View details for DOI 10.1007/s13311-021-01120-8

  View details for PubMedID 34731415

• Routine practices in use of onasemnogene abeparvovec (OA) in older patients with spinal muscular atrophy (SMA): Early findings from RESTORE Servais, L., De Vivo, D., Kirschner, J., Mercuri, E., Muntoni, F., Tizzano, E., Roy, S., Saito, K., Menier, M., LaMarca, N., Anderson, F., Dabbous, O., Finkel, R. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S138

  View details for DOI 10.1016/j.nmd.2021.07.314

  View details for Web of Science ID 000697873700299

• Real-world treatment patterns and outcomes in patients with spinal muscular atrophy (SMA): Updated findings from the RESTORE Registry Servais, L., Day, J., De Vivo, D., Mercuri, E., Muntoni, F., Shieh, P., Tizzano, E., Desguerre, I., Saito, K., Menier, M., LaMarca, N., Anderson, F., Dabbous, O., Finkel, R. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S138-S139

  View details for DOI 10.1016/j.nmd.2021.07.316

  View details for Web of Science ID 000697873700301

• Long-term follow-up (LTFU) of onasemnogene abeparvovec gene therapy in spinal muscular atrophy (SMA) Mendell, J., Finkel, R., Mercuri, E., Strauss, K., Day, J., Kleyn, A., Chand, D., Tauscher-Wisniewski, S., Meriggioli, M. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S132-S133

  View details for DOI 10.1016/j.nmd.2021.07.298

  View details for Web of Science ID 000697873700283

• Newborn screening (NBS) for spinal muscular atrophy (SMA) in the United States (US): Early findings from the RESTORE registry Servais, L., De Vivo, D., Kirschner, J., Mercuri, E., Muntoni, F., Tizzano, E., Roy, S., Saito, K., Menier, M., LaMarca, N., Anderson, F., Dabbous, O., Finkel, R. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S138

  View details for DOI 10.1016/j.nmd.2021.07.315

  View details for Web of Science ID 000697873700300

• IREFISH Parts 1 and 2: 24-month safety and efficacy of risdiplam in type 1 spinal muscular atrophy (SMA) Masson, R., Boespflug-Tanguy, O., Darras, B., Day, J., Deconinck, N., Klein, A., Mazurkiewicz-Beldzinska, M., Mercuri, E., Rose, K., Servais, L., Vlodavets, D., Xiong, H., Zanoteli, E., Dodman, A., El-Khairi, M., Gaki, E., Gerber, M., Gorni, K., Kletzl, H., Baranello, G. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S134

  View details for DOI 10.1016/j.nmd.2021.07.303

  View details for Web of Science ID 000697873700288

• SUNFISH Part 2: 24-month efficacy and safety of risdiplam in patients with Type 2 or non-ambulant Type 3 spinal muscular atrophy (SMA) Nascimento, A., Day, J., Deconinck, N., Mazzone, E., Oskoui, M., Saito, K., Vuillerot, C., Baranello, G., Boespflug-Tanguy, O., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Gerber, M., Gorni, K., Martin, C., Scalco, R., Staunton, H., Yeung, W., Mercuri, E. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S136

  View details for DOI 10.1016/j.nmd.2021.07.309

  View details for Web of Science ID 000697873700294

• Part A results from the ongoing DEVOTE study to explore higher-dose nusinersen in SMA Mercuri, E., Finkel, R., Day, J., Pascual, S., Ryan, M., De Vivo, D., Montes, J., Gurgel-Giannetti, J., Gambino, G., Nuzzo, R., Makepeace, C., Garafalo, S., Berger, Z. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S132

  View details for DOI 10.1016/j.nmd.2021.07.296

  View details for Web of Science ID 000697873700281

• Pooled safety data from the risdiplam clinical trial development program Baranello, G., Servais, L., Bertini, E., Chiriboga, C., Darras, B., Day, J., Deconinck, N., Fischer, D., Goemans, N., Kirschner, J., Klein, A., Masson, R., Mazurkiewicz-Beldzinska, M., Wang, Y., Bader-Weder, S., Gorni, K., Jaber, B., McIver, T., Scalco, R., Mercuri, E. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S135

  View details for DOI 10.1016/j.nmd.2021.07.305

  View details for Web of Science ID 000697873700290

• Scientific rationale for a higher dose of nusinersen Ryan, M., Finkel, R., Pascual, S., Day, J., Mercuri, E., De Vivo, D., Montes, J., Gurgel-Giannetti, J., MacCannell, D., Berger, Z. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S131

  View details for DOI 10.1016/j.nmd.2021.07.294

  View details for Web of Science ID 000697873700279

• The international spinal muscular atrophy registry (ISMAR): baseline characteristics Montes, J., Coratti, G., Scoto, M., Balashkin, J., Pera, M., Samsuddin, S., Martens, W., Bozzardi, A., Rodriguez, A., Civitello, M., Madden, M., Lings, B., Rohwer, A., Hall, S., Zolkipli, Z., Day, J., Darras, B., De Vivo, D., Muntoni, F., Finkel, R., Mercuri, E. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S126

  View details for DOI 10.1016/j.nmd.2021.07.278

  View details for Web of Science ID 000697873700262

• Apitegromab in SMA: an analysis of multiple endpoints and PD relationships to efficacy in the TOPAZ trial Crawford, T., Darras, B., Day, J., Nomikos, G., Song, G., Place, A., Barrett, D., Bilic, S., O'Neil, J., Kertesz, N., Cote, S., Patel, J., Chyung, Y. PERGAMON-ELSEVIER SCIENCE LTD. 2021

  View details for Web of Science ID 000697873700392

• Quality of life in dysferlinopathy can be good despite poor function Moore, U., James, M., Spuler, S., Day, J., Jones, K., Bharucha-Goebel, D., Salort-Campana, E., Pestronk, A., Walter, M., Paradas, C., Stojkovic, T., Yoshimura, M., Bravver, E., Pegoraro, E., Mendell, J., Bushby, K., Straub, V., Mayhew, A. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S104

  View details for DOI 10.1016/j.nmd.2021.07.207

  View details for Web of Science ID 000697873700191

• Disease progression in Charcot-Marie-Tooth disease related to MPZ mutations: A longitudinal study using rasch analysis-based weighted CMT examination Fridman, V., Sillau, S., Bockhorst, J., Smith, K., Moroni, I., Pagliano, E., Pisciotta, C., Piscosquito, G., laura, M., Muntoni, F., Bacha, A., Feely, S., Grider, T., Gutmann, L., Shy, R., Wilcox, J., Scherer, S., Herrmann, D., Li, J., Ramchandren, S., Sumner, C., Lloyd, T., Day, J., Siskind, C., Yum, S., Reza, S., Finkel, R., Reilly, M., Pareyson, D., Shy, M. WILEY. 2021: 374

  View details for Web of Science ID 000696233800152

• Different trajectories in upper limb and gross motor function in spinal muscular atrophy. Muscle & nerve Coratti, G., Pera, M. C., Montes, J., Pasternak, A., Scoto, M., Baranello, G., Messina, S., Dunaway Young, S., Glanzman, A. M., Duong, T., de Sanctis, R., Mazzone, E. S., Milev, E., Rohwer, A., Civitello, M., Pane, M., Antonaci, L., Frongia, A. L., Sframeli, M., Vita, G. L., D'Amico, A., Mizzoni, I., Albamonte, E., Darras, B. T., Bertini, E., Sansone, V. A., Bovis, F., Day, J., Bruno, C., Muntoni, F., De Vivo, D. C., Finkel, R., Mercuri, E. 2021

  Abstract

  Ref: Different trajectories in upper limb and gross motor function in spinal muscular atrophy INTRODUCTION: The Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM) have been widely used in natural history studies and clinical trials. Our aim was to establish how the scales relate to each other at different age points in spinal muscular atrophy (SMA) type 2 and 3, and to describe their coherence over 12 months.METHODS: The study was performed by cross-sectional and longitudinal reanalysis of previously published natural history data. The longitudinal analysis of the 12-month changes also included the analysis of concordance between scales with changes grouped as stable (+2 points), improved (>+2) or declined (>-2).RESULTS: Three hundred sixty-four patients were included in the cross-sectional analysis, showing different trends in score and point of slope change for the two scales. For type 2 the point of slope change was 4.1years for the HFMSE and 5.8 for the RULM, while for type 3 it was 6years for the HFMSE and 7.3 for the RULM. One-hundred-twenty-one patients had at least 2 assessments at 12-month. Full concordance was found in 57.3% of the assessments, and in 40.4% one scale remained stable and the other changed. Each scale appeared to be more sensitive to specific age or functional subgroups.DISCUSSION: The two scales, when used in combination, may increase the sensitivity to detect clinically meaningful changes in motor function in patients with SMA types 2 and 3.

  View details for DOI 10.1002/mus.27384

  View details for PubMedID 34327716

• Advances in the therapy of Spinal Muscular Atrophy. The Journal of pediatrics Klotz, J., Rocha, C. T., Young, S. D., Duong, T., Buu, M., Sampson, J., Day, J. W. 2021

  View details for DOI 10.1016/j.jpeds.2021.06.033

  View details for PubMedID 34197889

• Nusinersen in pediatric and adult patients with type III spinal muscular atrophy. Annals of clinical and translational neurology Pera, M. C., Coratti, G., Bovis, F., Pane, M., Pasternak, A., Montes, J., Sansone, V. A., Dunaway Young, S., Duong, T., Messina, S., Mizzoni, I., D'Amico, A., Civitello, M., Glanzman, A. M., Bruno, C., Salmin, F., Morando, S., De Sanctis, R., Sframeli, M., Antonaci, L., Frongia, A. L., Rohwer, A., Scoto, M., De Vivo, D. C., Darras, B. T., Day, J., Martens, W., Patanella, K. A., Bertini, E., Muntoni, F., Finkel, R., Mercuri, E., iSMAC group 2021

  Abstract

  OBJECTIVE: We report longitudinal data from 144 type III SMA pediatric and adult patients treated with nusinersen as part of an international effort.METHODS: Patients were assessed using Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and 6-Minute Walk Test (6MWT) with a mean follow-up of 1.83years after nusinersen treatment.RESULTS: Over 75% of the 144 patients had a 12-month follow-up. There was an increase in the mean scores from baseline to 12months on both HFMSE (1.18 points, p=0.004) and RULM scores (0.58 points, p=0.014) but not on the 6MWT (mean difference=6.65m, p=0.33). When the 12-month HFMSE changes in the treated cohort were compared to an external cohort of untreated patients, in all untreated patients older than 7years, the mean changes were always negative, while always positive in the treated ones. To reduce a selection bias, we also used a multivariable analysis. On the HFMSE scale, age, gender, baseline value, and functional status contributed significantly to the changes, while the number of SMN2 copies did not contribute. The effect of these variables was less obvious on the RULM and 6MWT.INTERPRETATION: Our results expand the available data on the effect of Nusinersen on type III patients, so far mostly limited to data from adult type III patients.

  View details for DOI 10.1002/acn3.51411

  View details for PubMedID 34165911

• Adeno-associated virus serotype 9 antibodies in patients screened for treatment with onasemnogene abeparvovec. Molecular therapy. Methods & clinical development Day, J. W., Finkel, R. S., Mercuri, E., Swoboda, K. J., Menier, M., van Olden, R., Tauscher-Wisniewski, S., Mendell, J. R. 2021; 21: 76–82

  Abstract

  Spinal muscular atrophy is a progressive, recessively inherited monogenic neurologic disease, the genetic root cause of which is the absence of a functional survival motor neuron 1 gene. Onasemnogene abeparvovec (formerly AVXS-101) is an adeno-associated virus serotype 9 vector-based gene therapy that delivers a fully functional copy of the human survival motor neuron gene. We report anti-adeno-associated virus serotype 9 antibody titers for patients with spinal muscular atrophy when they were screened for eligibility in the onasemnogene abeparvovec clinical trials (intravenous and intrathecal administration) and managed access programs (intravenous). Through December 31, 2019, 196 patients and 155 biologic mothers were screened for anti-adeno-associated virus serotype 9 binding antibodies with an enzyme-linked immunosorbent assay. Of these, 15 patients (7.7%) and 23 biologic mothers (14.8%) had titers >1:50 on their initial screening tests. Eleven patients (5.6%) had elevated titers on their final screening tests. The low percentage of patients with exclusionary antibody titers indicates that most infants with spinal muscular atrophy type 1 should be able to receive onasemnogene abeparvovec. Retesting may identify patients whose antibody titers later decrease to below the threshold for treatment, and retesting should be considered for patients with anti-adeno-associated virus serotype 9 antibody titers >1:50.

  View details for DOI 10.1016/j.omtm.2021.02.014

  View details for PubMedID 33768131

• Treatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study. The Lancet. Child & adolescent health Finkel, R. S., Chiriboga, C. A., Vajsar, J., Day, J. W., Montes, J., De Vivo, D. C., Bishop, K. M., Foster, R., Liu, Y., Ramirez-Schrempp, D., Schneider, E., Bennett, C. F., Wong, J., Farwell, W. 2021

  Abstract

  BACKGROUND: Nusinersen showed a favourable benefit-risk profile in participants with infantile-onset spinal muscular atrophy at the interim analysis of a phase 2 clinical study. We present the study's final analysis, assessing the efficacy and safety of nusinersen over 3 years.METHODS: This phase 2, open-label, multicentre, dose-escalation study was done in three university hospital sites in the USA and one in Canada. Infants aged between 3 weeks and 6 months with two or three SMN2 gene copies and infantile-onset spinal muscular atrophy were eligible for inclusion. Eligible participants received multiple intrathecal loading doses of 6 mg equivalent nusinersen (cohort 1) or 12 mg dose equivalent (cohort 2), followed by maintenance doses of 12 mg equivalent nusinersen. The protocol amendment on Jan 25, 2016, changed the primary efficacy endpoint from safety and tolerability to reaching motor milestones, assessed using the Hammersmith Infant Neurological Examination section 2 (HINE-2) at the last study visit, in all participants who successfully completed the loading dose period and day 92 assessment. The statistical analysis plan was amended on Feb 10, 2016, to include additional analyses of the subgroup of participants with two SMN2 copies. Adverse events were assessed in all participants who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov (NCT01839656).FINDINGS: Between May 3, 2013, and July 9, 2014, 20 symptomatic participants with infantile-onset spinal muscular atrophy (12 boys and 8 girls; median age at diagnosis 78 days [range 0-154]) were enrolled. Median time on study was 36·2 months (IQR 20·6-41·3). The primary endpoint of an incremental improvement in HINE-2 developmental motor milestones was reached by 12 (63%) of 19 evaluable participants. In the 13 participants with two SMN2 copies treated with 12 mg nusinersen, the HINE-2 motor milestone total score increased steadily from a baseline mean of 1·46 (SD 0·52) to 11·86 (6·18) at day 1135, representing a clinically significant change of 10·43 (6·05). At study closure (Aug 21, 2017), 15 (75%) of 20 participants were alive. 101 serious adverse events were reported in 16 (80%) of 20 participants; all five deaths (one in cohort 1 and four in cohort 2) were likely to be related to spinal muscular atrophy disease progression.INTERPRETATION: Our findings are consistent with other trials of nusinersen and show improved survival and attainment of motor milestones over 3 years in patients with infantile-onset spinal muscular atrophy, with a favourable safety profile.FUNDING: Biogen and Ionis Pharmaceuticals.

  View details for DOI 10.1016/S2352-4642(21)00100-0

  View details for PubMedID 34089650

• Pooled safety data from the risdiplam clinical trial development program Servais, L., Baranello, G., Bertini, E., Chiriboga, C., Darras, B. T., Day, J. W., Deconinck, N., Fischer, D., Goemans, N., Kirschner, J., Klein, A., Masson, R., Mazurkiewicz-Beldzinska, M., Wang, Y., Bader-Weder, S., Gorni, K., Jaber, B., McIver, T., Scalco, R. S., Mercuri, E., FIREFISH Study Grp, SUNFISH Study Grp, JEWELFISH Study Grp WILEY. 2021: 397-398

  View details for Web of Science ID 000663065900585

• Nusinersen Treatment in Adults With Spinal Muscular Atrophy. Neurology. Clinical practice Duong, T., Wolford, C., McDermott, M. P., Macpherson, C. E., Pasternak, A., Glanzman, A. M., Martens, W. B., Kichula, E., Darras, B. T., De Vivo, D. C., Zolkipli-Cunningham, Z., Finkel, R. S., Zeineh, M., Wintermark, M., Sampson, J., Hagerman, K. A., Young, S. D., Day, J. W. 2021; 11 (3): e317-e327

  Abstract

  Objective: To determine changes in motor and respiratory function after treatment with nusinersen in adults with spinal muscular atrophy (SMA) during the first two years of commercial availability in the USA.Methods: Data were collected prospectively on adult (age >17 years at treatment initiation) SMA participants in the Pediatric Neuromuscular Clinical Research (PNCR) Network. Baseline assessments of SMA outcomes including the Expanded Hammersmith Functional Rating Scale (HFMSE), Revised Upper Limb Module (RULM), and 6-Minute Walk Test (6MWT) occurred <5 months before treatment, and post-treatment assessments were made up to 24 months after nusinersen initation. Patient-reported experiences, safety laboratory tests and adverse events were monitored. The mean annual rate of change over time was determined for outcome measures using linear mixed effects models.Results: Forty-two adult SMA participants (mean age: 34 years, range 17-66) receiving nusinersen for a mean of 12.5 months (range 3-24 months) were assessed. Several motor and respiratory measures showed improvement distinct from the progressive decline typically seen in untreated adults. Participants also reported qualitative improvements including muscle strength, stamina, breathing and bulbar related outcomes. All participants tolerated nusinersen with normal surveillance labs and no significant adverse events.Conclusions: Trends of improvement emerged in functional motor, patient-reported, and respiratory measures, suggesting nusinersen may be efficacious in adults with SMA. Larger well-controlled studies and additional outcome measures are needed to firmly establish the efficacy of nusinersen in adults with SMA.Classification of Evidence: This study provides Class IV evidence regarding nusinersen tolerability and efficacy based on reported side effects and pulmonary and physical therapy assessments in an adult SMA cohort.

  View details for DOI 10.1212/CPJ.0000000000001033

  View details for PubMedID 34476123

• FIREFISH Parts 1 and 2: 24-Month Safety and Efficacy of Risdiplam in Type 1 SMA Masson, R., Boespflug-Tanguy, O., Darras, B. T., Day, J. W., Deconinck, N., Klein, A., Mazurkiewicz-Bedziska, M., Mercuri, E., Rose, K., Servais, L., Vlodavets, D., Xiong, H., Zanoteli, E., Dodman, A., El-Khairi, M., Gaki, E., Gerber, M., Gorni, K., Kletzl, H., Baranello, G., FIREFISH Working Grp WILEY. 2021: 395-396

  View details for Web of Science ID 000663065900582

• SUNFISH Part 2: 24-month efficacy and safety of risdiplam in patients with Type 2 or non-ambulant Type 3 SMA Nascimento, A., Day, J. W., Deconinck, N., Mazzone, E., Oskoui, M., Saito, K., Vuillerot, C., Baranello, G., Boespflug-Tanguy, O., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Gerber, M., Gorni, K., Kletzl, H., Martin, C., Scalco, R. S., Staunton, H., Yeung, W., Mercuri, E., SUNFISH Working Grp WILEY. 2021: 187-188

  View details for Web of Science ID 000663065900284

• Increased tissue stiffness triggers contractile dysfunction and telomere shortening in dystrophic cardiomyocytes. Stem cell reports Chang, A. C., Pardon, G., Chang, A. C., Wu, H., Ong, S., Eguchi, A., Ancel, S., Holbrook, C., Ramunas, J., Ribeiro, A. J., LaGory, E. L., Wang, H., Koleckar, K., Giaccia, A., Mack, D. L., Childers, M. K., Denning, C., Day, J. W., Wu, J. C., Pruitt, B. L., Blau, H. M. 2021

  Abstract

  Duchenne muscular dystrophy (DMD) is a rare X-linked recessive disease that is associated with severe progressive muscle degeneration culminating in death due to cardiorespiratory failure. We previously observed an unexpected proliferation-independent telomere shortening in cardiomyocytes of a DMD mouse model. Here, we provide mechanistic insights using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Using traction force microscopy, we show that DMD hiPSC-CMs exhibit deficits in force generation on fibrotic-like bioengineered hydrogels, aberrant calcium handling, and increased reactive oxygen species levels. Furthermore, we observed a progressive post-mitotic telomere shortening in DMD hiPSC-CMs coincident with downregulation of shelterin complex, telomere capping proteins, and activation of the p53 DNA damage response. This telomere shortening is blocked by blebbistatin, which inhibits contraction in DMD cardiomyocytes. Our studies underscore the role of fibrotic stiffening in the etiology of DMD cardiomyopathy. In addition, our data indicate that telomere shortening is progressive, contraction dependent, and mechanosensitive, and suggest points of therapeutic intervention.

  View details for DOI 10.1016/j.stemcr.2021.04.018

  View details for PubMedID 34019816

• SUNFISH Part 2: 24-month Efficacy and Safety of Risdiplam in Patients with Type 2 or Non-ambulant Type 3 Spinal Muscular Atrophy (SMA) Oskoui, M., Day, J. W., Deconinck, N., Mazzone, E., Nascimento, A., Saito, K., Vuillerot, C., Baranello, G., Bloespflug-Tanguy, O., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Gerber, M., Gorni, K., Kletzl, H., Martin, C., Scalco, R. S., Staunton, H., Yeung, W., Mercuri, E. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for Web of Science ID 000729283602038

• Pooled Safety Data from the Risdiplam Clinical Trial Development Program Servais, L., Baranello, G., Bertini, E., Chiriboga, C., Darras, B. T., Day, J. W., Deconinck, N., Fischer, D., Goemans, N., Kirschner, J., Klein, A., Masson, R., Mazurkiewicz-Beldzinska, M., Wang, Y., Bader-Weder, S., Gorni, K., Jaber, B., McIver, T., Scalco, R. S., Mercuri, E. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for Web of Science ID 000729283604033

• Long-Term Follow-Up (LTFU) of Onasemnogene Abeparvovec Gene Therapy in Spinal Muscular Atrophy (SMA) Mendell, J., Finkel, R., Mercuri, E., Strauss, K., Day, J., Kleyn, A., Chand, D., Tauscher-Wisniewski, S., Meriggioli, M. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for Web of Science ID 000729283602081

• Efficacy and Safety Results of the Avalglucosidase alfa Phase 3 COMET Trial in Late-Onset Pompe Disease Patients Kushlaf, H., Attarian, S., Borges, J., Bouhour, F., Chien, Y., Choi, Y., Clemens, P., Day, J., Diaz-Manera, J., Erdem-Ozdamar, S., Goker-Alpan, O., Illarioshkin, S., Kishnani, P., Kostera-Pruszczyk, A., Ladha, S., Mozaffar, T., Roberts, M., Straub, V., Toscano, A., van der Ploeg, A., Haack, K., Hug, C., Huynh-Ba, O., Zhou, T., Johnson, J., Dimachkie, M., Schoser, B. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for Web of Science ID 000729283604042

• Escalating Dose and Randomized, Controlled Study of Nusinersen in Participants With Spinal Muscular Atrophy (SMA); Study Design and Part A Data for the Phase 2/3 DEVOTE (232SM203) Study to Explore High Dose Nusinersen Day, J. W., Pascual, S., Finkel, R. S., Ryan, M. M., Mercuri, E., De Vivo, D. C., Montes, J., Gurgel-Giannetti, J., Gambino, G., Nuzzo, R., Makepeace, C., Berger, Z. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for Web of Science ID 000729283602113

• Results of Double-blind, Placebo-controlled, Dose Range Finding, Crossover Study of Single Day Administration of ERX-963 (IV Flumazenil) in Adults with Myotonic Dystrophy Type 1 Sampson, J., Wang, E., Day, J., Gutmann, L., Mezerhane, E., Seto, A., Ehrich, E. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for Web of Science ID 000729283603135

• A phase I/II open-label gene replacement clinical study for late onset Pompe disease Mozaffar, T., Day, J., Foo, C., Bachtell, N., Conner, E. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for Web of Science ID 000729283604190

• Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. The Lancet. Neurology Day, J. W., Finkel, R. S., Chiriboga, C. A., Connolly, A. M., Crawford, T. O., Darras, B. T., Iannaccone, S. T., Kuntz, N. L., Pena, L. D., Shieh, P. B., Smith, E. C., Kwon, J. M., Zaidman, C. M., Schultz, M., Feltner, D. E., Tauscher-Wisniewski, S., Ouyang, H., Chand, D. H., Sproule, D. M., Macek, T. A., Mendell, J. R. 2021; 20 (4): 284–93

  Abstract

  BACKGROUND: Spinal muscular atrophy type 1 is a motor neuron disorder resulting in death or the need for permanent ventilation by age 2 years. We aimed to evaluate the safety and efficacy of onasemnogene abeparvovec (previously known as AVXS-101), a gene therapy delivering the survival motor neuron gene (SMN), in symptomatic patients (identified through clinical examination) with infantile-onset spinal muscular atrophy.METHODS: STR1VE was an open-label, single-arm, single-dose, phase 3 trial done at 12 hospitals and universities in the USA. Eligible patients had to be younger than 6 months and have spinal muscular atrophy with biallelic SMN1 mutations (deletion or point mutations) and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 * 1014 vector genomes per kg) for 30-60 min. During the outpatient follow-up, patients were assessed once per week, beginning at day 7 post-infusion for 4 weeks and then once per month until the end of the study (age 18 months or early termination). Coprimary efficacy outcomes were independent sitting for 30 s or longer (Bayley-III item 26) at the 18 month of age study visit and survival (absence of death or permanent ventilation) at age 14 months. Safety was assessed through evaluation of adverse events, concomitant medication usage, physical examinations, vital sign assessments, cardiac assessments, and laboratory evaluation. Primary efficacy endpoints for the intention-to-treat population were compared with untreated infants aged 6 months or younger (n=23) with spinal muscular atrophy type 1 (biallelic deletion of SMN1 and two copies of SMN2) from the Pediatric Neuromuscular Clinical Research (PNCR) dataset. This trial is registered with ClinicalTrials.gov, NCT03306277 (completed).FINDINGS: From Oct 24, 2017, to Nov 12, 2019, 22 patients with spinal muscular atrophy type 1 were eligible and received onasemnogene abeparvovec. 13 (59%, 97·5% CI 36-100) of 22 patients achieved functional independent sitting for 30 s or longer at the 18 month of age study visit (vs 0 of 23 patients in the untreated PNCR cohort; p<0·0001). 20 patients (91%, 79-100]) survived free from permanent ventilation at age 14 months (vs 6 [26%], 8-44; p<0·0001 in the untreated PNCR cohort). All patients who received onasemnogene abeparvovec had at least one adverse event (most common was pyrexia). The most frequently reported serious adverse events were bronchiolitis, pneumonia, respiratory distress, and respiratory syncytial virus bronchiolitis. Three serious adverse events were related or possibly related to the treatment (two patients had elevated hepatic aminotransferases, and one had hydrocephalus).INTERPRETATION: Results from this multicentre trial build on findings from the phase 1 START study by showing safety and efficacy of commercial grade onasemnogene abeparvovec. Onasemnogene abeparvovec showed statistical superiority and clinically meaningful responses when compared with observations from the PNCR natural history cohort. The favourable benefit-risk profile shown in this study supports the use of onasemnogene abeparvovec for treatment of symptomatic patients with genetic or clinical characteristics predictive of infantile-onset spinal muscular atrophy type 1.FUNDING: Novartis Gene Therapies.

  View details for DOI 10.1016/S1474-4422(21)00001-6

  View details for PubMedID 33743238

• Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial LANCET NEUROLOGY Day, J. W., Finkel, R. S., Chiriboga, C. A., Connolly, A. M., Crawford, T. O., Darras, B. T., Iannaccone, S. T., Kuntz, N. L., Pena, L. M., Shieh, P. B., Smith, E. C., Kwon, J. M., Zaidman, C. M., Schultz, M., Feltner, D. E., Tauscher-Wisniewski, S., Ouyang, H., Chand, D. H., Sproule, D. M., Macek, T. A., Mendell, J. R. 2021; 20 (4): 284–93

  View details for Web of Science ID 000630325700019

• Exome testing most useful for people with recessive CMT Siskind, C., Sampson, J., Goyal, N., Rocha, A., Day, J. WILEY. 2021: 141–42

  View details for Web of Science ID 000626893200065

• Efficacy and safety results of the avalglucosidase alfa phase 3 COMET trial in late-onset Pompe disease patients Kishnani, P. S., Attarian, S., Borges, J., Bouhourd, F., Chien, Y., Choi, Y., Clemens, P., Day, J., Diaz-Manera, J., Erdem-Ozdamar, S., Goker-Alpan, O., Illarioshkin, S., Kostera-Pruszczyk, A., Kushlaf, H., Ladha, S., Mozaffar, T., Roberts, M., Straub, V., Toscano, A., van der Ploeg, A., Haack, K., Huynh-Ba, O., Zhou, T., Dimachkie, M., Schoser, B. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2021: S57

  View details for DOI 10.1016/j.ymgme.2020.12.127

  View details for Web of Science ID 000614651500123

• ONASEMNOGENE ABEPARVOVEC GENE THERAPY FOR SPINAL MUSCULAR ATROPHY TYPE 1: PHASE 3 STUDY (STR1VE-US) Day, J. W., Finkel, R. S., Connolly, A. M., Darras, B. T., Iannaccone, S. T., Kuntz, N. L., Pena, L. M., Smith, E. C., Chiriboga, C. A., Crawford, T. O., Shieh, P. B., Kwon, J. M., Zaidman, C. M., Schultz, M., Kausar, I., Chand, D., Tauscher-Wisniewski, S., Ouyang, H., Macek, T. A., Mendell, J. R. BMJ PUBLISHING GROUP. 2021: A10-A11

  View details for DOI 10.1136/thorax-2020-BTSabstracts.18

  View details for Web of Science ID 000721357200015

• A phase I/II open-label gene replacement clinical study for late onset Pompe disease Day, J. W., Mozaffar, T., Foo, C., Bachtell, N., Conner, E. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2021: S32

  View details for DOI 10.1016/j.ymgme.2020.12.059

  View details for Web of Science ID 000614651500055

• Miyoshi myopathy and limb girdle muscular dystrophy R2 are the same disease. Neuromuscular disorders : NMD Moore, U., Gordish, H., Diaz-Manera, J., James, M. K., Mayhew, A. G., Guglieri, M., Fernandez-Torron, R., Rufibach, L. E., Feng, J., Blamire, A. M., Carlier, P. G., Spuler, S., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Pestronk, A., Walter, M. C., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Pegoraro, E., Lowes, L. P., Mendell, J. R., Bushby, K., Straub, V., Jain COS Consortium 2021

  Abstract

  This study aims to determine clinically relevant phenotypic differences between the two most common phenotypic classifications in dysferlinopathy, limb girdle muscular dystrophy R2 (LGMDR2) and Miyoshi myopathy (MMD1). LGMDR2 and MMD1 are reported to involve different muscles, with LGMDR2 showing predominant limb girdle weakness and MMD1 showing predominant distal lower limb weakness. We used heatmaps, regression analysis and principle component analysis of functional and Magnetic Resonance Imaging data to perform a cross-sectional review of the pattern of muscle involvement in 168 patients from the Jain Foundation's international Clinical Outcomes Study for Dysferlinopathy. We demonstrated that there is no clinically relevant difference in proximal vs distal involvement between diagnosis. There is a continuum of distal involvement at any given degree of proximal involvement and patients do not fall into discrete distally or proximally affected groups. There appeared to be geographical preference for a particular diagnosis, with MMD1 being more common in Japan and LGMDR2 in Europe and the USA. We conclude that the dysferlinopathies do not form two distinct phenotypic groups and therefore should not be split into separate cohorts of LGMDR2 and MM for the purposes of clinical management, enrolment in clinical trials or access to subsequent treatments.

  View details for DOI 10.1016/j.nmd.2021.01.009

  View details for PubMedID 33610434

• Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study. Brain : a journal of neurology Pipis, M., Feely, S. M., Polke, J. M., Skorupinska, M., Perez, L., Shy, R. R., Laura, M., Morrow, J. M., Moroni, I., Pisciotta, C., Taroni, F., Vujovic, D., Lloyd, T. E., Acsadi, G., Yum, S. W., Lewis, R. A., Finkel, R. S., Herrmann, D. N., Day, J. W., Li, J., Saporta, M., Sadjadi, R., Walk, D., Burns, J., Muntoni, F., Ramchandren, S., Horvath, R., Johnson, N. E., Zuchner, S., Pareyson, D., Scherer, S. S., Rossor, A. M., Shy, M. E., Reilly, M. M., Inherited Neuropathies Consortium - Rare Disease Clinical Research Network (INC-RDCRN) 2021

  Abstract

  Mitofusin-2 (MFN2) is one of two ubiquitously expressed homologous proteins in eukaryote cells, playing a critical role in mitochondrial fusion. Mutations in MFN2 (most commonly autosomal dominant) cause Charcot-Marie-Tooth disease type 2A (CMT2A), the commonest axonal form of CMT, with significant allelic heterogeneity. Previous, moderately-sized, cross sectional genotype-phenotype studies of CMT2A have described the phenotypic spectrum of the disease, but longitudinal natural history studies are lacking. In this large multicentre prospective cohort study of 196 patients with dominant and autosomal recessive CMT2A, we present an in-depth genotype-phenotype study of the baseline characteristics of patients with CMT2A and longitudinal data (1-2 years) to describe the natural history. A childhood onset of autosomal dominant CMT2A is the most predictive marker of significant disease severity and is independent of the disease duration. When compared to adult onset autosomal dominant CMT2A, it is associated with significantly higher rates of use of ankle-foot orthoses, full-time use of wheelchair, dexterity difficulties and also has significantly higher CMT Examination Score (CMTESv2) and CMT Neuropathy Score (CMTNSv2) at initial assessment. Analysis of longitudinal data using the CMTESv2 and its Rasch-weighted counterpart, CMTESv2-R, show that over 1 year, the CMTESv2 increases significantly in autosomal dominant CMT2A (mean change 0.84±2.42; two-tailed paired t-test P=0.039). Furthermore, over 2 years both the CMTESv2 (mean change 0.97±1.77; two-tailed paired t-test P=0.003) and the CMTESv2-R (mean change 1.21±2.52; two-tailed paired t-test P=0.009) increase significantly with respective standardized response means of 0.55 and 0.48. In the paediatric CMT2A population (autosomal dominant and autosomal recessive CMT2A grouped together), the CMT Pediatric Scale increases significantly both over 1 year (mean change 2.24±3.09; two-tailed paired t-test P=0.009) and over 2 years (mean change 4.00±3.79; two-tailed paired t-test P=0.031) with respective standardized response means of 0.72 and 1.06. This cross-sectional and longitudinal study of the largest CMT2A cohort reported to date provides guidance for variant interpretation, informs prognosis and also provides natural history data that will guide clinical trial design.

  View details for DOI 10.1093/brain/awaa323

  View details for PubMedID 33415332

• Transcriptome alterations in myotonic dystrophy frontal cortex. Cell reports Otero, B. A., Poukalov, K. n., Hildebrandt, R. P., Thornton, C. A., Jinnai, K. n., Fujimura, H. n., Kimura, T. n., Hagerman, K. A., Sampson, J. B., Day, J. W., Wang, E. T. 2021; 34 (3): 108634

  Abstract

  Myotonic dystrophy (DM) is caused by expanded CTG/CCTG repeats, causing symptoms in skeletal muscle, heart, and central nervous system (CNS). CNS issues are debilitating and include hypersomnolence, executive dysfunction, white matter atrophy, and neurofibrillary tangles. Here, we generate RNA-seq transcriptomes from DM and unaffected frontal cortex and identify 130 high-confidence splicing changes, most occurring only in cortex, not skeletal muscle or heart. Mis-spliced exons occur in neurotransmitter receptors, ion channels, and synaptic scaffolds, and GRIP1 mis-splicing modulates kinesin association. Optical mapping of expanded CTG repeats reveals extreme mosaicism, with some alleles showing >1,000 CTGs. Mis-splicing severity correlates with CTG repeat length across individuals. Upregulated genes tend to be microglial and endothelial, suggesting neuroinflammation, and downregulated genes tend to be neuronal. Many gene expression changes strongly correlate with mis-splicing, suggesting candidate biomarkers of disease. These findings provide a framework for mechanistic and therapeutic studies of the DM CNS.

  View details for DOI 10.1016/j.celrep.2020.108634

  View details for PubMedID 33472074

• Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial. The Lancet. Neurology Diaz-Manera, J., Kishnani, P. S., Kushlaf, H., Ladha, S., Mozaffar, T., Straub, V., Toscano, A., van der Ploeg, A. T., Berger, K. I., Clemens, P. R., Chien, Y. H., Day, J. W., Illarioshkin, S., Roberts, M., Attarian, S., Borges, J. L., Bouhour, F., Choi, Y. C., Erdem-Ozdamar, S., Goker-Alpan, O., Kostera-Pruszczyk, A., Haack, K. A., Hug, C., Huynh-Ba, O., Johnson, J., Thibault, N., Zhou, T., Dimachkie, M. M., Schoser, B. 2021; 20 (12): 1012-1026

  Abstract

  Pompe disease is a rare, progressive neuromuscular disorder caused by deficiency of acid α-glucosidase (GAA) and accumulation of lysosomal glycogen. We assessed the safety and efficacy of avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy specifically designed for enhanced mannose-6-phosphate-receptor targeting and enzyme uptake aimed at increased glycogen clearance, compared with the current approved standard of care, alglucosidase alfa, in patients with late-onset Pompe disease.We did a randomised, double-blind, phase 3 trial at 55 sites in 20 countries. We enrolled individuals (aged ≥3 years) with enzymatically confirmed late-onset Pompe disease who had never received treatment. We used a centralised treatment allocation system to randomly allocate participants to either avalglucosidase alfa or alglucosidase alfa. Participants and investigators were unaware of their treatment allocation. The primary outcome measure was change from baseline to week 49 in upright forced vital capacity percent (FVC%) predicted. We used a hierarchical fixed sequential testing strategy, whereby non-inferiority of avalglucosidase alfa compared with alglucosidase alfa was assessed first, with a non-inferiority margin of 1·1. If non-inferiority was seen, then superiority was tested with a 5% significance level. The key secondary objective was effect on functional endurance, measured by the 6-minute walk test (6MWT). Safety was assessed, including treatment-emergent adverse events and infusion-associated reactions. The modified intent-to-treat population was the primary analysis population for all efficacy analyses. The safety population was the analysis population for safety analyses. This trial is registered with ClinicalTrials.gov, NCT02782741. We report results of the 49-week primary analysis period.Between Nov 2, 2016, and March 29, 2019, 100 participants were randomly allocated avalglucosidase alfa (n=51) or alglucosidase alfa (n=49). Treatment with avalglucosidase alfa resulted in a least-squares mean improvement in upright FVC% predicted of 2·89% (SE 0·88) compared with 0·46% (0·93) with alglucosidase alfa at week 49 (difference 2·43% [95% CI -0·13 to 4·99]). Non-inferiority was shown because the lower bound of the 95% CI for the difference far exceeded the predefined non-inferiority margin but did not exclude 0 (p=0·0074). Superiority was not reached (p=0·063), so formal testing was stopped, as per the testing hierarchy. Improvements were also seen in the 6MWT with avalglucosidase alfa compared with alglucosidase alfa, with greater increases in distance covered (difference 30·01 m [95% CI 1·33 to 58·69]) and percent predicted (4·71% [0·25 to 9·17]). Treatment-emergent adverse events potentially related to treatment were reported in 23 (45%) of 51 participants in the avalglucosidase alfa group and in 24 (49%) of 49 in the alglucosidase alfa group, and infusion-associated reactions were reported in 13 (26%) participants in the avalglucosidase alfa group and 16 (33%) in the alglucosidase alfa group. Of the five trial withdrawals, all in the alglucosidase alfa group, four were due to adverse events, including two infusion-associated reactions. Serious treatment-emergent adverse events were reported in eight (16%) participants who received avalglucosidase alfa and in 12 (25%) who received alglucosidase alfa. One participant treated with alglucosidase alfa died because of acute myocardial infarction determined to be unrelated to treatment. Antidrug antibody responses were similar in both groups. High and persistent titres (≥12 800) and neutralising antibodies were more common with alglucosidase alfa (in 16 [33%] participants) than with avalglucosidase alfa (ten [20%]).We consider that this study provides evidence of clinically meaningful improvement with avalglucosidase alfa therapy over alglucosidase alfa in respiratory function, ambulation, and functional endurance, with no new safety signals reported. An open-label extended-treatment period is ongoing to confirm the long-term safety and efficacy of avalglucosidase alfa, with the aim for this therapy to become the new standard treatment in late-onset Pompe disease.Sanofi Genzyme.

  View details for DOI 10.1016/S1474-4422(21)00241-6

  View details for PubMedID 34800399

• Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy. Drug safety Day, J. W., Mendell, J. R., Mercuri, E., Finkel, R. S., Strauss, K. A., Kleyn, A., Tauscher-Wisniewski, S., Tukov, F. F., Reyna, S. P., Chand, D. H. 2021

  Abstract

  This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy.We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data.Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials, n = 102 patients; postmarketing surveillance, n = 665 reported adverse event [AE] cases). In clinical trials, safety was assessed through AE monitoring, vital-sign and cardiac assessments, laboratory evaluations, physical examinations, and concomitant medication use. AE reporting and available objective clinical data from postmarketing programs were evaluated.The main target organs of toxicity in mice were the heart and liver. Dorsal root ganglia (DRG) inflammation was observed in NHPs. Patients exhibited no evidence of sensory neuropathy upon clinical examination. In clinical trials, 101/102 patients experienced at least one treatment-emergent AE. In total, 50 patients experienced serious AEs, including 11 considered treatment related. AEs consistent with hepatotoxicity resolved with prednisolone in clinical trials. Transient decreases in mean platelet count were detected but were without bleeding complications. Thrombotic microangiopathy (TMA) was observed in the postmarketing setting. No evidence of intracardiac thrombi was observed for NHPs or patients.Risks associated with onasemnogene abeparvovec can be anticipated, monitored, and managed. Hepatotoxicity events resolved with prednisolone. Thrombocytopenia was transient. TMA may require medical intervention. Important potential risks include cardiac AEs and DRG toxicity.

  View details for DOI 10.1007/s40264-021-01107-6

  View details for PubMedID 34383289

• Age related treatment effect in type II Spinal Muscular Atrophy pediatric patients treated with nusinersen. Neuromuscular disorders : NMD Coratti, G., Pane, M., Lucibello, S., Pera, M. C., Pasternak, A., Montes, J., Sansone, V. A., Duong, T., Dunaway Young, S., Messina, S., D'Amico, A., Civitello, M., Glanzman, A. M., Bruno, C., Salmin, F., Tacchetti, P., Carnicella, S., Sframeli, M., Antonaci, L., Frongia, A. L., De Vivo, D. C., Darras, B. T., Day, J., Bertini, E., Muntoni, F., Finkel, R., Mercuri, E. 2021

  Abstract

  Previous natural history studies suggest that type II SMA patients remain stable over one year but show some progression over two years. Since nusinersen approval, there has been increasing attention to identify more specific age-related changes. The aim of the study was to establish 12-month changes in a cohort of pediatric type II SMA treated with nusinersen and to establish possible patterns of treatment effect in relation to different variables such as age, baseline value and SMN2 copy number. The Hammersmith Functional Motor Scale Expanded and the Revised Upper Limb Module were performed at T0 and 12 months after treatment (T12). Data in treated patients were compared to available data in untreated patients collected by the same evaluators.Seventy-seven patients of age between 2.64 and 17.88 years (mean:7.47, SD:3.79) were included. On t-test there was an improvement, with increased mean scores between T0 and T12 on both scales (p < 0.001). Using multivariate linear regression analysis, age and baseline scores were predictive of changes on both scales (p < 0.05) while SMN2 copy number was not. Differences were also found between study cohort and untreated data on both scales (p < 0.001). At 12 months, an increase in scores was observed in all the age subgroups at variance with natural history data. Our real-world data confirm the treatment effect of nusinersen in pediatric type II SMA patients and that the data interpretation should take into account different variables. These data confirm and expand the ones already reported in the Cherish study.

  View details for DOI 10.1016/j.nmd.2021.03.012

  View details for PubMedID 34099377

• Toward Developing Robust Myotonic Dystrophy Brain Biomarkers using White Matter Tract Profiles Sub-Band Energy and A Framework of Ensemble Predictive Learning. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference Kamali, T., Parker, D., Day, J. W., Sampson, J., Deutsch, G. K., Wozniak, J. R. 2021; 2021: 3838-3841

  Abstract

  The myotonic dystrophies (DM1 and DM2) are dominantly inherited disorders that cause pathological changes throughout the body and the brain. DM patients have difficulties with memory, attention, executive functioning, social cognition, and visuospatial function. Quantifying and understanding diffusion measures along main brain white matter fiber tracts offer a unique opportunity to reveal new insights into DM development and characterization. In this work, a novel supervised system is proposed, which is based on Tract Profiles sub-band energy information. The proposed system utilizes a Bayesian stacked random forest to diagnose, characterize, and predict DM clinical outcomes. The evaluation data consists of fractional anisotropies calculated for twelve major white matter tracts of 96 healthy controls and 62 DM patients. The proposed system discriminates DM vs. control with 86% accuracy, which is significantly higher than previous works. Additionally, it discovered DM brain biomarkers that are accurate and robust and will be helpful in planning clinical trials and monitoring clinical performance.

  View details for DOI 10.1109/EMBC46164.2021.9630544

  View details for PubMedID 34892071

• Reldesemtiv in Patients with Spinal Muscular Atrophy: a Phase 2 Hypothesis-Generating Study. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics Rudnicki, S. A., Andrews, J. A., Duong, T. n., Cockroft, B. M., Malik, F. I., Meng, L. n., Wei, J. n., Wolff, A. A., Genge, A. n., Johnson, N. E., Tesi-Rocha, C. n., Connolly, A. M., Darras, B. T., Felice, K. n., Shieh, P. B., Mah, J. K., Statland, J. n., Campbell, C. n., Habib, A. A., Kuntz, N. L., Oskoui, M. n., Day, J. W. 2021

  Abstract

  This phase 2, double-blind, placebo-controlled, hypothesis-generating study evaluated the effects of oral reldesemtiv, a fast skeletal muscle troponin activator, in patients with spinal muscular atrophy (SMA). Patients ≥ 12 years of age with type II, III, or IV SMA were randomized into 2 sequential, ascending reldesemtiv dosing cohorts (cohort 1: 150 mg bid or placebo [2:1]; cohort 2: 450 mg bid or placebo [2:1]). The primary objective was to determine potential pharmacodynamic effects of reldesemtiv on 8 outcome measures in SMA, including 6-minute walk distance (6MWD) and maximum expiratory pressure (MEP). Changes from baseline to weeks 4 and 8 were determined. Pharmacokinetics and safety were also evaluated. Patients were randomized to reldesemtiv 150 mg, 450 mg, or placebo (24, 20, and 26, respectively). The change from baseline in 6MWD was greater for reldesemtiv 450 mg than for placebo at weeks 4 and 8 (least squares [LS] mean difference, 35.6 m [p = 0.0037] and 24.9 m [p = 0.058], respectively). Changes from baseline in MEP at week 8 on reldesemtiv 150 and 450 mg were significantly greater than those on placebo (LS mean differences, 11.7 [p = 0.038] and 13.2 cm H2O [p = 0.03], respectively). For 6MWD and MEP, significant changes from placebo were seen in the highest reldesemtiv peak plasma concentration quartile (Cmax > 3.29 μg/mL; LS mean differences, 43.3 m [p = 0.010] and 28.8 cm H2O [p = 0.0002], respectively). Both dose levels of reldesemtiv were well tolerated. Results suggest reldesemtiv may offer clinical benefit and support evaluation in larger SMA patient populations.

  View details for DOI 10.1007/s13311-020-01004-3

  View details for PubMedID 33624184

• Risdiplam in Type 1 Spinal Muscular Atrophy. The New England journal of medicine Baranello, G. n., Darras, B. T., Day, J. W., Deconinck, N. n., Klein, A. n., Masson, R. n., Mercuri, E. n., Rose, K. n., El-Khairi, M. n., Gerber, M. n., Gorni, K. n., Khwaja, O. n., Kletzl, H. n., Scalco, R. S., Seabrook, T. n., Fontoura, P. n., Servais, L. n. 2021

  Abstract

  Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein.We report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds.A total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study.In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.).

  View details for DOI 10.1056/NEJMoa2009965

  View details for PubMedID 33626251

• Assessing Dysferlinopathy Patients Over Three Years With A New Motor Scale. Annals of neurology Jacobs, M. n., James, M. K., Lowes, L. P., Alfano, L. N., Eagle, M. n., Lofra, R. M., Moore, U. n., Feng, J. n., Rufibach, L. E., Rose, K. n., Duong, T. n., Bello, L. n., Pedrosa-Hernández, I. n., Holsten, S. n., Sakamoto, C. n., Canal, A. n., Práxedes, N. S., Thiele, S. n., Siener, C. n., Vandevelde, B. n., DeWolf, B. n., Maron, E. n., Guglieri, M. n., Hogrel, J. Y., Blamire, A. M., Carlier, P. G., Spuler, S. n., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E. n., Pestronk, A. n., Walter, M. C., Paradas, C. n., Stojkovic, T. n., Mori-Yoshimura, M. n., Bravver, E. n., Díaz-Manera, J. n., Pegoraro, E. n., Mendell, J. R., Mayhew, A. G., Straub, V. n. 2021

  Abstract

  Dysferlinopathy is a muscular dystrophy with a highly variable clinical presentation and currently unpredictable progression. This variability and unpredictability presents difficulties for prognostication and clinical trial design. The Jain Clinical Outcomes Study of Dysferlinopathy aims to establish the validity of the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) scale and identify factors that influence the rate of disease progression using NSAD.We collected a longitudinal series of functional assessments from 187 dysferlinopathy patients over three years. Rasch analysis was used to develop the NSAD, a motor performance scale suitable for ambulant and non-ambulant patients. Generalized estimating equations were used to evaluate the impact of patient factors on outcome trajectories.The NSAD detected significant change in clinical progression over 1 year. The steepest functional decline occurred during the first 10 years after symptom onset, with more rapid decline noted in patients who developed symptoms at a younger age (p = 0.04). The most rapidly deteriorating group over the study was patients 3-8 years post symptom onset at baseline.The NSAD is the first validated limb girdle specific scale of motor performance, suitable for use in clinics practice and clinical trials. Longitudinal analysis showed it may be possible to identify patient factors associated with greater functional decline both across the disease course and in the short-term for clinical trial preparation. Through further work and validation in this cohort, we anticipate that a disease model incorporating functional performance will allow for more accurate prognosis for patients with dysferlinopathy. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ana.26044

  View details for PubMedID 33576057

• Author Correction: Humanizing the mdx mouse model of DMD: the long and the short of it. NPJ Regenerative medicine Yucel, N., Chang, A. C., Day, J. W., Rosenthal, N., Blau, H. M. 2020; 5 (1): 25

  View details for DOI 10.1038/s41536-020-00112-0

  View details for PubMedID 33349636

• Deep phenotypic dissection and natural history of a large multicentre CMT2A cohort Pipis, M., Feely, S., Skorupinska, M., Polke, J., Quiros, L., Laura, M., Moroni, I., Pisciotta, C., Vujovic, D., Lloyd, T., Acsadi, G., Yum, S., Lewis, R., Finkel, R., Herrmann, D., Day, J., Li, J., Saporta, M., Sadjadi, R., Walk, D., Burns, J., Ramchandren, S., Horvath, R., Johnson, N., Zuchner, S., Pareyson, D., Scherer, S., Rossor, A., Shy, M., Reilly, M. WILEY. 2020: 559

  View details for Web of Science ID 000596008100279

• Development and Validation of the Pediatric CMT Quality of Life Outcome Measure. Annals of neurology Ramchandren, S., Wu, T. T., Finkel, R. S., Siskind, C. E., Feely, S. M., Burns, J., Reilly, M. M., Estilow, T., Shy, M. E., Childhood CMT Study Group, Bacon, C. J., Shy, R. R., Cornett, K., Muntoni, F., Day, J. W., Lloyd, T., Sumner, C. J., Herrmann, D. N., Kirk, C., Yum, S. W. 2020

  Abstract

  OBJECTIVE: Charcot-Marie-Tooth disease (CMT) reduces health-related quality of life (QOL), especially in children. Defining QOL in pediatric CMT can help physicians monitor disease burden clinically and in trials. We identified items pertaining to QOL in children with CMT and conducted validation studies to develop a pediatric CMT-specific QOL outcome measure (pCMT-QOL).METHODS: Development and validation of the pCMT-QOL patient-reported outcome measure was iterative, involving identifying relevant domains, item pool generation, prospective pilot testing and clinical assessments, structured focus-group interviews, and psychometric testing. Testing was conducted in children with CMT seen at participating sites from the USA, United Kingdom, and Australia.RESULTS: We conducted systematic literature reviews and analysis of generic QOL measures to identify six domains relevant to QOL in children with CMT. 60 items corresponding to those domains were developed de novo, or identified from literature review and CMT-specific modification of items from the pediatric Neuro-QOL measures. The draft version underwent prospective feasibility and face content validity assessments to develop a working version of the pCMT-QOL measure. From 2010-2016, the pCMT-QOL working version was administered to 398 children ages 8-18 seen at the participating study sites of the Inherited Neuropathies Consortium. The resulting data underwent rigorous psychometric analysis, including factor analysis, test-retest reliability, internal consistency, convergent validity, IRT analysis, and longitudinal analysis, to develop the final pCMT-QOL patient-reported outcome measure.INTERPRETATION: The pCMT-QOL patient-reported outcome measure is a reliable, valid, and sensitive measure of health-related QOL for children with CMT. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ana.25966

  View details for PubMedID 33222249

• Respiratory trajectories in type 2 and non-ambulant 3 Spinal muscular atrophy in the iSMAC cohort study. Neurology Trucco, F., Ridout, D., Scoto, M., Coratti, G., Main, M. L., Lofra, R. M., Mayhew, A. G., Montes, J., Pane, M., Sansone, V., Albamonte, E., D'Amico, A., Bertini, E., Messina, S., Bruno, C., Parasuraman, D., Childs, A., Gowda, V., Willis, T., Ong, M., Marini-Bettolo, C., De Vivo, D. C., Darras, B. T., Day, J., Kichula, E. A., Mayer, O. H., Navas Nazario, A. A., Finkel, R. S., Mercuri, E., Muntoni, F., international SMA consortium (iSMAc) 2020

  Abstract

  OBJECTIVE: To describe the respiratory trajectories and their correlation with motor function in an international paediatric cohort of patients with type 2 and non-ambulant type 3 spinal muscular atrophy (SMA).METHODS: Eight-year retrospective observational study of patients in the iSMAc natural history study. We retrieved anthropometrics, forced vital capacity (FVC) absolute, FVC% predicted (FVC%P.), Non-Invasive ventilation (NIV) requirement. Hammersmith functional motor scale (HFMS) and Revised performance of upper limb (RULM) were correlated with respiratory function. We excluded patients in interventional clinical trials and on Nusinersen commercial therapy.RESULTS: There were 437 patients with SMA: 348 type 2, 89 non-ambulant type 3. Mean age at first visit was 6.9(±4.4) and 11.1(±4) years. In SMA type 2 FVC%P declined by 4.2%/year from 5 to 13 years, followed by a slower decline (1.0%/year). In type 3 FVC%P declined by 6.3%/year between 8 and 13 years, followed by a slower decline (0.9%/year). 39% SMA type 2 and 9% type 3 required NIV at median age 5.0(1.8-16.6) and 15.1(13.8-16.3) years. 84% SMA type 2 and 80% type 3 had scoliosis, 54% and 46% required surgery, which did not significantly affect respiratory decline. FVC%P positively correlated with HFMS and RULM in both subtypes.CONCLUSIONS: In SMA type 2 and non-ambulant type 3 lung function declines differently, with a common levelling after age 13 years. Lung and motor function correlated in both subtypes. Our data further defines the milder SMA phenotypes and provides novel information to benchmark the long-term efficacy of new treatments for SMA.

  View details for DOI 10.1212/WNL.0000000000011051

  View details for PubMedID 33067401

• Switching between disease-modifying therapies in patients with spinal muscular atrophy: real-world data collected from the RESTORE Registry Servais, L., Day, J., De Vivo, D., Kirschner, J., Mercuri, E., Muntoni, F., Shieh, P., Tizzano, E., Desguerre, I., Quijano-Roy, S., Saito, K., Droege, M., Dabbous, O., Shah, A., Anderson, F., Finkel, R. PERGAMON-ELSEVIER SCIENCE LTD. 2020: S97

  View details for DOI 10.1016/j.nmd.2020.08.175

  View details for Web of Science ID 000579727800171

• One-time administration of AVXS-101 intrathecal (IT) for spinal muscular atrophy in the phase 1 study (STRONG): safety report Chand, D., Finkel, R., Day, J., Darris, B., Kuntz, N., Connolly, A., Zaidman, C., Crawford, T., Butterfield, R., Shieh, P., Tennekoon, G., Brandesma, J., Iannaccone, S., Meriggioli, M., Tauscher-Wisniewski, S., Shoffner, J., Ogrinc, F., Kavanagh, S., Feltner, D., Mendell, J. PERGAMON-ELSEVIER SCIENCE LTD. 2020: S120

  View details for DOI 10.1016/j.nmd.2020.08.254

  View details for Web of Science ID 000579727800247

• Escalating dose and randomized, controlled study of high-dose nusinersen in SMA; study design and updated enrollment for the DEVOTE Study Finkel, R., Day, J., Ryan, M., Mercuri, E., De Vivo, D., Pascual, S., Montes, J., Gurgel-Giannetti, J., Mitchell-Sweeney, N., Foster, R., Sun, P., Ramirez-Schrempp, D., Kandinov, B., Farwell, W. PERGAMON-ELSEVIER SCIENCE LTD. 2020: S124

  View details for DOI 10.1016/j.nmd.2020.08.264

  View details for Web of Science ID 000579727800257

• SUNFISH Part 1: 24-month safety and exploratory outcomes of risdiplam (RG7916) treatment in patients with Type 2 or 3 spinal muscular atrophy (SMA) Day, J., Baranello, G., Boespflug-Tanguy, O., Borell, S., Goemans, N., Kirschner, J., Masson, R., Pera, M., Servais, L., Fuhrer, S., Gerber, M., Gorni, K., Kletzl, H., Martin, C., Scalco, R., Staunton, H., Yeung, W., Mercuri, E. PERGAMON-ELSEVIER SCIENCE LTD. 2020: S123

  View details for DOI 10.1016/j.nmd.2020.08.262

  View details for Web of Science ID 000579727800255

• FIREFISH Part 1: 24-month safety and exploratory outcomes of risdiplam (RG7916) in infants with Type 1 spinal muscular atrophy (SMA) Baranello, G., Bloespflug-Tanguy, O., Darras, B., Day, J., Deconinck, N., Klein, A., Masson, R., Mercuri, E., Dodman, A., El-Khairi, M., Gerber, M., Gorni, K., Kletzl, H., Scalco, R., Servais, L. PERGAMON-ELSEVIER SCIENCE LTD. 2020: S122

  View details for DOI 10.1016/j.nmd.2020.08.258

  View details for Web of Science ID 000579727800251

• Nusinersen in adolescents and young adults with SMA: Longitudinal experience from an expanded cohort of CS2/CS12 and SHINE participants Darras, B., Day, J., Swoboda, K., Chiriboga, C., Iannaccone, S., De Vivo, D., Deconinck, N., Finkel, R., Tulinius, M., Saito, K., Montes, J., Foster, R., Ramirez-Schrempp, D., Kandinov, B., Wong, J., Farwell, W. PERGAMON-ELSEVIER SCIENCE LTD. 2020: S120

  View details for DOI 10.1016/j.nmd.2020.08.253

  View details for Web of Science ID 000579727800246

• FIREFISH Parts 1 and 2: 12-month pooled safety and efficacy outcomes of risdiplam (RG7916) in infants with Type 1 spinal muscular atrophy (SMA) Servais, L., Bloespflug-Tanguy, O., Darras, B., Day, J., Deconinck, N., Klein, A., Masson, R., Mazurkiewicz-Beldzinska, M., Mercuri, E., Rose, K., Vlodavets, D., Xiong, H., Zanoteli, E., Dodman, A., El-Khairi, M., Gerber, M., Gorni, K., Kletzl, H., Scalco, R., Baranello, G. PERGAMON-ELSEVIER SCIENCE LTD. 2020: S126

  View details for DOI 10.1016/j.nmd.2020.08.270

  View details for Web of Science ID 000579727800263

• Analysis of Cobb angle and clinical characteristics in children with spinal muscular atrophy who enrolled in CHERISH and SHINE Young, S., Montes, J., Glanzman, A., Gee, R., Day, J., Finkel, R., Darras, B., De Vivo, D., Gambino, G., Foster, R., Wong, J., Kandinov, B., Berger, Z. PERGAMON-ELSEVIER SCIENCE LTD. 2020: S70

  View details for DOI 10.1016/j.nmd.2020.08.085

  View details for Web of Science ID 000579727800081

• Clinical variability in spinal muscular atrophy type III. Annals of neurology Coratti, G., Messina, S., Lucibello, S., Pera, M. C., Montes, J., Pasternak, A., Stat, F. B., Escudero, J. E., Mazzone, E. S., Mayhew, A., Glanzman, A. M., Young, S. D., Salazar, R., Duong, T., Lofra, R. M., de Sanctis, R., Carnicella, S., Milev, E., Civitello, M., Pane, M., Scoto, M., Bettolo, C. M., Antonaci, L., Frongia, A., Sframeli, M., Vita, G. L., D'Amico, A., van den Hauwe, M., Albamonte, E., Goemans, N., Darras, B. T., Bertini, E., Sansone, V., Day, J., Osorio, A. N., Bruno, C., Muntoni, F., De Vivo, D. C., Finkel, R. S., Mercuri, E. 2020

  Abstract

  OBJECTIVE: We report natural history data in a large cohort of 199 spinal muscular atrophy (SMA) type III patients assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE). The aim of the study was to establish annual rate and possible patterns of progression according to a number of variables, such as age of onset, age at assessment, SMN2 copy number and functional status.METHODS: HFMSE longitudinal changes were assessed using piecewise linear mixed-effects models. The dependency in the data due to repeated measures was accounted for by a random intercept per individual and an unstructured covariance R matrix was used as correlation structure. An additional descriptive analysis was performed for 123 patients, for a total of 375 12-month assessments.RESULTS: A break point at age 7 was set for the whole cohort and for SMA IIIA and IIIB. Age, SMA type and ambulatory status were significantly associated with changes in mean HFMSE score while sex and SMN2 copy number were not. The increase in response before the break point of age 7 is significant only for SMA IIIA (beta=1.79, p<.0001). After the break point the change in the rate of HFMSE score significantly decrease for both SMA IIIA (beta=1.15, p<.0001) and IIIB (beta=0.69, p=0.002).INTERPRETATION: Our findings contribute to the understanding of the natural history of type III SMA and will be helpful in the interpretation of the real-world data of patients treated with commercially available drugs. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ana.25900

  View details for PubMedID 32926458

• Cobblestone Malformation in LAMA2 Congenital Muscular Dystrophy (MDC1A). Journal of neuropathology and experimental neurology Jayakody, H., Zarei, S., Nguyen, H., Dalton, J., Chen, K., Hudgins, L., Day, J., Withrow, K., Pandya, A., Teasley, J., Dobyns, W. B., Mathews, K. D., Moore, S. A. 2020

  Abstract

  Congenital muscular dystrophy type 1A (MDC1A) is caused by recessive variants in laminin alpha2 (LAMA2). Patients have been found to have white matter signal abnormalities on magnetic resonance imaging (MRI) but rarely structural brain abnormalities. We describe the autopsy neuropathology in a 17-year-old with white matter signal abnormalities on brain MRI. Dystrophic pathology was observed in skeletal muscle, and the sural nerve manifested a mild degree of segmental demyelination and remyelination. A diffuse, bilateral cobblestone appearance, and numerous points of fusion between adjacent gyri were apparent on gross examination of the cerebrum. Brain histopathology included focal disruptions of the glia limitans associated with abnormal cerebral cortical lamination or arrested cerebellar granule cell migration. Subcortical nodular heterotopia was present within the cerebellar hemispheres. Sampling of the centrum semiovale revealed no light microscopic evidence of leukoencephalopathy. Three additional MDC1A patients were diagnosed with cobblestone malformation on brain MRI. Unlike the autopsied patient whose brain had a symmetric distribution of cobblestone pathology, the latter patients had asymmetric involvement, most severe in the occipital lobes. These cases demonstrate that cobblestone malformation may be an important manifestation of the brain pathology in MDC1A and can be present even when patients have a structurally normal brain MRI.

  View details for DOI 10.1093/jnen/nlaa062

  View details for PubMedID 32827036

• Procedural Patterns and Safety of Atrial Fibrillation Ablation: Findings from Get with The Guidelines-Atrial Fibrillation. Circulation. Arrhythmia and electrophysiology Loring, Z., Holmes, D. N., Matsouaka, R. A., Curtis, A. B., Day, J. D., Desai, N., Ellenbogen, K. A., Feld, G. K., Fonarow, G. C., Frankel, D. S., Hurwitz, J. L., Knight, B. P., Joglar, J. A., Russo, A. M., Sidhu, M. S., Turakhia, M. P., Lewis, W. R., Piccini, J. P. 2020

  Abstract

  Background - Catheter ablation is an increasingly utilized treatment for symptomatic atrial fibrillation (AF). However, there are limited prospective, nationwide data on patient selection and procedural characteristics. This study describes patient characteristics, techniques, treatment patterns, and safety outcomes of patients undergoing AF ablation. Methods - A total of 3,139 patients undergoing AF ablation between 2016-2018 in the Get With The Guidelines-Atrial Fibrillation registry from 24 US centers were included. Patient demographics, medical history, procedural details and complications were abstracted. Differences between paroxysmal and persistent AF patients were compared using Pearson's Chi-square and Wilcoxon rank-sum tests. Results - Patients undergoing AF ablation were predominantly male (63.9%) and Caucasian (93.2%) with a median age of 65. Hypertension was the most common comorbidity (67.6%) and persistent AF patients had more comorbidities than paroxysmal AF patients. Drug refractory, paroxysmal AF was the most common ablation indication (Class I, 53.6%) followed by drug refractory, persistent AF (Class I, 41.8%). Radiofrequency (RF) ablation with contact force (CF) sensing was the most common ablation modality (70.5%); 23.7% of patients underwent cryoballoon ablation. Pulmonary vein isolation (PVI) was performed in 94.6% of de novo ablations; the most common adjunctive lesions included left atrial roof or posterior/inferior lines, and cavotricuspid isthmus ablation. Complications were uncommon (5.1%), and were life-threatening in 0.7% of cases. Conclusions - More than 98% of AF ablations among participating sites are performed for Class I or Class IIA indications. CF-guided RF ablation is the dominant technique and PVI the principal lesion set. In-hospital complications are uncommon and rarely life-threatening.

  View details for DOI 10.1161/CIRCEP.119.007944

  View details for PubMedID 32703018

• Gain and loss of abilities in type II SMA: A 12-month natural history study. Neuromuscular disorders : NMD Coratti, G., Lucibello, S., Pera, M. C., Duong, T., Muni Lofra, R., Civitello, M., D'Amico, A., Goemans, N., Darras, B. T., Bruno, C., Sansone, V. A., Day, J., Nascimento Osorio, A., Muntoni, F., Montes, J., Sframeli, M., Finkel, R., Mercuri, E., ISMAC group 2020

  Abstract

  The advent of clinical trials in spinal muscular atrophy (SMA) has highlighted the need to define patterns of progression using functional scales. It has recently been suggested that the analysis of abilities gained or lost applied to functional scales better reflects meaningful changes. We defined as "gain" a positive change between scores from 0 to either 1 or 2 and as "loss" a negative change from either 2 or 1 to 0. The aim of this study was to describe, over 12 months, which abilities on the Hammersmith Functional Motor Scale Expanded (HFMSE) were more frequently lost or gained in patients with SMA II. The cohort included 614 12-month assessments from 243 patients (age range: 30 months - 63 years; mean 9.94, SD ±7.91). The peak of abilities gained occurred before the age of 5 years while the highest number of lost abilities was found in the group 5-13 years. A correlation between the HFMSE baseline score and the ordinal number of the items was found for both lost (p<0.001) or gained (p<0.001) activities. No correlation was found with SMN2 copy number. These findings will have implications for clinical trial design and for the interpretation of real-world data using new therapeutic approaches.

  View details for DOI 10.1016/j.nmd.2020.07.004

  View details for PubMedID 32893082

• Determining An Appropriate Cardiopulmonary Exercise Testing Protocol For Individuals With Neuromuscular Disease Duong, T., Day, J., Dunaway-Young, S., Stevens, V. LIPPINCOTT WILLIAMS & WILKINS. 2020: 640

  View details for Web of Science ID 000590026302410

• Diagnosis of Myotonic Dystrophy Based on Resting State fMRI Using Convolutional Neural Networks. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference Kamali, T., Hagerman, K. A., Day, J. W., Sampson, J., Lim, K. O., Mueller, B. A., Wozniak, J. 2020; 2020: 1714–17

  Abstract

  Myotonic dystrophies (DM) are neuromuscular conditions that cause widespread effects throughout the body. There are brain white matter changes on MRI in patients with DM that correlate with neuropsychological functional changes. How these brain alterations causally relate to the presence and severity of cognitive symptoms remains largely unknown. Deep neural networks have significantly improved the performance of image classification of huge datasets. However, its application in brain imaging is limited and not well described, due to the scarcity of labeled training data. In this work, we propose an approach for the diagnosis of DM based on a spatio-temporal deep learning paradigm. The obtained accuracy (73.71%) and sensitivities and specificities showed that the implemented approach based on 4-D convolutional neural networks leads to a compact, discriminative, and fast computing DM-based clinical medical decision support system.Clinical relevance- Many adults with DM experience cognitive and neurological effects impacting their quality of life, and ability to maintain employment. A robust and reliable DM-based clinical decision support system may help reduce the long diagnostic delay common to DM. Furthermore, it can help neurologists better understand the pathophysiology of the disease and analyze effects of new drugs that aim to address the neurological symptoms of DM.

  View details for DOI 10.1109/EMBC44109.2020.9176455

  View details for PubMedID 33018327

• Descriptive analysis of varying real-world treatment patterns and outcomes in patients with spinal muscular atrophy collected from the RESTORE registry Finkel, R. S., Day, J. W., De Vivo, D. C., Kirschner, J., Mercuri, E., Muntoni, F., Shieh, P. B., Tizzano, E., Desguerre, I., Quijano-Roy, S., Saito, K., Droege, M., Dabbous, C., Shah, A., Khan, F., Anderson, F. A., Servais, L. WILEY. 2020: 620–21

  View details for Web of Science ID 000534616801471

• SUNFISH Part 2: Efficacy and safety of risdiplam (RG7916) in patients with Type 2 or non-ambulant Type 3 spinal muscular atrophy (SMA) Mercuri, E., Barisic, N., Boespflug-Tanguy, O., Day, J. W., Deconinck, N., Kostera-Pruszczyk, A., Masson, R., Mazzone, E., Nascimento, A., Saito, K., Vlodavets, D., Fuerst-Recktenwald, S., Fuhrer, S., Gerber, M., Gorni, K., Kletzl, H., Martin, C., Yeung, W. Y., Vuillerot, C. WILEY. 2020: 869

  View details for Web of Science ID 000534616802271

• Real-World Treatment Patterns and Outcomes in Patients with Spinal Muscular Atrophy Collected from the RESTORE Registry Servais, L., Day, J. W., De Vivo, D. C., Kirschner, J., Mercuri, E., Muntoni, F., Shieh, P. B., Tizzano, E., Desguerre, I., Quijano-Roy, S., Saito, K., Droege, M., Dabbous, O., Shah, A., Khan, F., Anderson, F. A., Finkel, R. S. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058005054

• SUNFISH Part 2: Efficacy and Safety of Risdiplam (RG7916) in Patients with Type 2 or Non-Ambulant Type 3 Spinal Muscular Atrophy (SMA) Mercuri, E., Barisic, N., Boespflug-Tanguy, O., Deconinck, N., Kostera-Pruszczyk, A., Masson, R., Mazzone, E., Nascimento, A., Saito, K., Vlodavets, D., Vuillerot, C., Fuerst-Recktenwald, S., Fuhrer, S., Gerber, M., Gorni, K., Kletzl, H., Martin, C., Yeung, W., Day, J. W., SUNFISH Study Grp LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058002084

• One-Time Intrathecal (IT) Administration of AVXS-101 IT Gene-Replacement Therapy for Spinal Muscular Atrophy: Phase 1 Study (STRONG) Finkel, R. S., Day, J. W., Darras, B. T., Kuntz, N. L., Connolly, A. M., Crawford, T., Butterfield, R. J., Shieh, P. B., Tennekoon, G., Iannaccone, S. T., Meriggioli, M., Tauscher-Wisniewski, S., Shoffner, J., Ogrinc, F. G., Kavanagh, S., Kernbauer, E., Whittle, J., Sproule, D. M., Feltner, D. E., Mendell, J. R. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058005070

• JEWELFISH: Safety and Pharmacodynamic Data in Non-Naive Patients with Spinal Muscular Atrophy (SMA) Receiving Treatment with Risdiplam (RG7916) Chiriboga, C., Bruno, C., Day, J. W., Duong, T., Fischer, D., Kirschner, J., Muntoni, F., Fuerst-Recktenwald, S., Gerber, M., Gorni, K., Kletzl, H., Warren, F., Yeung, W., Mercuri, E., JEWELFISH Study Grp LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058001105

• Pooled Safety Data from the Risdiplam (RG7916) Clinical Trial Development Program Baranello, G., Bertini, E., Chiriboga, C., Darras, B. T., Day, J. W., Deconinck, N., Fischer, D., Goemans, N., Kirschner, J., Klein, A., Masson, R., Mazurkiewicz-Beldzinska, M., Servais, L., Wang, Y., Fuerst-Recktenwald, S., Gerber, M., Gorni, K., Jaber, B., McIver, T., Scalco, R., Eugenio Mercuri FIREFISH, SUNFISH, JEWELFISH Study Grp LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058002128

• Onasemnogene Abeparvovec-xioi Gene-Replacement Therapy for Spinal Muscular Atrophy Type 1 (SMA1): Phase 3 US Study (STR1VE) Update Day, J. W., Chiriboga, C. A., Crawford, T. O., Darras, B. T., Finkel, R. S., Connolly, A. M., Iannaccone, S. T., Kuntz, N. L., Pena, L. M., Shieh, P. B., Smith, E. C., Schultz, M., Feltner, D. E., Tauscher-Wisniewski, S., Ogrinc, F. G., Shah, A., Ouyang, H., Macek, T., Kernbauer, E., Sproule, D. M., Mendell, J. R. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058003217

• Escalating Dose and Randomized, Controlled Study of Nusinersen in Participants with Spinal Muscular Atrophy; Study Design of the Phase 2/3 DEVOTE (232SM203) Study to Explore High Dose Nusinersen Finkel, R. S., Day, J. W., Mitchell-Sweeney, N., Foster, R., Sun, P., Bhan, I., Kandinov, B., Farwell, W. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058002055

• Longer-term Experience with Nusinersen in Teenagers and Young Adults with Spinal Muscular Atrophy: Results from the CS2/CS12 and SHINE Studies Day, J. W., Swoboda, K. J., Darras, B. T., Chiriboga, C. A., Iannaccone, S. T., De Vivo, D. C., Deconinck, N., Finkel, R. S., Tulinius, M., Saito, K., Montes, J., Sun, P., Bhan, I., Kandinov, B., Wong, J., Farwell, W. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058002026

• RESTORE: A Prospective Multinational Registry of Patients with Genetically Confirmed Spinal Muscular Atrophy - Rationale and Study Design. Journal of neuromuscular diseases Finkel, R. S., Day, J. W., De Vivo, D. C., Kirschner, J., Mercuri, E., Muntoni, F., Shieh, P. B., Tizzano, E., Desguerre, I., Quijano-Roy, S., Saito, K., Droege, M., Dabbous, O., Khan, F., Renault, L., Anderson, F. A., Servais, L. 2020

  Abstract

  BACKGROUND: Dramatic improvements in spinal muscular atrophy (SMA) treatment have changed the prognosis for patients with this disease, leading to important new questions. Gathering representative, real-world data about the long-term efficacy and safety of emerging SMA interventions is essential to document their impact on patients and caregivers.OBJECTIVES: This registry will assess outcomes in patients with genetically confirmed SMA and provide information on the effectiveness and long-term safety of approved and emerging treatments.DESIGN AND METHODS: RESTORE is a prospective, multicenter, multinational observational registry. Patients will be managed according to usual clinical practice. Both newly recruitedSMAtreatment centers and sites involved in existing SMA registries, including iSMAC, Treat-NMD, French SMA Assistance Publique- Hopitaux de Paris (AP-HP), Cure-SMA, SMArtCARE, will be eligible to participate; de novo; sites already participating in another registry may be included via consortium agreements. Data from patients enrolled in partnering registries will be shared with the RESTORE Registry and data for newly diagnosed patients will be added upon enrollment. Patients will be enrolled over a 5-year period and followed for 15 years or until death. Assessments will include SMA history and treatment, pulmonary, nutritional, and motor milestones, healthcare resource utilization, work productivity, activity impairment, adverse events, quality of life, caregiver burden, and survival.Status:Recruitment started in September 2018. As of January 3, 2020, 64 patients were enrolled at 25 participating sites.CONCLUSIONS: The RESTORE Registry has begun recruiting recently diagnosed patients with genetically confirmed SMA, enabling assessment of both short- and long-term patient outcomes.

  View details for DOI 10.3233/JND-190451

  View details for PubMedID 32039859

• Revised Recommendations for the Treatment of Infants Diagnosed with Spinal Muscular Atrophy Via Newborn Screening Who Have 4 Copies of SMN2. Journal of neuromuscular diseases Glascock, J., Sampson, J., Connolly, A. M., Darras, B. T., Day, J. W., Finkel, R., Howell, R. R., Klinger, K. W., Kuntz, N., Prior, T., Shieh, P. B., Crawford, T. O., Kerr, D., Jarecki, J. 2020

  View details for DOI 10.3233/JND-190468

  View details for PubMedID 32007960

• Onasemnogene Abeparvovec-xioi Gene-Replacement Therapy for Spinal Muscular Atrophy Type 1: Pulmonary and Ventilatory Findings from the Pivotal Phase 3 US Study (STR1VE) Shell, R., Day, J. W., Chiriboga, C. A., Crawford, T. O., Darras, B. T., Finkel, R. S., Connolly, A. M., Iannaconne, S. T., Kuntz, N. L., Pena, L. M., Shieh, P. B., Smith, E. C., Kwon, J. M., Zaidman, C., Schultz, M., Feltner, D. E., Tauscher-Wisniewski, S., Ogrinc, F. G., Thomasma, P., Ouyang, H., Macek, T. A., Kernbauer, E., Sproule, D. M., Mendell, J. R. AMER THORACIC SOC. 2020

  View details for Web of Science ID 000556622802306

• A longitudinal study of CMT1A using Rasch analysis based CMT neuropathy and examination scores. Neurology Fridman, V. n., Sillau, S. n., Acsadi, G. n., Bacon, C. n., Dooley, K. n., Burns, J. n., Day, J. n., Feely, S. n., Finkel, R. S., Grider, T. n., Gutmann, L. n., Herrmann, D. N., Kirk, C. A., Knause, S. A., Laurá, M. n., Lewis, R. A., Li, J. n., Lloyd, T. E., Moroni, I. n., Muntoni, F. n., Pagliano, E. n., Pisciotta, C. n., Piscosquito, G. n., Ramchandren, S. n., Saporta, M. n., Sadjadi, R. n., Shy, R. R., Siskind, C. E., Sumner, C. J., Walk, D. n., Wilcox, J. n., Yum, S. W., Züchner, S. n., Scherer, S. S., Pareyson, D. n., Reilly, M. M., Shy, M. E. 2020

  Abstract

  To evaluate the sensitivity of Rasch analysis-based, weighted Charcot-Marie-Tooth Neuropathy and Examination Scores (CMTNS-R and CMTES-R) to clinical progression in patients with Charcot-Marie-Tooth disease type 1A (CMT1A).Patients with CMT1A from 18 sites of the Inherited Neuropathies Consortium were evaluated between 2009 and 2018. Weighted CMTNS and CMTES modified category responses were developed with Rasch analysis of the standard scores. Change from baseline for CMTNS-R and CMTES-R was estimated with longitudinal regression models.Baseline CMTNS-R and CMTES-R scores were available for 517 and 1,177 participants, respectively. Mean ± SD age of participants with available CMTES-R scores was 41 ± 18 (range 4-87) years, and 56% were female. Follow-up CMTES-R assessments at 1, 2, and 3 years were available for 377, 321, and 244 patients. A mixed regression model showed significant change in CMTES-R score at years 2 through 6 compared to baseline (mean change from baseline 0.59 points at 2 years, p = 0.0004, n = 321). Compared to the original CMTES, the CMTES-R revealed a 55% improvement in the standardized response mean (mean change/SD change) at 2 years (0.17 vs 0.11). Change in CMTES-R at 2 years was greatest in mildly to moderately affected patients (1.48-point mean change, 95% confidence interval 0.99-1.97, p < 0.0001, for baseline CMTES-R score 0-9).The CMTES-R demonstrates change over time in patients with CMT1A and is more sensitive than the original CMTES. The CMTES-R was most sensitive to change in patients with mild to moderate baseline disease severity and failed to capture progression in patients with severe CMT1A.NCT01193075.

  View details for DOI 10.1212/WNL.0000000000009035

  View details for PubMedID 32047073

• Intensive Teenage Activity Is Associated With Greater Muscle Hyperintensity on T1W Magnetic Resonance Imaging in Adults With Dysferlinopathy. Frontiers in neurology Moore, U. n., Jacobs, M. n., Fernandez-Torron, R. n., LLauger Rossello, J. n., Smith, F. E., James, M. n., Mayhew, A. n., Rufibach, L. n., Carlier, P. G., Blamire, A. M., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E. n., Pestronk, A. n., Walter, M. C., Paradas, C. n., Stojkovic, T. n., Mori-Yoshimura, M. n., Bravver, E. n., Pegoraro, E. n., Mendell, J. R., Bushby, K. n., Straub, V. n., Diaz-Manera, J. n. 2020; 11: 613446

  Abstract

  Practice of sports during childhood or adolescence correlates with an earlier onset and more rapidly progressing phenotype in dysferlinopathies. To determine if this correlation relates to greater muscle pathology that persists into adulthood, we investigated the effect of exercise on the degree of muscle fatty replacement measured using muscle MRI. We reviewed pelvic, thigh and leg T1W MRI scans from 160 patients with genetically confirmed dysferlinopathy from the Jain Foundation International clinical outcomes study in dysferlinopathy. Two independent assessors used the Lamminen-Mercuri visual scale to score degree of fat replacement in each muscle. Exercise intensity for each individual was defined as no activity, minimal, moderate, or intensive activity by using metabolic equivalents and patient reported frequency of sports undertaken between the ages of 10 and 18. We used ANCOVA and linear modeling to compare the mean Lamminen-Mercuri score for the pelvis, thigh, and leg between exercise groups, controlling for age at assessment and symptom duration. Intensive exercisers showed greater fatty replacement in the muscles of the pelvis than moderate exercisers, but no significant differences of the thigh or leg. Within the pelvis, Psoas was the muscle most strongly associated with this exercise effect. In patients with a short symptom duration of <15 years there was a trend toward greater fatty replacement in the muscles of the thigh. These findings define key muscles involved in the exercise-phenotype effect that has previously been observed only clinically in dysferlinopathy and support recommendations that pre-symptomatic patients should avoid very intensive exercise.

  View details for DOI 10.3389/fneur.2020.613446

  View details for PubMedID 33391171

  View details for PubMedCentralID PMC7773023

• Diagnosis of Myotonic Dystrophy Based on Resting State fMRI Using Convolutional Neural Networks Kamali, T., Hagerman, K. A., Day, J. W., Sampson, J., Lim, K. O., Mueller, B. A., Wozniak, J., IEEE IEEE. 2020: 1714–17

  View details for Web of Science ID 000621592202014

• ONASEMNOGENE ABEPARVOVEC GENE-REPLACEMENT THERAPY (GRT) FOR SPINAL MUSCULAR ATROPHY TYPE 1 (SMA1): PRELIMINARY PULMONARY AND VENTILATORY FINDINGS FROM THE PHASE 3 STUDY (STR1VE) Shell, R., Day, J. W., Chiriboga, C. A., Crawford, T. O., Darras, B. T., Finkel, R. S., Connolly, A. M., Iannaccone, S. T., Kuntz, N. L., Pena, L. M., Shieh, P. B., Smith, E. C., Kausar, I., Schultz, M., Feltner, D. E., Ogrinc, F. G., Macek, T. A., Kernbauer, E., L'Italien, J., Sproule, D. M., Kaspar, B. K., Mendell, J. R. BMJ PUBLISHING GROUP. 2019: A42

  View details for DOI 10.1136/thorax-2019-BTSabstracts2019.67

  View details for Web of Science ID 000572473500067

• AVXS-101 PHASE 3 STUDY IN SPINAL MUSCULAR ATROPHY TYPE 1 Day, J. W., Chiriboga, C. A., Crawford, T. O., Darras, B. T., Finkel, R. S., Connolly, A. M., Iannaccone, S. T., Kuntz, N. L., Pena, L. M., Schultz, M., Shieh, P. B., Smith, E. C., Kausar, I., Feltner, D. E., Ogrinc, F. G., Ouyang, H., Macek, T. A., Kernbauer, E., Muehring, L. M., L'Italien, J., Sproule, D. M., Kaspar, B. K., Mendell, J. R. BMJ PUBLISHING GROUP. 2019: E69

  View details for DOI 10.1136/jnnp-2019-ABN-2.202

  View details for Web of Science ID 000522138000226

• Clinical characteristics and genotypes in the ADVANCE baseline data set, a comprehensive cohort of US children and adolescents with Pompe disease GENETICS IN MEDICINE Kishnani, P. S., Gibson, J. B., Gambello, M. J., Hillman, R., Stockton, D. W., Kronn, D., Leslie, N. D., Pena, L. M., Tanpaiboon, P., Day, J. W., Wang, R. Y., Goldstein, J. L., Haack, K., Sparks, S. E., Zhao, Y., Hahn, S., Pompe ADVANCE Study Consortium 2019; 21 (11): 2543–51

  View details for DOI 10.1038/s41436-019-0527-9

  View details for Web of Science ID 000494989200018

• Adeno-associated virus serotype 9 (AAV9) antibodies in patients with spinal muscular atrophy (SMA) screened for treatment with onasemnogene abeparvovec Day, J. W., Finkel, R. S., Mercuri, E., Swoboda, K. J., Meriggioli, M., Kernbauer, E., Ogrinc, F. G., Menier, M., Sproule, D. M., Feltner, D. E., Mendell, J. R. MARY ANN LIEBERT, INC. 2019: A96

  View details for Web of Science ID 000495173100273

• Intrathecal administration of AVXS-101 gene-replacement therapy (GRT) for spinal muscular atrophy type 2 (SMA2): Phase 1/2A study (strong) Finkel, R. S., Day, J. W., Darras, B. T., Kuntz, N. L., Connolly, A. M., Crawford, T. O., Butterfield, R. J., Shieh, P. B., Tennekoon, G., Iannaccone, S. T., Meriggioli, M., Ogrinc, F. G., Kavanagh, S., Kernbauer, E., Whittle, J., L'Italien, J., Kaspar, B., Sproule, D. M., Spector, S. A., Feltner, D. E., Mendell, J. R. ELSEVIER. 2019

  View details for DOI 10.1016/j.jns.2019.10.322

  View details for Web of Science ID 000516770701125

• Onasemnogene abeparvovec gene-replacement therapy (GRT) for spinal muscular atrophy type 1 (SMA1): Global pivotal phase 3 study program (STR1VE-US, STR1VE-EU, STR1VE-AP) Mercuri, E., Baranello, G., Day, J. W., Bruno, C., Corti, S., Chiriboga, C. A., Crawford, T. O., Darras, B. T., Finkel, R. S., Connolly, A. M., Iannaccone, S. T., Kuntz, N. L., Masson, R., Pena, L. M., Baldinetti, F., Schultz, M., Shieh, P. B., Smith, E. C., Saito, K., Scoto, M., Spector, S. A., Truncated, A., Sproule, D. M., Mendell, J. R., Muntoni, F. ELSEVIER. 2019

  View details for DOI 10.1016/j.jns.2019.10.1338

  View details for Web of Science ID 000516770700551

• The restore registry: A resource for measuring and improving spinal muscular atrophy outcomes Servais, L., Day, J. W., De Vivo, D. C., Kirschner, J., Mercuri, E., Muntoni, F., Shieh, P. B., Tizzano, E., Droege, M., Dabbous, O., Khan, F., Anderson, F. A., Finkel, R. S. ELSEVIER. 2019

  View details for DOI 10.1016/j.jns.2019.10.330

  View details for Web of Science ID 000516770701133

• The revised Hammersmith scale (RHS) for spinal muscular atrophy: longitudinal trajectories in a large international cohort of patients with type 2 and 3 SMA Ramsey, D., Scoto, M., Mayhew, A., Lofra, R., Main, M., Milev, E., Mazzone, E., Montes, J., Glanzman, A., Pasternak, A., Duong, T., Civitello, M., Coratti, G., Straub, V., Day, J., Darras, B., De Vivo, D., Finkel, R., Mercuri, E., Muntoni, F. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S131

  View details for DOI 10.1016/j.nmd.2019.06.334

  View details for Web of Science ID 000487768600321

• Onasemnogene Abeparvovec Gene-Replacement Therapy (GRT) for Spinal Muscular Atrophy Type 1 (SMA1): Pivotal Phase 3 Study (STR1VE) Update Day, J., Chiriboga, C., Crawford, T., Darras, B., Finkel, R., Connolly, A., Iannaccone, S., Kuntz, N., Pena, L., Schultz, M., Shieh, P., Smith, E., Feltner, D., Ogrinc, F., Shah, A., Ouyang, H., Macek, T., Kernbauer, E., L'Italien, J., Sproule, D., Kaspar, B., Mendell, J. WILEY. 2019: S118–S121

  View details for Web of Science ID 000502868300189

• Adeno-Associated Virus Serotype 9 (AAV9) Antibodies in Patients With Spinal Muscular Atrophy (SMA) Screened for Treatment With Gene-Replacement Therapy (GRT) Onasemnogene Abeparvovec Day, J., Finkel, R., Mercuri, E., Swoboda, K., Kernbauer, E., Ogrinc, F., Menier, M., Sproule, D., Feltner, D., Mendell, J. WILEY. 2019: S121

  View details for Web of Science ID 000502868300190

• The clinical outcome study for dysferlinopathy: pregnancy in dysferlinopathy Moore, U., James, M., Jacobs, M., Mayhew, A., Spuler, S., Day, J., Bharucha-Goebel, D., Stojkovic, T., Mendell, J., Straub, V. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S104

  View details for DOI 10.1016/j.nmd.2019.06.243

  View details for Web of Science ID 000487768600230

• RAINBOWFISH: A study of risdiplam (RG7916) in newborns with pre-symptomatic spinal muscular atrophy (SMA) Bertini, E., Day, J., Muhaizea, M., Xiong, H., Servais, L., Prufer, A., Tichy, M., Yeung, W., Gorni, K. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S187

  View details for DOI 10.1016/j.nmd.2019.06.524

  View details for Web of Science ID 000487768600510

• A clinical outcome study for dysferlinopathy: biobanking samples collected through a collaborative international multisite study Hilsden, H., Moore, U., Cox, D., Day, J., Jones, K., Bharucha-Goebel, D., Pestronk, A., Walter, M., Stojkovic, T., Bravver, E., Mendell, J., Rufibach, L., Paradas, C., Diaz-Manera, J., Pegoraro, E., Straub, V. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S98

  View details for DOI 10.1016/j.nmd.2019.06.226

  View details for Web of Science ID 000487768600213

• Measuring what matters in dysferlinopathy - linking functional ability to patient reported outcome measures Mayhew, A., James, M., Hilsden, H., Sutherland, H., Jacobs, M., Spuler, S., Day, J., Jones, K., Bharucha-Goebel, D., Salort-Campana, E., Pestronk, A., Walter, M., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Diaz Manera, J., Pegoraro, E., Mendell, J., Rufibach, L., Straub, V. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S100

  View details for DOI 10.1016/j.nmd.2019.06.232

  View details for Web of Science ID 000487768600219

• Intrathecal administration of onasemnogene abeparvovec gene-replacement therapy (GRT) for spinal muscular atrophy type 2 (SMA2): phase 1/2a study (STRONG) Finkel, R., Day, J., Darras, B., Kuntz, N., Connolly, A., Crawford, T., Butterfield, R., Shieh, P., Tennekoon, G., Iannaccone, S., Ogrinc, F., Kavanagh, S., Kernbauer, E., Whittle, J., L'Italien, J., Kaspar, B., Sproule, D., Spector, S., Feltner, D., Mendell, J. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S207

  View details for DOI 10.1016/j.nmd.2019.06.594

  View details for Web of Science ID 000487768600581

• JEWELFISH: safety and pharmacodynamic data in patients with spinal muscular atrophy (SMA) receiving treatment with risdiplam (RG7916) that have previously been treated with nusinersen Chiriboga, C., Mercuri, E., Fischer, D., Day, J., Kraus, D., Yeung, W., Kletzl, H., Gerber, M., Cleary, Y., Gorni, K. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S187

  View details for DOI 10.1016/j.nmd.2019.06.525

  View details for Web of Science ID 000487768600511

• Functional progression in dysferlinopathy: results of a 3-year natural history study Jacobs, M., James, M., Mayhew, A., Hilsden, H., Sutherland, H., Spuler, S., Day, J., Jones, K., Bharucha-Goebel, D., Salort-Campana, E., Pestronk, A., Walter, M., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Diaz Manera, J., Pegoraro, E., Mendell, J., Rufibach, L., Straub, V. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S102

  View details for DOI 10.1016/j.nmd.2019.06.238

  View details for Web of Science ID 000487768600225

• Onasemnogene abeparvovec gene-replacement therapy (GRT) for spinal muscular atrophy Type 1 (SMA1): Pivotal phase 3 study (STR1VE) update Day, J., Chiriboga, C., Crawford, T., Darras, B., Finkel, R., Connolly, A., Iannaccone, S., Kuntz, N., Pena, L., Schultz, M., Shieh, P., Smith, E., Feltner, D., Ogrinc, F., Ouyang, H., Macek, T., Kernbauer, E., Sproule, D., Mendell, J. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S183

  View details for DOI 10.1016/j.nmd.2019.06.511

  View details for Web of Science ID 000487768600498

• FIREFISH Part 1: 16-month safety and exploratory outcomes of risdiplam (RG7916) treatment in infants with type 1 spinal muscular atrophy Baranello, G., Servais, L., Day, J., Deconinck, N., Mercuri, E., Klein, A., Darras, B., Masson, R., Kletzl, H., Cleary, Y., El-Khairi, M., Seabrook, T., Czech, C., Gerber, M., Nguyen, C., Gelblin, K., Gorni, K. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S184

  View details for DOI 10.1016/j.nmd.2019.06.515

  View details for Web of Science ID 000487768600502

• The RESTORE registry: a resource for measuring and improving spinal muscular atrophy (SMA) outcomes Servais, L., Day, J., De Vivo, D., Kirschner, J., Mercuri, E., Muntoni, F., Shieh, P., Tizzano, E., Droege, M., Dabbous, O., Khan, F., Anderson, F., Finkel, R. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S195

  View details for DOI 10.1016/j.nmd.2019.06.550

  View details for Web of Science ID 000487768600537

• Trajectories of disease progression in ambulant and non ambulant SMA: 12 month follow-up Mercuri, E., Coratti, G., Pera, M., Scoto, M., Goemans, N., Pane, M., D'amico, A., Sansone, V., Messina, S., Nascimiento, A., Bertini, E., Finkel, R., Darras, B., De Vivo, D., Day, J., Muntoni, F. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S131

  View details for DOI 10.1016/j.nmd.2019.06.335

  View details for Web of Science ID 000487768600322

• Long-term Outcomes After Low Power, Slower Movement versus High Power, Faster Movement Irrigated-Tip Catheter Ablation for Atrial Fibrillation. Heart rhythm Bunch, T. J., May, H. T., Bair, T. L., Crandall, B. G., Cutler, M. J., Mallender, C., Weiss, J. P., Osborn, J. S., Day, J. D. 2019

  Abstract

  BACKGROUND: High power, shorter duration (HPSD) ablation strategies have been advocated to increase efficacy and minimize posterior wall deep tissue thermal injury during atrial fibrillation (AF) ablation.OBJECTIVE: Determine the long-term outcomes of arrhythmia free-survival from AF and atrial flutter (AFL) between HPSD and low power, longer duration (LPLD) ablation strategies.METHODS: Of a total of 1,333 first time AF ablation with 3 years of follow up, propensity-matched populations for baseline risk factors were created comprising of 402 patients treated with low power LPLD (30 W for 5 seconds: posterior wall, 30 W for 10-20 seconds: anterior wall) and 402 patients treated with HPSD (50 W for 2-3 seconds: posterior wall and 50 W for 5-15 seconds: anterior wall). AF/AFL outcomes after a 90-day blacking period were assessed.RESULTS: HPSD ablation was associated with shorter procedures and fluoroscopy times (p<0.0001 for both). Recurrence of AF at 1 (12.9% vs 16.2%, p=0.19) and 3 years (26.5% vs 30.7%, p=0.23) was similar between LPLD and HPSD, respectively. AFL was higher at 1 (7.2% vs 11.2%, p=0.03) and 3 years (16.1% vs 21.8%, p=0.06, p=0.04 after multivariate adjustment) with HPSD ablation. Patients with a LPLD approach had lower rates of need for a repeat ablation (21% vs 30%, p=0.002).CONCLUSIONS: Long-term freedom from AF rates were not significantly different between both approaches. A HPSD ablation strategy compared to a LPLD approach was associated with an increased risk of AFL and need for repeat ablation, but lowered procedure times.

  View details for DOI 10.1016/j.hrthm.2019.08.001

  View details for PubMedID 31398477

• Nusinersen experience in teenagers and young adults with spinal muscular atrophy (SMA): Results from CS2/CS12 and SHINE Deconinck, N., Darras, B. T., Day, J. W., Chiriboga, C. A., Iannaccone, S. T., Swoboda, K. J., Finkel, R. S., Tulinius, M., Saito, K., Montes, J., Mignon, L., Sun, P., Bhan, I., Gheuens, S., Bevernage, S. P., Farwell, W., De Vivo, D. C. WILEY. 2019: 143–44

  View details for Web of Science ID 000474481000229

• Avxs-101 gene-replacement therapy (GRT) for spinal muscular atrophy type 1 (SMA1): pivotal phase 3 study (STR1VE) update Day, J. W., Chiriboga, C. A., Crawford, T. O., Darras, B. T., Finkel, R. S., Connolly, A. M., Iannaccone, S. T., Kuntz, N. L., Pena, L. M., Schultz, M., Shieh, P. B., Smith, E. C., Farrar, M., Feltner, D. E., Ogrinc, F. G., Macek, T. A., Kernbauer, E., Muehring, L. M., L'Italien, J., Sproule, D. M., Kaspar, B. K., Mendell, J. R. BMJ PUBLISHING GROUP. 2019

  View details for DOI 10.1136/jnnp-2019-anzan.58

  View details for Web of Science ID 000478895700059

• FIREFISH Part 1: survival, ventilation and swallowing ability in infants with type 1 spinal muscular atrophy (SMA) treated with risdiplam (RG7916) Vlodavets, D., Servais, L., Baranello, G., Day, J. W., Deconinck, N., Mercuri, E., Klein, A., Darras, B., Masson, R., Kletzl, H., Cleary, Y., El-Khairi, M., Seabrook, T., Czech, C., Gerber, M., Nguyen, C., Gelblin, K., Gorni, K., Khwaja, O. WILEY. 2019: 310–11

  View details for Web of Science ID 000474481001127

• The RESTORE Registry: a resource for measuring and improving Spinal Muscular Atrophy (SMA) outcomes Servais, L., Day, J. W., De Vivo, D. C., Kirschner, J., Mercuri, E., Muntoni, F., Shieh, P. B., Tizzano, E., Droege, M., Dabbous, O., Khan, F., Anderson, F. A., Finkel, R. S. WILEY. 2019: 437

  View details for Web of Science ID 000474481001331

• RAINBOWFISH: a study of risdiplam (RG7916) in infants with pre-symptomatic spinal muscular atrophy (SMA) Bertini, E., Day, J. W., Al Muhaizea, M., Xiong, H., Servais, L., Prufer, A., Buchbjerg, J., Yeung, W. Y., Gorni, K., Khwaja, O. WILEY. 2019: 445

  View details for Web of Science ID 000474481001344

• AVXS-101 gene replacement therapy (GRT) for spinal muscular atrophy type 1 (SMA1): pivotal studies clinical update (STR1VE-EU and STR1VE) Mercuri, E., Baranello, G., Day, J. W., Bruno, C., Corti, S., Chiriboga, C. A., Crawford, T. O., Darras, B. T., Finkel, R. S., Connolly, A. M., Iannaccone, S. T., Kuntz, N. L., Masson, R., Pena, L. D., Schultz, M., Shieh, P. B., Smith, E. C., Feltner, D. E., Ouyang, H., Lavrov, A., Truncated, A., L'italien, J., Sproule, D. M., Mendell, J. R., Muntoni, F. WILEY. 2019: 224–25

  View details for Web of Science ID 000474481000355

• Towards regulatory endorsement of drug development tools to promote the application of model-informed drug development in Duchenne muscular dystrophy. Journal of pharmacokinetics and pharmacodynamics Conrado, D. J., Larkindale, J., Berg, A., Hill, M., Burton, J., Abrams, K. R., Abresch, R. T., Bronson, A., Chapman, D., Crowther, M., Duong, T., Gordish-Dressman, H., Harnisch, L., Henricson, E., Kim, S., McDonald, C. M., Schmidt, S., Vong, C., Wang, X., Wong, B. L., Yong, F., Romero, K., Duchenne Muscular Dystrophy Regulatory Science Consortium (D-RSC), Vishwanathan, V., Chidambaranathan, S., Douglas Biggar, W., McAdam, L. C., Mah, J. K., Tulinius, M., Cnaan, A., Morgenroth, L. P., Leshner, R., Tesi-Rocha, C., Thangarajh, M., Duong, T., Kornberg, A., Ryan, M., Nevo, Y., Dubrovsky, A., Clemens, P. R., Abdel-Hamid, H., Connolly, A. M., Pestronk, A., Teasley, J., Bertorini, T. E., Webster, R., Kolski, H., Kuntz, N., Driscoll, S., Bodensteiner, J. B., Gorni, K., Lotze, T., Day, J. W., Karachunski, P., Henricson, E. K., Abresch, R. T., Joyce, N. C., McDonald, C. M., McDonald, C. M., Campbell, C., Torricelli, R. E., Finkel, R. S., Flanigan, K. M., Goemans, N., Heydemann, P., Kaminska, A., Kirschner, J., Muntoni, F., Osorio, A. N., Schara, U., Sejersen, T., Shieh, P. B., Sweeney, H. L., Topaloglu, H., Tulinius, M., Vilchez, J. J., Voit, T., Wong, B., Alfano, L. N., Eagle, M., James, M. K., Lowes, L., Mayhew, A., Mazzone, E. S., Nelson, L., Rose, K. J., Abdel-Hamid, H. Z., Apkon, S. D., Barohn, R. J., Bertini, E., Bloetzer, C., deVaud, L. C., Butterfield, R. J., Chabrol, B., Chae, J. H., Jongno-Gu, D. R., Comi, G. P., Darras, B. T., Dastgir, J., Desguerre, I., Escobar, R. G., Finanger, E., Guglieri, M., Hughes, I., Iannaccone, S. T., Jones, K. J., Karachunski, P., Kudr, M., Lotze, T., Mah, J. K., Mathews, K., Nevo, Y., Parsons, J., Pereon, Y., de Queiroz Campos Araujo, A. P., Renfroe, J. B., de Resende, M. B., Ryan, M., Selby, K., Tennekoon, G., Vita, G., Abdel-Hamid, H., Apkon, S., Barohn, R., Belousova, E., Bertini, E., Brandsema, J., Bruno, C., Burnette, W., Butterfield, R., Byrne, B., Campbell, C., Carlo, J., Chae, J. H., Chandratre, S., Comi, G., Connolly, A., De Groot I, I., Deconinck, N., Dooley, J., Dubrovsky, A., Durigneux, J., Finanger, E., Finkel, R., Frank, L. M., Goemans, N., Harper, A., Hattori, A., Herguner, O., Iannaccone, S., Janas, J., Jong, Y. J., Kirschner, J., Komaki, H., Kuntz, N., Lee, W. T., Leung, E., Mah, J., Mathews, K., McDonald, C. M., Mercuri, E., McMillan, H., Mueller-Felber, W., de Munain A, L., Nakamura, A., Niks, E., Ogata, K., Pascual, S., Pegoraro, E., Pereon, Y., Renfroe, B., Sanka, R. B., Schallner, J., Schara, U., Selby, K., Sendra, I. I., Servais, L., Smith, E., Sparks, S., Topaloglu, H., Victor, R., Vilchez, J. J., Wicklund, M., Wilichoswki, E., Wong, B., Abresch, R. T., Carter, G. T., Henricson, E., McDonald, C. M. 2019

  Abstract

  Drug development for rare diseases is challenged by small populations and limited data. This makes development of clinical trial protocols difficult and contributes to the uncertainty around whether or not a potential therapy is efficacious. The use of data standards to aggregate data from multiple sources, and the use of such integrated databases to develop statistical models can inform protocol development and reduce the risks in developing new therapies. Achieving regulatory endorsement of such models through defined pathways at the US Food and Drug Administration and European Medicines Authority allows such tools to be used by the drug development community for defined contexts of use without further need for discussion of the underlying model(s). The Duchenne Regulatory Science Consortium (D-RSC) has brought together multiple stakeholders to develop a clinical trial simulation tool for Duchenne muscular dystrophy using such an approach. Here we describe the work of D-RSC as an example of how such an approach may be effective at reducing uncertainty in drug development for rare diseases, and thus bringing effective therapies to patients faster.

  View details for DOI 10.1007/s10928-019-09642-7

  View details for PubMedID 31127458

• Clinical characteristics and genotypes in the ADVANCE baseline data set, a comprehensive cohort of US children and adolescents with Pompe disease. Genetics in medicine : official journal of the American College of Medical Genetics Kishnani, P. S., Gibson, J. B., Gambello, M. J., Hillman, R., Stockton, D. W., Kronn, D., Leslie, N. D., Pena, L. D., Tanpaiboon, P., Day, J. W., Wang, R. Y., Goldstein, J. L., An Haack, K., Sparks, S. E., Zhao, Y., Hahn, S. H., Pompe ADVANCE Study Consortium 2019

  Abstract

  PURPOSE: To characterize clinical characteristics and genotypes of patients in the ADVANCE study of 4000L-scale alglucosidase alfa (NCT01526785), the largest prospective United States Pompe disease cohort to date.METHODS: Patients aged ≥1 year with confirmed Pompe disease previously receiving 160L alglucosidase alfa were eligible. GAA genotypes were determined before/at enrollment. Baseline assessments included histories/physical exams, Gross Motor Function Measure-88 (GMFM-88), pulmonary function tests, and cardiac assessments.RESULTS: Of 113 enrollees (60 male/53 female) aged 1-18 years, 87 had infantile-onset Pompe disease (IOPD) and 26 late-onset (LOPD). One hundred eight enrollees with GAA genotypes had 215 pathogenic variants (220 including combinations): 118 missense (4 combinations), 23 splice, 35 nonsense, 34 insertions/deletions, 9 duplications (1 combination), 6 other; c.2560C>T (n=23), c.-32-13T>G (n=13), and c.525delT (n=12) were most common. Four patients had previously unpublished variants, and 14/83 (17%) genotyped IOPD patients were cross-reactive immunological material-negative. All IOPD and 6/26 LOPD patients had cardiac involvement, all without c.-32-13T>G. Thirty-two (26 IOPD, 6 LOPD) were invasively ventilated. GMFM-88 total %scores (mean±SD, median, range): overall 46.3±33.0% (47.9%, 0.0-100.0%), IOPD 41.6±31.64% (38.9%, 0.0-99.7%), LOPD: 61.8±33.2 (70.9%, 0.0-100.0%).CONCLUSION: ADVANCE, a uniformly assessed cohort comprising most US children and adolescents with treated Pompe disease, expands understanding of the phenotype and observed variants in the United States.

  View details for PubMedID 31086307

• Transcriptome alterations in myotonic dystrophy skeletal muscle and heart HUMAN MOLECULAR GENETICS Wang, E. T., Treacy, D., Eichinger, K., Struck, A., Estabrook, J., Olafson, H., Wang, T. T., Bhatt, K., Westbrook, T., Sedehizadeh, S., Ward, A., Day, J., Brook, D., Berglund, J., Cooper, T., Housman, D., Thornton, C., Burge, C. 2019; 28 (8): 1312–21

  View details for DOI 10.1093/hmg/ddy432

  View details for Web of Science ID 000467482600007

• Nusinersen Efficacy in Adults with Spinal Muscular Atrophy Day, J., Wolford, C., MacPherson, C., Martens, W., McDermott, M., Darras, B., De Vivo, D., Cunningham, Z., Finkel, R., Zeineh, M., Sampson, J., Hagerman, K., Duong, T. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000475965907110

• Phase 1 Study of Intrathecal Administration of AVXS-101 Gene-Replacement Therapy (GRT) for Spinal Muscular Atrophy Type 2 (SMA2) (STRONG) Finkel, R. S., Day, J. W., Darras, B. T., Kuntz, N. L., Connolly, A. M., Crawford, T., Butterfield, R. J., Shieh, P. B., Tennekoon, G., Iannaccone, S. T., Meriggioli, M., Spector, S. A., Ogrinc, F. G., L'Italien, J., Wells, C., Kaspar, B., Sproule, D. M., Feltner, D. E., Mendell, J. R. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000475965900298

• Treatment Algorithm for Infants Diagnosed with Spinal Muscular Atrophy Through Newborn Screening Glascock, J., Sampson, J., Haidet-Phillips, A., Connolly, A., Darras, B., Day, J., Finkel, R., Howell, R., Klinger, K., Kuntz, N., Prior, T., Shieh, P., Crawford, T., Kerr, D., Jarecki, J. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000475965900291

• AVXS-101 Gene-Replacement Therapy (GRT) for Spinal Muscular Atrophy Type 1 (SMA1): Pivotal Phase 3 Study (STR1VE) Update Day, J. W., Chiriboga, C. A., Crawford, T. O., Darras, B. T., Finkel, R. S., Connolly, A. M., Iannaccone, S. T., Kuntz, N. L., Pena, L. M., Schultz, M., Shieh, P. B., Smith, E. C., Feltner, D. E., Ogrinc, F. G., Macek, T. A., Wells, C., Muehring, L. M., L'Italien, J., Sproule, D. M., Kaspar, B. K., Mendell, J. R. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000475965900297

• FIREFISH Part 1: Survival, Ventilation and Swallowing Ability in Infants with Type 1 SMA Receiving Risdiplam (RG7916) Servais, L., Baranello, G., Day, J. W., Deconinck, N., Mercuri, E., Klein, A., Darras, B., Masson, R., Kletzl, H., Cleary, Y., El-Khairi, M., Seabrook, T., Czech, C., Gerber, M., Nguyen, C., Gelblin, K., Gorni, K., Khwaja, O. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000475965906187

• FIREFISH Part 1: 1-Year Results on Motor Function in Babies with Type 1 SMA Baranello, G., Servais, L., Day, J. W., Deconinck, N., Mercuri, E., Klein, A., Darras, B., Masson, R., Kletzl, H., Cleary, Y., El-Khairi, M., Seabrook, T., Czech, C., Gerber, M., Nguyen, C., Gelblin, K., Gorni, K., Khwaja, O. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000475965906182

• Modifier Gene Candidates in Charcot-Marie-Tooth Disease Type 1A: A Case-Only Genome-Wide Association Study. Journal of neuromuscular diseases Tao, F., Beecham, G. W., Rebelo, A. P., Blanton, S. H., Moran, J. J., Lopez-Anido, C., Svaren, J., Abreu, L., Rizzo, D., Kirk, C. A., Wu, X., Feely, S., Verhamme, C., Saporta, M. A., Herrmann, D. N., Day, J. W., Sumner, C. J., Lloyd, T. E., Li, J., Yum, S. W., Taroni, F., Baas, F., Choi, B., Pareyson, D., Scherer, S. S., Reilly, M. M., Shy, M. E., Zuchner, S., Inherited Neuropathy Consortium 2019

  Abstract

  BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a uniform 1.5-Mb duplication on chromosome 17p, which includes the PMP22 gene. Patients often present the classic neuropathy phenotype, but also with high clinical variability.OBJECTIVE: We aimed to identify genetic variants that are potentially associated with specific clinical outcomes in CMT1A.METHODS: We genotyped over 600,000 genomic markers using DNA samples from 971 CMT1A patients and performed a case-only genome-wide association study (GWAS) to identify potential genetic association in a subset of 644 individuals of European ancestry. A total of 14 clinical outcomes were analyzed in this study.RESULTS: The analyses yielded suggestive association signals in four clinical outcomes: difficulty with eating utensils (lead SNP rs4713376, chr6 : 30773314, P = 9.91*10-7, odds ratio = 3.288), hearing loss (lead SNP rs7720606, chr5 : 126551732, P = 2.08*10-7, odds ratio = 3.439), decreased ability to feel (lead SNP rs17629990, chr4 : 171224046, P = 1.63*10-7, odds ratio = 0.336), and CMT neuropathy score (lead SNP rs12137595, chr1 : 4094068, P = 1.14*10-7, beta = 3.014).CONCLUSIONS: While the results require validation in future genetic and functional studies, the detected association signals may point to novel genetic modifiers in CMT1A.

  View details for PubMedID 30958311

• Revised upper limb module for spinal muscular atrophy: 12 month changes MUSCLE & NERVE Pera, M., Coratti, G., Mazzone, E. S., Montes, J., Scoto, M., De Sanctis, R., Main, M., Mayhew, A., Lofra, R., Young, S., Glanzman, A. M., Duong, T., Pasternak, A., Ramsey, D., Darras, B., Day, J. W., Finkel, R. S., De Vivo, D. C., Sormani, M., Bovis, F., Straub, V., Muntoni, F., Pane, M., Mercuri, E., Bettolo, C., Civitiello, M., Mirek, E., Salazar, R., Forcina, N., Norcia, G., Carnicella, S., Antonaci, L., ISMAC Consortium Grp 2019; 59 (4): 426–30

  View details for DOI 10.1002/mus.26419

  View details for Web of Science ID 000461232700011

• Variation in SIPA1L2 is correlated with phenotype modification in Charcot- Marie- Tooth disease type 1A ANNALS OF NEUROLOGY Tao, F., Beecham, G. W., Rebelo, A. P., Svaren, J., Blanton, S. H., Moran, J. J., Lopez-Anido, C., Morrow, J. M., Abreu, L., Rizzo, D., Kirk, C. A., Wu, X., Feely, S., Verhamme, C., Saporta, M. A., Herrmann, D. N., Day, J. W., Sumner, C. J., Lloyd, T. E., Li, J., Yum, S. W., Taroni, F., Baas, F., Choi, B., Pareyson, D., Scherer, S. S., Reilly, M. M., Shy, M. E., Zuechner, S., Lewis, R., Acsadi, G., Finkel, R., Fridman, V., Ramchandren, S., Walk, D., Logigian, E., Stanton, M., Eichinger, K., Guntrum, D., Gibson, C., Burns, J., Moroni, I., Pisciotta, C., Laura, M., Muntoni, F., Sowden, J. E., Mountain, J., Bai, Y., Bacon, C., Gutmann, L., Grider, T., Phetteplace, J., Seyedsadjadi, R., Houlden, H., Cortese, A., Pandraud, A., Calabrese, D., Saveri, P., Richardson, J., Dankwa, L., Lee, D., Siskind, C., Maciel, R., Bis, D., Inherited Neuropathy Consortium 2019; 85 (3): 316–30

  View details for DOI 10.1002/ana.25426

  View details for Web of Science ID 000459920600003

• Variation in SIPA1L2 is Correlated with Phenotype Modification in CMT Type 1A. Annals of neurology Tao, F., Beecham, G. W., Rebelo, A. P., Blanton, S. H., Moran, J. J., Lopez-Anido, C., Svaren, J., Morrow, J. M., Abreu, L., Rizzo, D., Kirk, C. A., Wu, X., Feely, S., Verhamme, C., Saporta, M. A., Herrmann, D. N., Day, J. W., Sumner, C. J., Lloyd, T. E., Li, J., Yum, S. W., Taroni, F., Baas, F., Choi, B., Pareyson, D., Scherer, S. S., Reilly, M. M., Shy, M. E., Zuchner, S., Inherited Neuropathy Consortium 2019

  Abstract

  OBJECTIVE: Genetic modifiers in rare disease have long been suspected to contribute to the considerable variance in disease expression, including Charcot-Marie-Tooth disease type 1A (CMT1A). To address this question the Inherited Neuropathy Consortium collected a large standardized sample of such rare CMT1A patients over a period of eight years. CMT1A is caused in most patients by a uniformly sized 1.5Mb duplication event involving the gene PMP22.METHODS: We genotyped DNA samples from 971 CMT1A patients on Illumina beadchips. Genome-wide analysis was performed in a subset of 330 of these patients, who expressed the extremes of a hallmark symptom: mild and severe foot dorsiflexion strength impairment. SIPA1L2 (signal induced proliferation associated 1 like 2), the top identified candidate modifier gene, was expressed in the peripheral nerve and our functional studies identified and confirmed interacting proteins using co-immunoprecipitation analysis, mass spectrometry, and immunocytochemistry. Chromatin immunoprecipitation and in vitro siRNA experiments were used to analyze gene regulation.RESULTS: We identified significant association of four SNPs (rs10910527, rs7536385, rs4649265, rs1547740) in SIPA1L2 with foot dorsiflexion strength (P < 1*10-7 ). Co-immunoprecipitation and mass-spectroscopy studies identified beta-actin and MYH9 as SIPA1L2 binding partners. Further, we show that SIPA1L2 is part of a myelination-associated co-expressed network regulated by the master transcription factor SOX10. Importantly, in vitro knock-down of SIPA1L2 in Schwannoma cells lead to a significant reduction of PMP22 expression, hinting at a potential strategy for drug development.INTERPRETATION: offers a new pathway to therapeutic interventions. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30706531

• Assessment of disease progression in dysferlinopathy: A 1-year cohort study NEUROLOGY Moore, U., Jacobs, M., James, M. K., Mayhew, A. G., Fernandez-Torron, R., Feng, J., Cnaan, A., Eagle, M., Bettinson, K., Rufibach, L. E., Lofra, R., Blamire, A. M., Carlier, P. G., Mittal, P., Lowes, L., Alfano, L., Rose, K., Duong, T., Berry, K. M., Montiel-Morillo, E., Pedrosa-Hernandez, I., Holsten, S., Sanjak, M., Ashida, A., Sakamoto, C., Tateishi, T., Yajima, H., Canal, A., Ollivier, G., Decostre, V., Mendez, J., Praxedes, N., Thiele, S., Siener, C., Shierbecker, J., Florence, J. M., Vandevelde, B., DeWolf, B., Hutchence, M., Gee, R., Pruegel, J., Maron, E., Hilsden, H., Lochmueller, H., Grieben, U., Spuler, S., Rocha, C., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Harms, M., Pestronk, A., Krause, S., Schreiber-Katz, O., Walter, M. C., Paradas, C., Hogrel, J., Stojkovic, T., Takeda, S., Mori-Yoshimura, M., Bravver, E., Sparks, S., Diaz-Manera, J., Bello, L., Semplicini, C., Pegoraro, E., Mendell, J. R., Bushby, K., Straub, V., Arrieta, A., Hwang, E., Lee, E., Illa, I., Gallardo, E., Belmonte Jimeno, I., Llauger Rossello, J., Harwick, B., Sykes, J., Yetter, B., Smith, M., Lapeyssonie, B., Bendahan, D., Le Fur, Y., Shahram, A., Albane, T., Coppenrath, E. M., Harris, E., Guglieri, M., Evangelista, T., Murphy, A., Moat, D., Hodgson, T., Wallace, D., Ward, L., Galley, D., Calore, C., Stramare, R., Rampado, A., Gidaro, T., Turk, S., Servais, L., Theis, C., Diabate, O., Schimmoeller, L., Foster, G., Carbonell, P., Cabrera, M., Morgado, Y., Gala, S., Perez, J., Sawyer, A., Clarke, N. F., Sandaradura, S., Ghaoui, R., Cornett, K., Miller, C., Foster, S., Peduto, A., Sato, N., Tamaru, T., Kobayashi, Y., Ashida, A., Nakayama, T., Segawa, K., Ohtaguro, S., Nakamura, H., Ohhata, M., Kimura, E., Endo, M., Brody, N., Leach, M. E., Toles, A., Fricke, S. T., Otero, H. J., Jain COS Consortium 2019; 92 (5): E461–E474

  View details for DOI 10.1212/WNL.0000000000006858

  View details for Web of Science ID 000462547500007

• Revised Upper Limb Module for Spinal Muscular Atrophy: 12 month changes. Muscle & nerve Pera, M. C., Coratti, G., Mazzone, E. S., Montes, J., Scoto, M., De Sanctis, R., Main, M., Mayhew, A., Muni Lofra, R., Dunaway Young, S., Glanzman, A. M., Duong, T., Pasternak, A., Ramsey, D., Darras, B., Day, J. W., Finkel, R. S., De Vivo, D. C., Sormani, M. P., Bovis, F., Straub, V., Muntoni, F., Pane, M., Mercuri, E., iSMAC Consortium Group 2019

  Abstract

  INTRODUCTION: The aim of the study was to assess 12 month changes in upper limb function in patients affected by spinal muscular atrophy type 2 and 3.METHODS: Longitudinal 12 month data was collected in 114 patients, 60 type 2 and 54 type 3, using the Revised Upper Limb Module.RESULTS: The 12 month changes ranged between -7 and 9 (mean: -0.41; SD: 2.93). The mean changes were not significantly different between the three spinal muscular atrophy groups (-0.45 in type 2, -0.23 in non-ambulant type 3 and -0.34 in ambulant type 3, p=0.96) and the relationship between 12 month change and age classes was not significantly different among the three types of SMA patients.DISCUSSION: Our results confirm that the Module explores a wide range of functional abilities and can be used in ambulant and non-ambulant patients of different ages in conjunction with other functional scales. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30677148

• Assessment of disease progression in dysferlinopathy: A 1-year cohort study. Neurology Moore, U., Jacobs, M., James, M. K., Mayhew, A. G., Fernandez-Torron, R., Feng, J., Cnaan, A., Eagle, M., Bettinson, K., Rufibach, L. E., Lofra, R. M., Blamire, A. M., Carlier, P. G., Mittal, P., Lowes, L. P., Alfano, L., Rose, K., Duong, T., Berry, K. M., Montiel-Morillo, E., Pedrosa-Hernandez, I., Holsten, S., Sanjak, M., Ashida, A., Sakamoto, C., Tateishi, T., Yajima, H., Canal, A., Ollivier, G., Decostre, V., Mendez, J. B., Sanchez-Aguilera Praxedes, N., Thiele, S., Siener, C., Shierbecker, J., Florence, J. M., Vandevelde, B., DeWolf, B., Hutchence, M., Gee, R., Prugel, J., Maron, E., Hilsden, H., Lochmuller, H., Grieben, U., Spuler, S., Tesi Rocha, C., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Harms, M., Pestronk, A., Krause, S., Schreiber-Katz, O., Walter, M. C., Paradas, C., Hogrel, J., Stojkovic, T., Takeda, S., Mori-Yoshimura, M., Bravver, E., Sparks, S., Diaz-Manera, J., Bello, L., Semplicini, C., Pegoraro, E., Mendell, J. R., Bushby, K., Straub, V., Jain COS Consortium 2019

  Abstract

  OBJECTIVE: To assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year.METHODS: One hundred ninety-three patients with dysferlinopathy were recruited to the Jain Foundation's International Clinical Outcome Study for Dysferlinopathy. Baseline, 6-month, and 1-year assessments included adapted North Star Ambulatory Assessment (a-NSAA), Motor Function Measure (MFM-20), timed function tests, 6-minute walk test (6MWT), Brooke scale, Jebsen test, manual muscle testing, and hand-held dynamometry. Patients also completed the ACTIVLIM questionnaire. Change in each measure over 6 months and 1 year was calculated and compared between disease severity (ambulant [mild, moderate, or severe based on a-NSAA score] or nonambulant [unable to complete a 10-meter walk]) and clinical diagnosis.RESULTS: The functional a-NSAA test was the most sensitive to deterioration for ambulant patients overall. The a-NSAA score was the most sensitive test in the mild and moderate groups, while the 6MWT was most sensitive in the severe group. The 10-meter walk test was the only test showing significant change across all ambulant severity groups. In nonambulant patients, the MFM domain 3, wrist flexion strength, and pinch grip were most sensitive. Progression rates did not differ by clinical diagnosis. Power calculations determined that 46 moderately affected patients are required to determine clinical effectiveness for a hypothetical 1-year clinical trial based on the a-NSAA as a clinical endpoint.CONCLUSION: Certain functional outcome measures can detect changes over 6 months and 1 year in dysferlinopathy and potentially be useful in monitoring progression in clinical trials.CLINICALTRIALSGOV IDENTIFIER: NCT01676077.

  View details for PubMedID 30626655

• AVXS-101 Gene Replacement Therapy (GRT) for Spinal Muscular Atrophy Type 1 (SMA1): Pivotal Phase 3 Study (STR1VE) Update Shell, R., Day, J., Chiriboga, C., Crawford, T. O., Darras, B. T., Finkel, R., Connolly, A. M., Iannaccone, S. T., Kuntz, N. L., Pena, L. M., Schultz, M., Shieh, P. B., Smith, E. C., Feltner, D. E., Ogrinc, F. G., Macek, T. A., Wells, C., Muehring, L. M., L'Italien, J., Sproule, D. M., Kaspar, B. K., Mendell, J. R. AMER THORACIC SOC. 2019

  View details for Web of Science ID 000466771103081

• Perspectives on Spinraza (Nusinersen) Treatment Study: Views of Individuals and Parents of Children Diagnosed with Spinal Muscular Atrophy JOURNAL OF NEUROMUSCULAR DISEASES Pacione, M., Siskind, C. E., Day, J. W., Tabor, H. K. 2019; 6 (1): 119-131

  View details for DOI 10.3233/JND-180330

  View details for Web of Science ID 000685097900011

• Modifier Gene Candidates in Charcot-Marie-Tooth Disease Type 1A: A Case-Only Genome-Wide Association Study JOURNAL OF NEUROMUSCULAR DISEASES Tao, F., Beecham, G. W., Rebelo, A. P., Blanton, S. H., Moran, J. J., Lopez-Anido, C., Svaren, J., Abreu, L., Rizzo, D., Kirk, C. A., Wu, X., Feely, S., Verhamme, C., Saporta, M. A., Herrmann, D. N., Day, J. W., Sumner, C. J., Lloyd, T. E., Li, J., Yum, S. W., Taroni, F., Baas, F., Choi, B., Pareyson, D., Scherer, S. S., Reilly, M. M., Shy, M. E., Zuchner, S., Inherited Neuropathy Consortium 2019; 6 (2): 201-211

  View details for DOI 10.3233/JND-190377

  View details for Web of Science ID 000685099200003

• Perspectives on Spinraza (Nusinersen) Treatment Study: Views of Individuals and Parents of Children Diagnosed with Spinal Muscular Atrophy. Journal of neuromuscular diseases Pacione, M., Siskind, C. E., Day, J. W., Tabor, H. K. 2018

  Abstract

  BACKGROUND: Spinal muscular atrophy (SMA) is a genetic disorder characterized by muscle loss. In December 2016 the FDA approved the first and only treatment drug for SMA: Spinraza (nusinersen). Despite excitement and optimism, there are no published data on the perceptions of individuals with SMA and their families about the benefits, risks, and challenges associated with treatment.OBJECTIVE: This qualitative interview study sought to characterize the perspectives of patients/families with SMA who did not want, or were unsure about, receiving this new innovative treatment for a previously untreatable and often fatal condition.METHODS: Individuals and families were recruited via advertisements on Facebook groups related to SMA and through the Stanford Neuromuscular Contact Registry. Participants completed a demographic questionnaire and participated in a semi-structured interview via voice conferencing. Interview questions focused on: 1) experiences with SMA, 2) opinions about Spinraza treatment, and 3) factors considered in decisions regarding treatment.RESULTS: Thirteen people were interviewed: ten adults with SMA (ages 27- 48, nine with Type II) and three parents of minor children with SMA (one each of Types I, II and III). Qualitative content analysis identified a range of opinions about Spinraza treatment: five were uninterested (2 adults, 3 parents), four adults were still deciding whether to pursue treatment, three adults were interested or in the process of pursuing treatment, and one adult was currently receiving the drug after overcoming significant reluctance. Participants described several key factors influencing their treatment decisions, including: concerns about risk factors and side effects, high cost, insurance coverage, time involvement, and lack of data about efficacy. Participants reported learning about most of these factors through parent/patient testimonials on SMA-specific social media groups.CONCLUSIONS: Participants reported basing decisions about pursuing Spinraza on a variety of practical and value-based considerations. They described carefully weighing the perceived potential benefits and risks of treatment through the lens of their current quality of life and prognosis. These findings suggest that providers should be aware that some patients and parents, especially those with Types II-IV, may approach treatment decisions differently than parents of children with SMA I. Informed treatment decisions can be supported through: 1) the collection and dissemination of better data on Spinraza treatment in these populations; 2) clear communication about risks, side effects and eligibility; 3) improved access to payment and treatment facilities; and 4) facilitation of discussions between providers and patients/families about identity and disability in the context of goals of care and other life and support challenges.

  View details for PubMedID 30594933

• Transcriptome alterations in myotonic dystrophy skeletal muscle and heart. Human molecular genetics Wang, E. T., Treacy, D., Eichinger, K., Struck, A., Estabrook, J., Olafson, H., Wang, T. T., Bhatt, K., Westbrook, T., Sedehizadeh, S., Ward, A., Day, J., Brook, D., Berglund, J. A., Cooper, T., Housman, D., Thornton, C., Burge, C. 2018

  Abstract

  Myotonic dystrophy (dystrophia myotonica, DM) is a multi-systemic disease caused by expanded CTG or CCTG microsatellite repeats. Characterized by symptoms in muscle, heart, and central nervous system, among others, it is one of the most variable diseases known. A major pathogenic event in DM is the sequestration of Muscleblind-like proteins by CUG or CCUG repeat-containing RNAs transcribed from expanded repeats, and differences in the extent of MBNL sequestration dependent on repeat length and expression level may account for some portion of the variability. However, many other cellular pathways are reported to be perturbed in DM, and the severity of specific disease symptoms varies among individuals. To help understand this variability and facilitate research into DM, we generated 120 RNASeq transcriptomes from skeletal and heart muscle derived from healthy and DM1 biopsies and autopsies. A limited number of DM2 and Duchenne Muscular Dystrophy samples were also sequenced. We analyzed splicing and gene expression, identified tissue-specific changes in RNA processing, and uncovered transcriptome changes strongly correlating with muscle strength. We created a web resource at http://DMseq.org that hosts raw and processed transcriptome data and provides a lightweight, responsive interface that enables browsing of processed data across the genome.

  View details for PubMedID 30561649

• Consensus-based care recommendations for adults with myotonic dystrophy type 1 NEUROLOGY-CLINICAL PRACTICE Ashizawa, T., Gagnon, C., Groh, W. J., Gutmann, L., Johnson, N. E., Meola, G., Moxley, R., Pandya, S., Rogers, M. T., Simpson, E., Angeard, N., Bassez, G., Berggren, K. N., Bhakta, D., Bozzali, M., Broderick, A., Byrne, J. B., Campbell, C., Cup, E., Day, J. W., De Mattia, E., Duboc, D., Duong, T., Eichinger, K., Ekstrom, A., van Engelen, B., Esparis, B., Eymard, B., Ferschl, M., Gadalla, S. M., Gallais, B., Goodglick, T., Heatwole, C., Hilbert, J., Holland, V., Kierkegaard, M., Koopman, W. J., Lane, K., Maas, D., Mankodi, A., Mathews, K. D., Monckton, D. G., Moser, D., Nazarian, S., Nguyen, L., Nopoulos, P., Petty, R., Phetteplace, J., Puymirat, J., Raman, S., Richer, L., Roma, E., Sampson, J., Sansone, V., Schoser, B., Sterling, L., Statland, J., Subramony, S. H., Tian, C., Trujillo, C., Tomaselli, G., Turner, C., Venance, S., Verma, A., White, M., Winblad, S., Myotonic Dystrophy Fdn 2018; 8 (6): 507–20

  Abstract

  Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects between 1 in 3,000 and 8,000 individuals globally. No evidence-based guideline exists to inform the care of these patients, and most do not have access to multidisciplinary care centers staffed by experienced professionals, creating a clinical care deficit.The Myotonic Dystrophy Foundation (MDF) recruited 66 international clinicians experienced in DM1 patient care to develop consensus-based care recommendations. MDF created a 2-step methodology for the project using elements of the Single Text Procedure and the Nominal Group Technique. The process generated a 4-page Quick Reference Guide and a comprehensive, 55-page document that provides clinical care recommendations for 19 discrete body systems and/or care considerations.The resulting recommendations are intended to help standardize and elevate care for this patient population and reduce variability in clinical trial and study environments.

  View details for DOI 10.1212/CPJ.0000000000000531

  View details for Web of Science ID 000456290100016

  View details for PubMedID 30588381

  View details for PubMedCentralID PMC6294540

• Zero incidence of adeno-associated virus serotype 9 (AAV9) antibodies in a cohort of spinal muscular atrophy (SMA) type 1 patients screened in STR1VE, a pivotal phase 3 study of AVXS-101 Day, J. W., Chiriboga-Klein, C. A., Crawford, T., Darras, B. T., Finkel, R. S., Connolly, A. M., Iannaccone, S. T., Kuntz, N. L., Pena, L. M., Schultz, M., Shieh, P. B., Smith, E. C., Ogrinc, F., Wells, C., Feltner, D., Sproule, D., Mendell, J. R. MARY ANN LIEBERT, INC. 2018: A82–A83

  View details for Web of Science ID 000453707700276

• Zero incidence of adeno-associated virus serotype 9 (AAV9) antibodies in a cohort of spinal muscular atrophy (SMA) type 1 patients screened in STR1VE, a pivotal phase 3 study of AVXS-101 Day, J. W., Chiriboga-Klein, C. A., Crawford, T., Darras, B. T., Finkel, R. S., Connolly, A. M., Iannaccone, S. T., Kuntz, N. L., Pena, L. M., Schultz, M., Shieh, P. B., Smith, E. C., Ogrinc, F., Wells, C., Feltner, D., Sproule, D., Mendell, J. R. MARY ANN LIEBERT, INC. 2018: A82–A83

  View details for Web of Science ID 000453707700264

• The Impact of Repeated Cardioversions and Escalation of Rhythm Control Therapies on Atrial Fibrillation Patients. Jacobs, V., May, H. T., Bair, T. L., Weiss, J. P., Day, J. D., Crandall, B. G., Cutler, M. J., Osborn, J. S., Mallender, C. D., Le, V. T., Bunch, T. J. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000528619400432

• Accelerated Aging in Duchenne Cardiomyopathy Chang, A. C., Pardon, G., Chang, A. C., Day, J. W., Wu, J. C., Pruitt, B., Blau, H. M. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000528619401070

• Teenage exercise is associated with earlier symptom onset in dysferlinopathy: a retrospective cohort study JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY Moore, U. R., Jacobs, M., Fernandez-Torron, R., Jang, J., James, M. K., Mayhew, A., Rufibach, L., Mittal, P., Eagle, M., Cnaan, A., Carlier, P. G., Blamire, A., Hilsden, H., Lochmueller, H., Grieben, U., Spuler, S., Rocha, C., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Harms, M., Pestronk, A., Krause, S., Schreiber-Katz, O., Walter, M. C., Paradas, C., Hogrel, J., Stojkovic, T., Takeda, S., Mori-Yoshimura, M., Bravver, E., Sparks, S., Diaz-Manera, J., Bello, L., Semplicini, C., Pegoraro, E., Mendell, J. R., Bushby, K., Straub, V. 2018; 89 (11): 1224-+

  View details for DOI 10.1136/jnnp-2017-317329

  View details for Web of Science ID 000450420200018

• Longitudinal pulmonary function testing outcome measures in Duchenne muscular dystrophy: Long-term natural history with and without glucocorticoids. Neuromuscular disorders : NMD McDonald, C. M., Gordish-Dressman, H., Henricson, E. K., Duong, T., Joyce, N. C., Jhawar, S., Leinonen, M., Hsu, F., Connolly, A. M., Cnaan, A., Abresch, R. T., CINRG investigators for PubMed, Dubrovsky, A., Kornberg, A., Ryan, M., Webster, R., Biggar, W. D., McAdam, L. C., Mah, J. K., Kolski, H., Vishwanathan, V., Chidambaranathan, S., Nevo, Y., Gorni, K., Carlo, J., Tulinius, M., Lotze, T., Bertorini, T. E., Day, J. W., Karachunski, P., Clemens, P. R., Abdel-Hamid, H., Teasley, J., Kuntz, N., Driscoll, S., Bodensteiner, J. B., Connolly, A. M., Pestronk, A., Abresch, R. T., Henricson, E. K., Joyce, N. C., McDonald, C. M., Cnaan, A., Morgenroth, L. P., Leshner, R., Tesi-Rocha, C., Thangarajh, M., Duong, T. 2018; 28 (11): 897–909

  Abstract

  We describe changes in pulmonary function measures across time in Duchenne muscular dystrophy patients treated with glucocorticoids (GCs) > 1 year compared to GC naive patients in the Cooperative International Research Group Duchenne Natural History Study, a multicenter prospective cohort study. 397 participants underwent 2799 pulmonary function assessments over a period up to 10 years. Fifty-three GC naive participants (< 1 month exposure) were compared to 322 subjects with > 1 year cumulative GC treatment. Forced vital capacity (FVC), peak expiratory flow rate (PEFr), maximal inspiratory and expiratory pressures were performed and calculated as a percent predicted (%p). GC treatment slowed the rate of pulmonary decline as measured by FVC%p, in patients aged 7-9.9 years. GC treatment slowed 12 and 24-month progression of percent predicted spirometry to a greater degree in those with baseline FVC%p from < 80-34%. GC treatment resulted in higher peak absolute FVC and PEFr values with later onset of decline. Progression to an absolute FVC < 1 liter was delayed by GC treatment. Patients who reached a FVC below 1L were 4.1 times more likely to die (p = 0.017). Long-term glucocorticoid treatment slows pulmonary disease progression in Duchenne dystrophy throughout the lifespan.

  View details for DOI 10.1016/j.nmd.2018.07.004

  View details for PubMedID 30336970

• Myelin Abnormality in Charcot-Marie-Tooth Type 4J Recapitulates Features of Acquired Demyelination Hu, B., McCollum, M., Ravi, V., Arpag, S., Moiseev, D., Castoro, R., Mobley, B., Burnette, B., Siskind, C., Day, J., Yawn, R., Feely, S., Li, Y., Yan, Q., Shy, M., Li, J. WILEY. 2018: S113

  View details for Web of Science ID 000446520900178

• Efficacy, safety profile, and immunogenicity of alglucosidase alfa produced at the 4,000-liter scale in US children and adolescents with Pompe disease: ADVANCE, a phase IV, open-label, prospective study GENETICS IN MEDICINE Hahn, S., Kronn, D., Leslie, N. D., Pena, L. M., Tanpaiboon, P., Gambello, M. J., Gibson, J. B., Hillman, R., Stockton, D. W., Day, J. W., Wang, R. Y., Haack, K., Shafi, R., Sparks, S., Zhao, Y., Wilson, C., Kishnani, P. S., Pompe ADV Study Consortium 2018; 20 (10): 1284–94

  Abstract

  PurposePompe disease results from lysosomal acid α-glucosidase (GAA) deficiency and its associated glycogen accumulation and muscle damage. Alglucosidase alfa (recombinant human GAA (rhGAA)) received approval in 2006 as a treatment for Pompe disease at the 160 L production scale. In 2010, larger-scale rhGAA was approved for patients up to 8 years old without cardiomyopathy. NCT01526785 evaluated 4,000 L rhGAA efficacy/safety in US infantile- or late-onset Pompe disease (IOPD, LOPD) patients up to 1 year old transitioned from 160 L rhGAA.MethodsA total of 113 patients (87 with IOPD; 26 with LOPD) received 4,000 L rhGAA for 52 weeks dosed the same as previous 160 L rhGAA. Efficacy was calculated as the percentage of patients stable/improved at week 52 (without death, new requirement for invasive ventilation, left ventricular mass z-score increase >1 if baseline was >2, upright forced vital capacity decrease ≥15% predicted, or Gross Motor Function Measure-88 decrease ≥8 percentage points). Safety evaluation included an extension ≤20 months.ResultsWeek 52 data was available for 104 patients, 100 of whom entered the extension. At week 52, 87/104 (83.7%) were stable/improved. Overall survival was 98.1% overall, 97.6% IOPD, 100% LOPD; 92.4% remained invasive ventilator-free (93.4% IOPD, 88.7% LOPD). Thirty-five patients had infusion-associated reactions. Eight IOPD patients died of drug-unrelated causes.ConclusionsMost Pompe disease patients were clinically stable/improved after transitioning to 4,000 L rhGAA. Safety profiles of both rhGAA forms were consistent.Genetics in Medicine advance online publication, 22 March 2018; doi:10.1038/gim.2018.2.

  View details for PubMedID 29565424

• Clinical outcome study in dysferlinopathy: random forest approach to assess the relationship between baseline muscle MRI and longitudinal functional outcome measures Diaz-Manera, J., Fernandez-Torron, R., James, M., Mayhew, A., Jacobs, M., Spuler, S., Day, J., Jones, K., Bharucha-Goebel, D., Salort-Campana, E., Pestronk, A., Walter, M., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Pegoraro, E., Mendell, J., Bushby, K., Straub, V. PERGAMON-ELSEVIER SCIENCE LTD. 2018: S34–S35

  View details for DOI 10.1016/j.nmd.2018.06.040

  View details for Web of Science ID 000449126600021

• Clinical outcome study in dysferlinopathy: medical comorbidities and polytherapy in a large population of dysferlinopathy patients Fernandez-Torron, R., Diaz-Manera, J., James, M., Mayhew, A., Spuler, S., Day, J., Jones, K., Bharucha-Goebel, D., Salort-Campana, E., Pestronk, A., Walter, M., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Pegoraro, E., Mendell, J., Bushby, K., Straub, V., Jain Consortium PERGAMON-ELSEVIER SCIENCE LTD. 2018: S35

  View details for DOI 10.1016/j.nmd.2018.06.041

  View details for Web of Science ID 000449126600022

• Rasch analysis of the individualised neuromuscular Quality of Life Questionnaire administered to patients with dysferlinopathy James, M., Mayhew, A., Jacobs, M., Spuler, S., Day, J., Jones, K., Bharucha-Goebel, D., Salort-Campana, E., Pestronk, A., Walter, M., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Diaz Manera, J., Pegoraro, E., Mendell, J., Bushby, K., Straub, V. PERGAMON-ELSEVIER SCIENCE LTD. 2018: S35

  View details for DOI 10.1016/j.nmd.2018.06.042

  View details for Web of Science ID 000449126600023

• FIREFISH Part 1: early clinical results following a significant increase of SMN protein in SMA type 1 babies treated with RG7916 Baranello, G., Servais, L., Day, J., Deconinck, N., Mercuri, E., Klein, A., Darras, B., Masson, R., Kletzl, H., Cleary, Y., Armstrong, G., Seabrook, T., Czech, C., Gerber, M., Gelblin, K., Gorni, K., Khwaja, O. PERGAMON-ELSEVIER SCIENCE LTD. 2018: S109

  View details for DOI 10.1016/j.nmd.2018.06.306

  View details for Web of Science ID 000449126600284

• A study of RG7916 in infants with pre-symptomatic spinal muscular atrophy Bertini, E., Day, J., Al Muhaizea, M., Xiong, H., Servais, L., Prufer, A., Buchbjerg, J., Armstrong, G., Gorni, K., Khwaja, O. PERGAMON-ELSEVIER SCIENCE LTD. 2018: S108–S109

  View details for DOI 10.1016/j.nmd.2018.06.304

  View details for Web of Science ID 000449126600282

• AVXS-101 gene replacement therapy for spinal muscular atrophy type 1: pivotal study (STRIVE) update Day, J., Feltner, D., Ogrinc, F., Macek, T., Wells, C., Muehring, L., Italien, J. L., Sproule, D., Nagendran, S., Kaspar, B., Mendell, J. PERGAMON-ELSEVIER SCIENCE LTD. 2018: S82–S83

  View details for DOI 10.1016/j.nmd.2018.06.209

  View details for Web of Science ID 000449126600188

• SMN protein levels before and after treatment with RG7916 in type 1, 2 and 3 SMA patients compared to healthy subjects Kletzl, H., Czech, C., Cleary, Y., Sturm, S., Gunther, A., Baranello, G., Mercuri, E., Servais, L., Day, J., Deconinck, N., Klein, A., Darras, B., Masson, R., Kirschner, J., Goemans, N., Pera, M., Chiriboga, C., Fischer, D., Gorni, K., Khwaja, O. PERGAMON-ELSEVIER SCIENCE LTD. 2018: S109–S110

  View details for DOI 10.1016/j.nmd.2018.06.307

  View details for Web of Science ID 000449126600285

• Experience using Spinraza to treat adults with spinal muscular atrophy Day, J., Wolford, C., Macpherson, C., Hagerman, K., Paulose, S., Zeineh, M., Martens, W., McDermott, M., Darras, B., De Vivo, D., Cunningham, Z., Finkel, R., Sampson, J., Duong, T. PERGAMON-ELSEVIER SCIENCE LTD. 2018: S81

  View details for DOI 10.1016/j.nmd.2018.06.204

  View details for Web of Science ID 000449126600183

• Telomere shortening is a hallmark of genetic cardiomyopathies PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Chang, A. Y., Chang, A. H., Kirillova, A., Sasagawa, K., Su, W., Weber, G., Lin, J., Termglinchan, V., Karakikes, I., Seeger, T., Dainis, A. M., Hinson, J. T., Seidman, J., Seidman, C. E., Day, J. W., Ashley, E., Wu, J. C., Blau, H. M. 2018; 115 (37): 9276–81

  View details for DOI 10.1073/pnas.1714538115

  View details for Web of Science ID 000444257200069

• RASCH ANALYSIS OF THE INDIVIDUALIZED NEUROMUSCULAR QUALITY OF LIFE QUESTIONNAIRE ADMINISTERED TO PATIENTS WITH DYSFERLINOPATHY Mayhew, A. G., James, M. K., Jacobs, M., Feng, J., Spuler, S., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Pestronk, A., Walter, M. C., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Manera, J., Pegoraro, E., Mendell, J. R., Bushby, K., Straub, V., Jain COS Consortium WILEY. 2018: S20

  View details for Web of Science ID 000443946800069

• A PHASE 2 CLINICAL TRIAL OF RELDESEMTIV, A FAST SKELETAL MUSCLE TROPONIN ACTIVATOR, FOR THE POTENTIAL TREATMENT OF SPINAL MUSCULAR ATROPHY (SMA) Rudnicki, S. A., Andrews, J. A., Malik, F. I., Meng, L., Wei, J., Wolff, A. A., Day, J. W. WILEY. 2018: S14

  View details for Web of Science ID 000443946800048

• Telomere shortening is a hallmark of genetic cardiomyopathies. Proceedings of the National Academy of Sciences of the United States of America Chang, A. C., Chang, A. C., Kirillova, A., Sasagawa, K., Su, W., Weber, G., Lin, J., Termglinchan, V., Karakikes, I., Seeger, T., Dainis, A. M., Hinson, J. T., Seidman, J., Seidman, C. E., Day, J. W., Ashley, E., Wu, J. C., Blau, H. M. 2018

  Abstract

  This study demonstrates that significantly shortened telomeres are a hallmark of cardiomyocytes (CMs) from individuals with end-stage hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM) as a result of heritable defects in cardiac proteins critical to contractile function. Positioned at the ends of chromosomes, telomeres are DNA repeats that serve as protective caps that shorten with each cell division, a marker of aging. CMs are a known exception in which telomeres remain relatively stable throughout life in healthy individuals. We found that, relative to healthy controls, telomeres are significantly shorter in CMs of genetic HCM and DCM patient tissues harboring pathogenic mutations: TNNI3, MYBPC3, MYH7, DMD, TNNT2, and TTN Quantitative FISH (Q-FISH) of single cells revealed that telomeres were significantly reduced by 26% in HCM and 40% in DCM patient CMs in fixed tissue sections compared with CMs from age- and sex-matched healthy controls. In the cardiac tissues of the same patients, telomere shortening was not evident in vascular smooth muscle cells that do not express or require the contractile proteins, an important control. Telomere shortening was recapitulated in DCM and HCM CMs differentiated from patient-derived human-induced pluripotent stem cells (hiPSCs) measured by two independent assays. This study reveals telomere shortening as a hallmark of genetic HCM and DCM and demonstrates that this shortening can be modeled in vitro by using the hiPSC platform, enabling drug discovery.

  View details for PubMedID 30150400

• Quantitative Evaluation of Lower Extremity Joint Contractures in Spinal Muscular Atrophy: Implications for Motor Function. Pediatric physical therapy : the official publication of the Section on Pediatrics of the American Physical Therapy Association Salazar, R., Montes, J., Dunaway Young, S., McDermott, M. P., Martens, W., Pasternak, A., Quigley, J., Mirek, E., Glanzman, A. M., Civitello, M., Gee, R., Duong, T., Mazzone, E. S., Main, M., Mayhew, A., Ramsey, D., Muni Lofra, R., Coratti, G., Fanelli, L., De Sanctis, R., Forcina, N., Chiriboga, C., Darras, B. T., Tennekoon, G. I., Scoto, M., Day, J. W., Finkel, R., Muntoni, F., Mercuri, E., De Vivo, D. C. 2018; 30 (3): 209–15

  Abstract

  PURPOSE: To quantitatively describe passive lower extremity range of motion in participants with spinal muscular atrophy (SMA) types 2 and 3, and to establish preliminary thresholds to identify individuals at risk for performing poorly on disease-specific motor function outcome measures.METHODS: Eighty participants with SMA types 2 and 3, enrolled in an international multicenter natural history study, were evaluated with lower extremity range of motion testing and the Hammersmith Functional Motor Scale-Expanded.RESULTS: A hip extension joint angle of -7.5° or less for SMA type 2 and 0° or less for SMA type 3 identified diminished motor ability with good sensitivity. For knee extension, a joint angle of -9.0° or less for SMA type 2 or 0° or less for SMA type 3 was similarly sensitive.CONCLUSIONS: Minimal hip and knee joint contractures were associated with diminished motor ability. Clinical trial designs should consider the effect of contractures on motor function.

  View details for PubMedID 29924070

• Quantitative Evaluation of Lower Extremity Joint Contractures in Spinal Muscular Atrophy: Implications for Motor Function PEDIATRIC PHYSICAL THERAPY Salazar, R., Montes, J., Young, S., McDermott, M. P., Martens, W., Pasternak, A., Quigley, J., Mirek, E., Glanzman, A. M., Civitello, M., Gee, R., Duong, T., Mazzone, E. S., Main, M., Mayhew, A., Ramsey, D., Lofra, R., Coratti, G., Fanelli, L., De Sanctis, R., Forcina, N., Chiriboga, C., Darras, B. T., Tennekoon, G. I., Scoto, M., Day, J. W., Finkel, R., Muntoni, F., Mercuri, E., De Vivo, D. C. 2018; 30 (3): 209–15

  View details for DOI 10.1097/PEP.0000000000000515

  View details for Web of Science ID 000437964600015

• Ambulatory function in spinal muscular atrophy: Age-related patterns of progression PLOS ONE Montes, J., McDermott, M. P., Mirek, E., Mazzone, E. S., Main, M., Glanzman, A. M., Duong, T., Young, S., Salazar, R., Pasternak, A., Gee, R., De Sanctis, R., Coratti, G., Forcina, N., Fanelli, L., Ramsey, D., Milev, E., Civitello, M., Pane, M., Pera, M., Scoto, M., Day, J. W., Tennekoon, G., Finkel, R. S., Darras, B. T., Muntoni, F., De Vivo, D. C., Mercuri, E. 2018; 13 (6): e0199657

  Abstract

  Individuals with spinal muscular atrophy (SMA) type 3 are able to walk but they have weakness, gait impairments and fatigue. Our primary study objective was to examine longitudinal changes in the six-minute walk test (6MWT) and to evaluate whether age and SMA type 3 subtype are associated with decline in ambulatory function. Data from three prospective natural history studies were used. Seventy-three participants who performed the 6MWT more than once, at least 6 months apart, were included; follow-up ranged from 0.5-9 years. Only data from patients who completed the 6MWT were included. The mean age of the participants was 13.5 years (range 2.6-49.1), with 52 having disease onset before age 3 years (type 3A). At baseline, type 3A participants walked a shorter distance on average (257.1 m) than type 3B participants (390.2 m) (difference = 133.1 m, 95% confidence interval [CI] 71.8-194.3, p < 0.001). Distance walked was weakly associated with age (r = 0.25, p = 0.04). Linear mixed effects models were used to estimate the mean annual rate of change. The overall mean rate of change was -7.8 m/year (95% CI -13.6 --2.0, p = 0.009) and this did not differ by subtype (type 3A: -8.5 m/year, type 3B: -6.6 m/year, p = 0.78), but it did differ by age group (< 6: 9.8 m/year; 6-10: -7.9 m/year; 11-19: -20.8 m/year; ≥ 20: -9.7 m/year; p = 0.005). Our results showed an overall decline on the 6MWT over time, but different trajectories were observed depending on age. Young ambulant SMA patients gain function but in adolescence, patients lose function. Future clinical trials in ambulant SMA patients should consider in their design the different trajectories of ambulatory function over time, based on age.

  View details for PubMedID 29944707

• rbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences NATURE COMMUNICATIONS Sellier, C., Cerro-Herreros, E., Blatter, M., Freyermuth, F., Gaucherot, A., Ruffenach, F., Sarkar, P., Puymirat, J., Udd, B., Day, J. W., Meola, G., Bassez, G., Fujimura, H., Takahashi, M. P., Schoser, B., Furling, D., Artero, R., Allain, F. T., Llamusi, B., Charlet-Berguerand, N. 2018; 9: 2009

  Abstract

  Myotonic dystrophy type 1 and type 2 (DM1, DM2) are caused by expansions of CTG and CCTG repeats, respectively. RNAs containing expanded CUG or CCUG repeats interfere with the metabolism of other RNAs through titration of the Muscleblind-like (MBNL) RNA binding proteins. DM2 follows a more favorable clinical course than DM1, suggesting that specific modifiers may modulate DM severity. Here, we report that the rbFOX1 RNA binding protein binds to expanded CCUG RNA repeats, but not to expanded CUG RNA repeats. Interestingly, rbFOX1 competes with MBNL1 for binding to CCUG expanded repeats and overexpression of rbFOX1 partly releases MBNL1 from sequestration within CCUG RNA foci in DM2 muscle cells. Furthermore, expression of rbFOX1 corrects alternative splicing alterations and rescues muscle atrophy, climbing and flying defects caused by expression of expanded CCUG repeats in a Drosophila model of DM2.

  View details for PubMedID 29789616

• Disease progression in Myotonic Dystrophy Type 1 during a non-interventional multicenter study Mankodi, A., Statland, J., Eichinger, K., Dekdebrun, J., Day, J., Subramony, S., Kissel, J., Ashizawa, T., Thornton, C., Myotonic Dystrophy Res Network LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090805272

• Nusinersen Efficacy in Adults with Spinal Muscular Atrophy Day, J., Wolford, C., MacPherson, C., Martens, W., McDermott, M., Darras, B., De Vivo, D., Cunningham, Z., Finkel, R., Sampson, J., Duong, T. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090806001

• Examining longitudinal functional changes in Dysferlinopathy: The JAIN Clinical Outcome Study Lowes, L., James, M., Mayhew, A., Alfano, L., Jacobs, M., Spuler, S., Jones, K. J., Day, J., Bharucha-Goebel, D., Campana-Salort, E., Pestronk, A., Walter, M., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Pegoraro, E., Diaz Manera, J., Duong, T., Rose, K., Mendell, J., Bushby, K., Straub, V. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090804250

• Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Feasibility for Individuals with Severe Spinal Muscular Atrophy II Kichula, E., Duong, T., Glanzman, A., Pasternak, A., Darras, B., Finkel, R., De Vivo, D., Zolkipli-Cunningham, Z., Day, J. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090806004

• Targeted Next Generation Sequencing (NGS) for Analysis of Splicing Biomarkers of Myotonic Dystrophy Type 1 (DM1) Thornton, C., Wang, W., Mankodi, A., Subramony, S., Ashizawa, T., Day, J., Statland, J., Arnold, W., Kissel, J., Myotonic Dystrophy Clinical Res N LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090805270

• Is cardiac dysfunction a feature of dysferlinopathy? Data from the Clinical Outcome Study of Dysferlinopathy Tiet, M., Fernandez-Torron, R., Bourke, J., Bettinson, K., Harris, E., Hilsden, H., Spuler, S., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Pestronk, A., Walter, M. C., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Manera, J., Pegoraro, E., Mendell, J. R., Bushby, K., Straub, V., Jain COS Consortium PERGAMON-ELSEVIER SCIENCE LTD. 2018: S5–S6

  View details for Web of Science ID 000432769200015

• Myelin abnormality in Charcot-Marie-Tooth type 4J recapitulates features of acquired demyelination ANNALS OF NEUROLOGY Hu, B., McCollum, M., Ravi, V., Arpag, S., Moiseev, D., Castoro, R., Mobley, B., Burnette, B., Siskind, C., Day, J., Yawn, R., Feely, S., Li, Y., Yan, Q., Shy, M., Li, J. 2018; 83 (4): 756–70

  Abstract

  Charcot-Marie-Tooth type 4J (CMT4J) is a rare autosomal recessive neuropathy caused by mutations in FIG4 that result in loss of FIG4 protein. This study investigates the natural history and mechanisms of segmental demyelination in CMT4J.Over the past 9 years, we have enrolled and studied a cohort of 12 CMT4J patients, including 6 novel FIG4 mutations. We evaluated these patients and related mouse models using morphological, electrophysiological, and biochemical approaches.We found sensory motor demyelinating polyneuropathy consistently in all patients. This underlying myelin pathology was associated with nonuniform slowing of conduction velocities, conduction block, and temporal dispersion on nerve conduction studies, which resemble those features in acquired demyelinating peripheral nerve diseases. Segmental demyelination was also confirmed in mice without Fig4 (Fig4-/- ). The demyelination was associated with an increase of Schwann cell dedifferentiation and macrophages in spinal roots where nerve-blood barriers are weak. Schwann cell dedifferentiation was induced by the increasing intracellular Ca2+ . Suppression of Ca2+ level by a chelator reduced dedifferentiation and demyelination of Schwann cells in vitro and in vivo. Interestingly, cell-specific knockout of Fig4 in mouse Schwann cells or neurons failed to cause segmental demyelination.Myelin change in CMT4J recapitulates the features of acquired demyelinating neuropathies. This pathology is not Schwann cell autonomous. Instead, it relates to systemic processes involving interactions of multiple cell types and abnormally elevated intracellular Ca2+ . Injection of a Ca2+ chelator into Fig4-/- mice improved segmental demyelination, thereby providing a therapeutic strategy against demyelination. Ann Neurol 2018;83:756-770.

  View details for PubMedID 29518270

• Clinical Outcome Study of Dysferlinopathy: what are the best outcome measures for dysferlinopathy patients? James, M. K., Jacobs, M., Mayhew, A., Feng, J., Spuler, S., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Pestronk, A., Walter, M. C., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Manera, J., Pegoraro, E., Mendell, J. R., Bushby, K., Straub, V., Jain COS Consortium PERGAMON-ELSEVIER SCIENCE LTD. 2018: S6

  View details for Web of Science ID 000432769200016

• Longitudinal upper limb muscle MRI in dysferlinopathy: examining the relationship between semi quantitative MRI and physiotherapy outcome measures Fernandez-Torron, R., James, M. K., Mayhew, A., Eagle, M., Lofra, R., Diaz-Manera, J., Blamire, A. M., Carlier, P. G., Hilsden, H., Stojkovic, T., Walter, M. C., Coppenrath, E. M., Peduto, A., Jones, K. J., Sawyer, A. M., Rocha, C., Day, J. W., Bushby, K., Straub, V., Jain COS Consortium PERGAMON-ELSEVIER SCIENCE LTD. 2018: S6–S7

  View details for Web of Science ID 000432769200017

• Humanizing the mdx mouse model of DMD: the long and the short of it NPJ REGENERATIVE MEDICINE Yucel, N., Chang, A. C., Day, J. W., Rosenthal, N., Blau, H. M. 2018; 3: 4

  Abstract

  Duchenne muscular dystrophy (DMD) is a common fatal heritable myopathy, with cardiorespiratory failure occurring by the third decade of life. There is no specific treatment for DMD cardiomyopathy, in large part due to a lack of understanding of the mechanisms underlying the cardiac failure. Mdx mice, which have the same dystrophin mutation as human patients, are of limited use, as they do not develop early dilated cardiomyopathy as seen in patients. Here we summarize the usefulness of the various commonly used DMD mouse models, highlight a model with shortened telomeres like humans, and identify directions that warrant further investigation.

  View details for PubMedID 29479480

• Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy NEW ENGLAND JOURNAL OF MEDICINE Mercuri, E., Darras, B. T., Chiriboga, C. A., Day, J. W., Campbell, C., Connolly, A. M., Iannaccone, S. T., Kirschner, J., Kuntz, N. L., Saito, K., Shieh, P. B., Tulinius, M., Mazzone, E. S., Montes, J., Bishop, K. M., Yang, Q., Foster, R., Gheuens, S., Bennett, C. F., Farwell, W., Schneider, E., De Vivo, D. C., Finkel, R. S., CHERISH Study Grp 2018; 378 (7): 625–35

  Abstract

  Nusinersen is an antisense oligonucleotide drug that modulates pre-messenger RNA splicing of the survival motor neuron 2 ( SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA).We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (≥3 points), an outcome that indicates improvement in at least two motor skills.In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by -1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; P<0.001). This result prompted early termination of the trial. Results of the final analysis were consistent with results of the interim analysis. In the final analysis, 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (P<0.001), and the overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively).Among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group. (Funded by Biogen and Ionis Pharmaceuticals; CHERISH ClinicalTrials.gov number, NCT02292537 .).

  View details for PubMedID 29443664

• Long-term effects of glucocorticoids on function, quality of life, and survival in patients with Duchenne muscular dystrophy: a prospective cohort study LANCET McDonald, C. M., Henricson, E. K., Abresch, R. T., Duong, T., Joyce, N. C., Hu, F., Clemens, P. R., Hoffman, E. P., Cnaan, A., Gordish-Dressman, H., CINRG Investigators 2018; 391 (10119): 451–61

  Abstract

  Glucocorticoid treatment is recommended as a standard of care in Duchenne muscular dystrophy; however, few studies have assessed the long-term benefits of this treatment. We examined the long-term effects of glucocorticoids on milestone-related disease progression across the lifespan and survival in patients with Duchenne muscular dystrophy.For this prospective cohort study, we enrolled male patients aged 2-28 years with Duchenne muscular dystrophy at 20 centres in nine countries. Patients were followed up for 10 years. We compared no glucocorticoid treatment or cumulative treatment duration of less than 1 month versus treatment of 1 year or longer with regard to progression of nine disease-related and clinically meaningful mobility and upper limb milestones. We used Kaplan-Meier analyses to compare glucocorticoid treatment groups for time to stand from supine of 5 s or longer and 10 s or longer, and loss of stand from supine, four-stair climb, ambulation, full overhead reach, hand-to-mouth function, and hand function. Risk of death was also assessed. This study is registered with ClinicalTrials.gov, number NCT00468832.440 patients were enrolled during two recruitment periods (2006-09 and 2012-16). Time to all disease progression milestone events was significantly longer in patients treated with glucocorticoids for 1 year or longer than in patients treated for less than 1 month or never treated (log-rank p<0·0001). Glucocorticoid treatment for 1 year or longer was associated with increased median age at loss of mobility milestones by 2·1-4·4 years and upper limb milestones by 2·8-8·0 years compared with treatment for less than 1 month. Deflazacort was associated with increased median age at loss of three milestones by 2·1-2·7 years in comparison with prednisone or prednisolone (log-rank p<0·012). 45 patients died during the 10-year follow-up. 39 (87%) of these deaths were attributable to Duchenne-related causes in patients with known duration of glucocorticoids usage. 28 (9%) deaths occurred in 311 patients treated with glucocorticoids for 1 year or longer compared with 11 (19%) deaths in 58 patients with no history of glucocorticoid use (odds ratio 0·47, 95% CI 0·22-1·00; p=0·0501).In patients with Duchenne muscular dystrophy, glucocorticoid treatment is associated with reduced risk of losing clinically meaningful mobility and upper limb disease progression milestones across the lifespan as well as reduced risk of death.US Department of Education/National Institute on Disability and Rehabilitation Research; US Department of Defense; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases; and Parent Project Muscular Dystrophy.

  View details for DOI 10.1016/S0140-6736(17)32160-8

  View details for Web of Science ID 000424333600034

  View details for PubMedID 29174484

• Charcot Marie Tooth disease type 4J with complex central nervous system features ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY Orengo, J. P., Khemani, P., Day, J. W., Li, J., Siskind, C. E. 2018; 5 (2): 222–25

  Abstract

  We describe a family with Charcot Marie Tooth disease type 4J presenting with features of Charcot Marie Tooth disease plus parkinsonism and aphemia. Genetic testing found two variants in the FIG4 gene: c.122T>C (p.I41T) - the most common Charcot Marie Tooth disease type 4J variant - and c.1949-10T>G (intronic). Proband fibroblasts showed absent FIG4 protein on western blot, and skipping of exon 18 by RT-PCR. As most patients with Charcot Marie Tooth disease type 4J do not have central nervous system deficits, we postulate the intronic variant and I41T mutation together are causing loss of FIG4 protein and subsequently the central nervous system findings in our family.

  View details for PubMedID 29468183

• Increased EEG Theta Spectral Power in Sleep in Myotonic Dystrophy Type 1. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine Cheung, J. n., Ruoff, C. n., Moore, H. n., Hagerman, K. A., Perez, J. n., Sakamuri, S. n., Warby, S. C., Mignot, E. n., Day, J. n., Sampson, J. n. 2018; 14 (2): 229–35

  Abstract

  Myotonic dystrophy type 1 (DM1) is a multisystemic disorder that involves the central nervous system (CNS). Individuals with DM1 commonly present with sleep dysregulation, including excessive daytime sleepiness and sleep-disordered breathing. We aim to characterize electroencephalogram (EEG) power spectra from nocturnal polysomnography (PSG) in patients with DM1 compared to matched controls to better understand the potential CNS sleep dysfunction in DM1.A retrospective, case-control (1:2) chart review of patients with DM1 (n = 18) and matched controls (n = 36) referred for clinical PSG at the Stanford Sleep Center was performed. Controls were matched based on age, sex, apnea-hypopnea index (AHI), body mass index (BMI), and Epworth Sleepiness Scale (ESS). Sleep stage and respiratory metrics for the two groups were compared. Power spectral analysis of the EEG C3-M2 signal was performed using the fast Fourier transformation.Patients with DM1 had significantly increased theta percent power in stage N2 sleep compared to matched controls. Theta/beta and theta/alpha percent power spectral ratios were found to be significantly increased in stage N2, N3, all sleep stages combined, and all wake periods combined in patients with DM1 compared to controls. A significantly lower nadir O2saturation was also found in patients with DM1 versus controls.Compared to matched controls, patients with DM1 had increased EEG theta spectral power. Increased theta/beta and theta/alpha power spectral ratios in nocturnal PSG may reflect DM1 pathology in the CNS.

  View details for PubMedID 29394960

• Teenage exercise is associated with earlier symptom onset in dysferlinopathy: a retrospective cohort study. Journal of neurology, neurosurgery, and psychiatry Moore, U. R., Jacobs, M. n., Fernandez-Torron, R. n., Jang, J. n., James, M. K., Mayhew, A. n., Rufibach, L. n., Mittal, P. n., Eagle, M. n., Cnaan, A. n., Carlier, P. G., Blamire, A. n., Hilsden, H. n., Lochmüller, H. n., Grieben, U. n., Spuler, S. n., Tesi Rocha, C. n., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E. n., Harms, M. n., Pestronk, A. n., Krause, S. n., Schreiber-Katz, O. n., Walter, M. C., Paradas, C. n., Hogrel, J. Y., Stojkovic, T. n., Takeda, S. n., Mori-Yoshimura, M. n., Bravver, E. n., Sparks, S. n., Diaz-Manera, J. n., Bello, L. n., Semplicini, C. n., Pegoraro, E. n., Mendell, J. R., Bushby, K. n., Straub, V. n. 2018

  View details for PubMedID 29378789

• Muscle MRI in patients with dysferlinopathy: pattern recognition and implications for clinical trials. Journal of neurology, neurosurgery, and psychiatry Diaz-Manera, J. n., Fernandez-Torron, R. n., LLauger, J. n., James, M. K., Mayhew, A. n., Smith, F. E., Moore, U. R., Blamire, A. M., Carlier, P. G., Rufibach, L. n., Mittal, P. n., Eagle, M. n., Jacobs, M. n., Hodgson, T. n., Wallace, D. n., Ward, L. n., Smith, M. n., Stramare, R. n., Rampado, A. n., Sato, N. n., Tamaru, T. n., Harwick, B. n., Rico Gala, S. n., Turk, S. n., Coppenrath, E. M., Foster, G. n., Bendahan, D. n., Le Fur, Y. n., Fricke, S. T., Otero, H. n., Foster, S. L., Peduto, A. n., Sawyer, A. M., Hilsden, H. n., Lochmuller, H. n., Grieben, U. n., Spuler, S. n., Tesi Rocha, C. n., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E. n., Harms, M. n., Pestronk, A. n., Krause, S. n., Schreiber-Katz, O. n., Walter, M. C., Paradas, C. n., Hogrel, J. Y., Stojkovic, T. n., Takeda, S. n., Mori-Yoshimura, M. n., Bravver, E. n., Sparks, S. n., Bello, L. n., Semplicini, C. n., Pegoraro, E. n., Mendell, J. R., Bushby, K. n., Straub, V. n. 2018

  Abstract

  Dysferlinopathies are a group of muscle disorders caused by mutations in the DYSF gene. Previous muscle imaging studies describe a selective pattern of muscle involvement in smaller patient cohorts, but a large imaging study across the entire spectrum of the dysferlinopathies had not been performed and previous imaging findings were not correlated with functional tests.We present cross-sectional T1-weighted muscle MRI data from 182 patients with genetically confirmed dysferlinopathies. We have analysed the pattern of muscles involved in the disease using hierarchical analysis and presented it as heatmaps. Results of the MRI scans have been correlated with relevant functional tests for each region of the body analysed.In 181 of the 182 patients scanned, we observed muscle pathology on T1-weighted images, with the gastrocnemius medialis and the soleus being the most commonly affected muscles. A similar pattern of involvement was identified in most patients regardless of their clinical presentation. Increased muscle pathology on MRI correlated positively with disease duration and functional impairment.The information generated by this study is of high diagnostic value and important for clinical trial development. We have been able to describe a pattern that can be considered as characteristic of dysferlinopathy. We have defined the natural history of the disease from a radiological point of view. These results enabled the identification of the most relevant regions of interest for quantitative MRI in longitudinal studies, such as clinical trials.NCT01676077.

  View details for PubMedID 29735511

• Treatment Algorithm for Infants Diagnosed with Spinal Muscular Atrophy through Newborn Screening. Journal of neuromuscular diseases Glascock, J., Sampson, J., Haidet-Phillips, A., Connolly, A., Darras, B., Day, J., Finkel, R., Howell, R. R., Klinger, K., Kuntz, N., Prior, T., Shieh, P. B., Crawford, T. O., Kerr, D., Jarecki, J. 2018; 5 (2): 145–58

  Abstract

  BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by the degeneration of alpha motor neurons in the spinal cord, leading to muscular atrophy. SMA is caused by deletions or mutations in the survival motor neuron 1 gene (SMN1). In humans, a nearly identical copy gene, SMN2, is present. Because SMN2 has been shown to decrease disease severity in a dose-dependent manner, SMN2 copy number is predictive of disease severity.OBJECTIVE: To develop a treatment algorithm for SMA-positive infants identified through newborn screening based upon SMN2 copy number.METHODS: A working group comprised of 15 SMA experts participated in a modified Delphi process, moderated by a neutral third-party expert, to develop treatment guidelines.RESULTS: The overarching recommendation is that all infants with two or three copies of SMN2 should receive immediate treatment (n = 13). For those infants in which immediate treatment is not recommended, guidelines were developed that outline the timing and appropriate screens and tests to be used to determine the timing of treatment initiation.CONCLUSIONS: The identification SMA affected infants via newborn screening presents an unprecedented opportunity for achievement of maximal therapeutic benefit through the administration of treatment pre-symptomatically. The recommendations provided here are intended to help formulate treatment guidelines for infants who test positive during the newborn screening process.

  View details for PubMedID 29614695

• Evaluator Training and Reliability for SMA Global Nusinersen Trials1. Journal of neuromuscular diseases Glanzman, A. M., Mazzone, E. S., Young, S. D., Gee, R., Rose, K., Mayhew, A., Nelson, L., Yun, C., Alexander, K., Darras, B. T., Zolkipli-Cunningham, Z., Tennekoon, G., Day, J. W., Finkel, R. S., Mercuri, E., De Vivo, D. C., Baldwin, R., Bishop, K. M., Montes, J. 2018; 5 (2): 159–66

  Abstract

  BACKGROUND: Training methodology was established to optimize reliability of outcome measures in the nusinersen clinical trials. The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), Hammersmith Functional Motor Scale Expanded (HFMSE), and Revised Upper Limb (RULM) were primary or secondary outcomes.METHODS: Video review, quarterly conference calls, and item scoring checks supported evaluator competence. Baseline and screening along with video review established intra and inter-rater reliability.RESULTS: Inter and intra-rater reliability were both excellent. Intraclass correlation coefficients (ICC) ranged between 0.906-0.994 across initial training meetings and 0.824-0.996 across annual retraining meetings. This was similar for CHOP INTEND (ICC = 0.824-0.951), HFMSE (ICC = 0.981-0.996), and RULM (ICC = 0.966-0.990). Intra-rater reliability for the CHOP INTEND, HFMSE, and RULM were ICC = 0.895 (95% CI: 0.852-0.926; n = 116), ICC = 0.959 (95% CI: 0.942-0.971; n = 125), and ICC = 0.948 (95% CI: 0.927-0.963; n = 126) respectively.CONCLUSIONS: Rigorous evaluator training ensures reliability of assessment of subjects with spinal muscular atrophy (SMA) in multicenter international trials.

  View details for PubMedID 29865090

• The clinical outcome study of dysferlinopathy: Muscle MRI pattern at baseline and longitudinal changes over one year Mori-Yoshimura, M., Fernandez-Torron, R., Meredith, J., Jabobs, M., Smith, F., Azzabou, N., Manera, J. D., Spuler, S., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campanak, E., Pestronk, A., Walter, M. C., Paradas, C., Stojkovic, T., Bravver, E., Pegoraro, E., Mendell, J. R., Straub, V. ELSEVIER SCIENCE BV. 2017: 819

  View details for DOI 10.1016/j.jns.2017.08.2305

  View details for Web of Science ID 000427450303170

• Clinical outcome study of dysferlinopathy: what are the best outcome measures for dysferlinopathy patients? James, M., Jacobs, M., Mayhew, A., Feng, J., Spuler, S., Day, J., Jones, K., Bharucha-Goebel, D., Salort-Campana, E., Pestronk, A., Walter, M., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Diaz-Manera, J., Pegoraro, E., Mendell, J., Bushby, K., Straub, V. PERGAMON-ELSEVIER SCIENCE LTD. 2017: S227

  View details for DOI 10.1016/j.nmd.2017.06.477

  View details for Web of Science ID 000412961500460

• Is cardiac dysfunction a feature of dysferlinopathy? Data from the clinical outcome study of dysferlinopathy Torron, R., Harris, E., Bourke, J., Bettinson, K., Hilsden, H., Spuler, S., Day, J., Jones, K., Bharucha-Goebel, D., Salort-Campana, E., Pestronk, A., Walter, M., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Diaz-Manera, J., Pegoraro, E., Mendell, J., Bushby, K., Straub, V. PERGAMON-ELSEVIER SCIENCE LTD. 2017: S145

  View details for DOI 10.1016/j.nmd.2017.06.190

  View details for Web of Science ID 000412961500173

• Results of a Phase 1b/2 Study of ATYR1940 in adolescents and young adults with early onset facioscapulohumeral muscular dystrophy (FSHD) (ATYR1940-C-003) Walker, G., Butterfield, R., Mathews, K., Servais, L., Day, J., Gidaro, T., Shukla, S., Maggi, L. PERGAMON-ELSEVIER SCIENCE LTD. 2017: S199

  View details for DOI 10.1016/j.nmd.2017.06.381

  View details for Web of Science ID 000412961500364

• DETERMINING THE PATHOGENICITY OF NEWLY IDENTIFIED ATP7A VARIANTS USING PRIMARY FIBROBLASTS Perez-Siles, G., Drew, A., Ellis, M., Kidambi, M., Takata, R., Speck-Martins, C. E., Hagerman, K. A., Siskind, C. E., Day, J. W., Ginzberg, M., Nicholson, G., Kennerson, M. L. WILEY. 2017: 357

  View details for Web of Science ID 000409243500329

• Cross-sectional analysis of a large cohort with X-linked Charcot-Marie-Tooth disease (CMTX1) NEUROLOGY Panosyan, F. B., laura, M., Rossor, A. M., Pisciotta, C., Piscosquito, G., Burns, J., Li, J., Yum, S. W., Lewis, R. A., Day, J., Horvath, R., Herrmann, D. N., Shy, M. E., Pareyson, D., Reilly, M. M., Scherer, S. S., INC-RDCRN 2017; 89 (9): 927–35

  Abstract

  To extend the phenotypic description of Charcot-Marie-Tooth disease (CMTX1) and to draw new genotype-phenotype relationships.Mutations in GJB1 cause the main X-linked form of CMTX (CMTX1). We report cross-sectional data from 160 patients (from 120 different families, with 89 different mutations) seen at the Inherited Neuropathies Consortium centers.We evaluated 87 males who had a mean age of 41 years (range 10-78 years) and 73 females who had a mean age of 46 years (range 15-84 years). Sensory-motor polyneuropathy affects both sexes, more severely in males than in females, and there was a strong correlation between age and disease burden in males but not in females. Compared with females, males had more severe reduction in motor and sensory neurophysiology parameters. In contrast to females, the radial nerve sensory response in older males tended to be more severely affected compared with younger males. Median and ulnar nerve motor amplitudes were also more severely affected in older males, whereas ulnar nerve motor potentials tended to be more affected in older females. Conversely, there were no statistical differences between the sexes in other features of the disease, such as problems with balance and hand dexterity.In the absence of a phenotypic correlation with specific GJB1 mutations, sex-specific distinctions and clinically relevant attributes need to be incorporated into the measurements for clinical trials in people with CMTX1.NCT01193075.

  View details for PubMedID 28768847

• Patient-Centered Therapy Development for Myotonic Dystrophy: Report of the Myotonic Dystrophy Foundation-Sponsored Workshop THERAPEUTIC INNOVATION & REGULATORY SCIENCE Hesterlee, S., Amur, S., Bain, L. J., Carulli, J., Clarke, S., Day, J. W., Gagnon, C., Hagerman, K., Heatwole, C., Johnson, N. E., Moxley, R., Patel, N., Thornton, C., Kessel, W., White, M. 2017; 51 (4): 516–22

  View details for DOI 10.1177/2168479016683988

  View details for Web of Science ID 000404999500017

• Patient-Centered Therapy Development for Myotonic Dystrophy: Report of the Myotonic Dystrophy Foundation-Sponsored Workshop. Therapeutic innovation & regulatory science Hesterlee, S., Amur, S., Bain, L. J., Carulli, J., Clarke, S., Day, J. W., Gagnon, C., Hagerman, K., Heatwole, C., Johnson, N. E., Moxley, R., Patel, N., Thornton, C., Kessel, W., White, M. 2017; 51 (4): 516-522

  Abstract

  Myotonic dystrophy (DM) is an autosomal dominant, repeat expansion, progressive disorder with no drug therapies. Consequently, to better define a regulatory pathway in anticipation of new treatment strategies under investigation, the Myotonic Dystrophy Foundation convened a workshop entitled "Patient-Centered Therapy Development for Myotonic Dystrophy" in September 2015. Participants included representatives from academia, industry, the patient community, the National Institutes of Health (NIH) and the Food and Drug Administration (FDA). Presenters described the symptom burden of the disease, and existing data on DM biomarkers, endpoints, natural history, and benefit-risk considerations. FDA participants helped clarify the regulatory requirements for new drug treatment approvals and DM-specific issues such as variability, slow progression, and low prevalence. Workshop attendees gained a better understanding of DM and the current status of existing data and tools to support therapeutic drug research and development.

  View details for DOI 10.1177/2168479016683988

  View details for PubMedID 30227044

• Functional outcome measures and muscle MRI pattern recognition in dysferlinopathy: The JAIN COS Study Fernandez-Torron, R., James, M., Diaz Manera, J., Mayhew, A., Llauger Rosello, J., Moore, U., Smith, F., Jacobs, M., Carlier, P., Rufibach, L., Spuler, S., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Pestronk, A., Walter, M. C., Paradas, C., Stojkovic, T., Takeda, S., Bravver, E., Pegoraro, E., Mendell, J. R., Bushby, K., Straub, V. WILEY. 2017: 96–97

  View details for Web of Science ID 000405530100159

• Increased EEG theta spectral power in polysomnography of myotonic dystrophy type 1 compared to matched controls. Ruoff, C., Cheung, J., Perez, J., Sakamuri, S., Mignot, E., Day, J., Sampson, J. LIPPINCOTT WILLIAMS & WILKINS. 2017

  View details for Web of Science ID 000577381503279

• Reliability of functional outcome measures in spinal muscular atrophy: Results from multi-centered, global, phase 3 clinical trials Glanzman, A., Mazzone, E., Young, S., Gee, R., Rose, K., Mayhew, A., Yun, C., Alexander, K., Tennekoon, G., Day, J., Finkel, R., Mercuri, E., De Vivo, D., Bennett, F., Bishop, K., Montes, J. LIPPINCOTT WILLIAMS & WILKINS. 2017

  View details for Web of Science ID 000577381505139

• Content validity and clinical meaningfulness of the HFMSE in spinal muscular atrophy. BMC neurology Pera, M. C., Coratti, G., Forcina, N., Mazzone, E. S., Scoto, M., Montes, J., Pasternak, A., Mayhew, A., Messina, S., Sframeli, M., Main, M., Lofra, R. M., Duong, T., Ramsey, D., Dunaway, S., Salazar, R., Fanelli, L., Civitello, M., De Sanctis, R., Antonaci, L., Lapenta, L., Lucibello, S., Pane, M., Day, J., Darras, B. T., De Vivo, D. C., Muntoni, F., Finkel, R., Mercuri, E. 2017; 17 (1): 39-?

  Abstract

  Reports on the clinical meaningfulness of outcome measures in spinal muscular atrophy (SMA) are rare. In this two-part study, our aim was to explore patients' and caregivers' views on the clinical relevance of the Hammersmith Functional Motor Scale Expanded- (HFMSE).First, we used focus groups including SMA patients and caregivers to explore their views on the clinical relevance of the individual activities included in the HFMSE. Then we asked caregivers to comment on the clinical relevance of possible changes of HFMSE scores over time. As functional data of individual patients were available, some of the questions were tailored according to their functional level on the HFMSE.Part 1: Sixty-three individuals participated in the focus groups. This included 30 caregivers, 25 patients and 8 professionals who facilitated the discussion. The caregivers provided a comparison to activities of daily living for each of the HFMSE items. Part 2: One hundred and forty-nine caregivers agreed to complete the questionnaire: in response to a general question, 72% of the caregivers would consider taking part in a clinical trial if the treatment was expected to slow down deterioration, 88% if it would stop deterioration and 97% if the treatment was expected to produce an improvement. Caregivers were informed of the first three items that their child could not achieve on the HFMSE. In response 75% indicated a willingness to take part in a clinical trial if they could achieve at least one of these abilities, 89% if they could achieve two, and 100% if they could achieve more than 2.Our findings support the use of the HFMSE as a key outcome measure in SMA clinical trials because the individual items and the detected changes have clear content validity and clinical meaningfulness for patients and their caregivers.

  View details for DOI 10.1186/s12883-017-0790-9

  View details for PubMedID 28231823

• Revised Hammersmith Scale for spinal muscular atrophy: A SMA specific clinical outcome assessment tool. PloS one Ramsey, D., Scoto, M., Mayhew, A., Main, M., Mazzone, E. S., Montes, J., De Sanctis, R., Dunaway Young, S., Salazar, R., Glanzman, A. M., Pasternak, A., Quigley, J., Mirek, E., Duong, T., Gee, R., Civitello, M., Tennekoon, G., Pane, M., Pera, M. C., Bushby, K., Day, J., Darras, B. T., De Vivo, D., Finkel, R., Mercuri, E., Muntoni, F. 2017; 12 (2)

  Abstract

  Recent translational research developments in Spinal Muscular Atrophy (SMA), outcome measure design and demands from regulatory authorities require that clinical outcome assessments are 'fit for purpose'. An international collaboration (SMA REACH UK, Italian SMA Network and PNCRN USA) undertook an iterative process to address discontinuity in the recorded performance of the Hammersmith Functional Motor Scale Expanded and developed a revised functional scale using Rasch analysis, traditional psychometric techniques and the application of clinical sensibility via expert panels. Specifically, we intended to develop a psychometrically and clinically robust functional clinician rated outcome measure to assess physical abilities in weak SMA type 2 through to strong ambulant SMA type 3 patients. The final scale, the Revised Hammersmith Scale (RHS) for SMA, consisting of 36 items and two timed tests, was piloted in 138 patients with type 2 and 3 SMA in an observational cross-sectional multi-centre study across the three national networks. Rasch analysis demonstrated very good fit of all 36 items to the construct of motor performance, good reliability with a high Person Separation Index PSI 0.98, logical and hierarchical scoring in 27/36 items and excellent targeting with minimal ceiling. The RHS differentiated between clinically different groups: SMA type, World Health Organisation (WHO) categories, ambulatory status, and SMA type combined with ambulatory status (all p < 0.001). Construct and concurrent validity was also confirmed with a strong significant positive correlation with the WHO motor milestones rs = 0.860, p < 0.001. We conclude that the RHS is a psychometrically sound and versatile clinical outcome assessment to test the broad range of physical abilities of patients with type 2 and 3 SMA. Further longitudinal testing of the scale with regards change in scores over 6 and 12 months are required prior to its adoption in clinical trials.

  View details for DOI 10.1371/journal.pone.0172346

  View details for PubMedID 28222119

• Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study LANCET Finkel, R. S., Chiriboga, C. A., Vajsar, J., Day, J. W., Montes, J., De Vivo, D. C., Yamashita, M., Rigo, F., Hung, G., Schneider, E., Norris, D. A., Xia, S., Bennett, C. F., Bishop, K. M. 2016; 388 (10063): 3017-3026

  Abstract

  Nusinersen is a 2'-O-methoxyethyl phosphorothioate-modified antisense drug being developed to treat spinal muscular atrophy. Nusinersen is specifically designed to alter splicing of SMN2 pre-mRNA and thus increase the amount of functional survival motor neuron (SMN) protein that is deficient in patients with spinal muscular atrophy.This open-label, phase 2, escalating dose clinical study assessed the safety and tolerability, pharmacokinetics, and clinical efficacy of multiple intrathecal doses of nusinersen (6 mg and 12 mg dose equivalents) in patients with infantile-onset spinal muscular atrophy. Eligible participants were of either gender aged between 3 weeks and 7 months old with onset of spinal muscular atrophy symptoms between 3 weeks and 6 months, who had SMN1 homozygous gene deletion or mutation. Safety assessments included adverse events, physical and neurological examinations, vital signs, clinical laboratory tests, cerebrospinal fluid laboratory tests, and electrocardiographs. Clinical efficacy assessments included event free survival, and change from baseline of two assessments of motor function: the motor milestones portion of the Hammersmith Infant Neurological Exam-Part 2 (HINE-2) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) motor function test, and compound motor action potentials. Autopsy tissue was analysed for target engagement, drug concentrations, and pharmacological activity. HINE-2, CHOP-INTEND, and compound motor action potential were compared between baseline and last visit using the Wilcoxon signed-rank test. Age at death or permanent ventilation was compared with natural history using the log-rank test. The study is registered at ClinicalTrials.gov, number NCT01839656.20 participants were enrolled between May 3, 2013, and July 9, 2014, and assessed through to an interim analysis done on Jan 26, 2016. All participants experienced adverse events, with 77 serious adverse events reported in 16 participants, all considered by study investigators not related or unlikely related to the study drug. In the 12 mg dose group, incremental achievements of motor milestones (p<0·0001), improvements in CHOP-INTEND motor function scores (p=0·0013), and increased compound muscle action potential amplitude of the ulnar nerve (p=0·0103) and peroneal nerve (p<0·0001), compared with baseline, were observed. Median age at death or permanent ventilation was not reached and the Kaplan-Meier survival curve diverged from a published natural history case series (p=0·0014). Analysis of autopsy tissue from patients exposed to nusinersen showed drug uptake into motor neurons throughout the spinal cord and neurons and other cell types in the brainstem and other brain regions, exposure at therapeutic concentrations, and increased SMN2 mRNA exon 7 inclusion and SMN protein concentrations in the spinal cord.Administration of multiple intrathecal doses of nusinersen showed acceptable safety and tolerability, pharmacology consistent with its intended mechanism of action, and encouraging clinical efficacy. Results informed the design of an ongoing, sham-controlled, phase 3 clinical study of nusinersen in infantile-onset spinal muscular atrophy.Ionis Pharmaceuticals, Inc and Biogen.

  View details for DOI 10.1016/S0140-6736(16)31408-8

  View details for PubMedID 27939059

• Revised upper limb module for spinal muscular atrophy: Development of a new module. Muscle & nerve Mazzone, E. S., Mayhew, A., Montes, J., Ramsey, D., Fanelli, L., Dunaway Young, S., Salazar, R., De Sanctis, R., Pasternak, A., Glanzman, A., Coratti, G., Civitello, M., Forcina, N., Gee, R., Duong, T., Pane, M., Scoto, M., Pera, M. C., Messina, S., Tennekoon, G., Day, J. W., Darras, B. T., De Vivo, D. C., Finkel, R., Muntoni, F., Mercuri, E. 2016

  Abstract

  There is a growing need for a robust clinical measure to assess upper limb motor function in spinal muscular atrophy (SMA), as the available scales lack sensitivity at the extremes of the clinical spectrum. We report the development of the Revised Upper Limb Module (RULM), an assessment specifically designed for upper limb function in SMA patients.An international panel with specific neuromuscular expertise performed a thorough review of scales currently available to assess upper limb function in SMA. This review facilitated a revision of the existing upper limb function scales to make a more robust clinical scale.Multiple revisions of the scale included statistical analysis and captured clinically relevant changes to fulfill requirements by regulators and advocacy groups.The resulting RULM scale shows good reliability and validity, making it a suitable tool to assess upper extremity function in the SMA population for multi-center clinical research. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/mus.25430

  View details for PubMedID 27701745

• Clinical trial readiness in non-ambulatory boys and men with duchenne muscular dystrophy: MDA-DMD network follow-up. Muscle & nerve Connolly, A. M., Florence, J. M., Zaidman, C. M., Golumbek, P. T., Mendell, J. R., Flanigan, K. M., Karachunski, P. I., Day, J. W., McDonald, C. M., Darras, B. T., Kang, P. B., Siener, C. A., Gadeken, R. K., Anand, P., Schierbecker, J. R., Malkus, E. C., Lowes, L. P., Alfano, L. N., Johnson, L., Nicorici, A., Kelecic, J. M., Quigley, J., Pasternak, A. E., Miller, J. P. 2016; 54 (4): 681-689

  Abstract

  Outcomes sensitive to change over time in non-ambulatory boys/men with Duchenne muscular dystrophy (DMD) are not well-established.Subjects (n = 91; 16.8 ± 4.5 years old) were assessed at baseline and 6-month intervals for 2 years. We analyzed all subjects using an intent-to-treat model and a subset of stronger subjects with Brooke Scale score ≤4, using repeated measures.Eight patients (12-33 years old) died during the study. Sixty-six completed 12-month follow-up, and 51 completed 24-month follow-up. Those taking corticosteroids performed better at baseline, but rates of decline were similar. Forced vital capacity percent predicted (FVC% predicted) declined significantly only after 2 years. However, Brooke and Egen Klassifikation (EK) Scale scores, elbow flexion, and grip strength declined significantly over both 1 and 2 years.Brooke and EK Scale scores, elbow flexion, and grip strength were outcomes most responsive to change. FVC% predicted was responsive to change over 2 years. Corticosteroids benefited non-ambulatory DMD subjects but did not affect decline rates of measures tested here. Muscle Nerve 54: 681-689, 2016.

  View details for DOI 10.1002/mus.25089

  View details for PubMedID 26930423

• Should motor function determine the timing of scoliosis surgery in spinal muscular atrophy? Young, S., Montes, J., Salazar, R., Glanzman, A., Pasternak, A., Quigley, J., Ciurylo, E., Riley, S., Martens, W., Gee, R., Duone, T., Civitello, M., Chiriboga, C., Tennekoon, G., Day, J., Finkel, R., Darras, B., De Vivo, D. PERGAMON-ELSEVIER SCIENCE LTD. 2016: S104

  View details for DOI 10.1016/j.nmd.2016.06.070

  View details for Web of Science ID 000384790100060

• Revised Hammersmith scale for spinal muscular atrophy: Longitudinal changes over six and twelve months in a large international cohort Ramsey, D., Scoto, M., Mayhew, A., Main, M., Mazzone, E., Montes, J., Dunaway, S., Salazar, R., Glanzman, A., Pasternak, A., Duong, T., Gee, R., Civitello, M., Bushby, K., Day, J., Darras, B., De Vivo, D., Finkel, R., Mercuri, E., Muntoni, F. PERGAMON-ELSEVIER SCIENCE LTD. 2016: S104

  View details for DOI 10.1016/j.nmd.2016.06.071

  View details for Web of Science ID 000384790100061

• CLINICAL FOLLOW-UP FOR DUCHENNE MUSCULAR DYSTROPHY NEWBORN SCREENING: A PROPOSAL MUSCLE & NERVE Kwon, J. M., Abdel-Hamid, H. Z., Al-Zaidy, S. A., Mendell, J. R., Kennedy, A., Kinnett, K., Cwik, V. A., Street, N., Bolen, J., Day, J. W., Connolly, A. M. 2016; 54 (2): 186-191

  Abstract

  New developments in the rapid diagnosis and treatment of boys with Duchenne muscular dystrophy (DMD) have led to growing enthusiasm for instituting DMD newborn screening (NBS) in the United States. Our group has been interested in developing clinical guidance to be implemented consistently in specialty care clinics charged with the care of presymptomatically identified newborns referred after DMD-NBS. We reviewed the existing literature covering patient-centered clinical follow-up after NBS, educational material from public health and advocacy sites, and federal recommendations on effective NBS follow-up. We discussed the review as a group and added our own experience to develop materials suitable for initial parent and primary care provider education. These materials and a series of templates for subspecialist encounters could be used to provide consistent care across centers and serve as the basis for ongoing quality improvement. Muscle Nerve 54: 186-191, 2016.

  View details for DOI 10.1002/mus.25185

  View details for PubMedID 27170260

• The Clinical Outcome Study for dysferlinopathy: An international multicenter study. Neurology. Genetics Harris, E., Bladen, C. L., Mayhew, A., James, M., Bettinson, K., Moore, U., Smith, F. E., Rufibach, L., Cnaan, A., Bharucha-Goebel, D. X., Blamire, A. M., Bravver, E., Carlier, P. G., Day, J. W., Díaz-Manera, J., Eagle, M., Grieben, U., Harms, M., Jones, K. J., Lochmüller, H., Mendell, J. R., Mori-Yoshimura, M., Paradas, C., Pegoraro, E., Pestronk, A., Salort-Campana, E., Schreiber-Katz, O., Semplicini, C., Spuler, S., Stojkovic, T., Straub, V., Takeda, S., Rocha, C. T., Walter, M. C., Bushby, K. 2016; 2 (4)

  Abstract

  To describe the baseline clinical and functional characteristics of an international cohort of 193 patients with dysferlinopathy.The Clinical Outcome Study for dysferlinopathy (COS) is an international multicenter study of this disease, evaluating patients with genetically confirmed dysferlinopathy over 3 years. We present a cross-sectional analysis of 193 patients derived from their baseline clinical and functional assessments.There is a high degree of variability in disease onset, pattern of weakness, and rate of progression. No factor, such as mutation class, protein expression, or age at onset, accounted for this variability. Among patients with clinical diagnoses of Miyoshi myopathy or limb-girdle muscular dystrophy, clinical presentation and examination was not strikingly different. Respiratory impairment and cardiac dysfunction were observed in a minority of patients. A substantial delay in diagnosis was previously common but has been steadily reducing, suggesting increasing awareness of dysferlinopathies.These findings highlight crucial issues to be addressed for both optimizing clinical care and planning therapeutic trials in dysferlinopathy. This ongoing longitudinal study will provide an opportunity to further understand patterns and variability in disease progression and form the basis for trial design.

  View details for DOI 10.1212/NXG.0000000000000089

  View details for PubMedID 27602406

• Ataluren: An Overview of Clinical Trial Results in Nonsense Mutation Duchenne Muscular Dystrophy McDonald, C., Bushby, K., Tulinius, M., Finkel, R., Topaloglu, H., Day, J., Flanigan, K., Lowes, L., Eagle, M., Luo, X., Elfring, G., Kroger, H., Riebling, P., Ong, T., Spiegel, R., Peltz, S., Kirschner, J. LIPPINCOTT WILLIAMS & WILKINS. 2016

  View details for Web of Science ID 000411279007391

• Interim Results of a Phase 2 Clinical Study of Nusinersen (ISIS-SMNRx) in Patients with Infantile-Onset Spinal Muscular Atrophy Finkel, R., Chiriboga, C., Vajsar, J., Day, J., Montes, J., De Vivo, D., Yamashita, M., Rigo, F., Hung, G., Schneider, E., Norris, D., Xia, S., Bennett, F., Bishop, K. LIPPINCOTT WILLIAMS & WILKINS. 2016

  View details for Web of Science ID 000411328605106

• Should Motor Function Determine the Timing of Scoliosis Surgery in Spinal Muscular Atrophy (SMA)? Young, S., Montes, J., Salazar, R., Glanzman, A., Pasternak, A., Quigley, J., Ciurylo, E., Riley, S., Martens, W., Gee, R., Duong, T., Civitello, M., Chiriboga, C., Tennekoon, G., Day, J., Finkel, R., Darras, B., De Vivo, D. LIPPINCOTT WILLIAMS & WILKINS. 2016

  View details for Web of Science ID 000411328604216

• Study Design of a Phase 1/2a Trial with ISIS-DMPKRx for the Treatment of Myotonic Dystrophy Type 1 Thornton, C., Moxley, R., Day, J., Ashizawa, T., Barohn, R., Leung, D., Kissel, J., Johnson, N., Eichinger, K., Hardage, J., Lott, D., Currence, M., Stinson, N., King, W., Hayes, H., Bennett, F., Bishop, K., Mignon, L. LIPPINCOTT WILLIAMS & WILKINS. 2016

  View details for Web of Science ID 000411279007396

• Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy NATURE COMMUNICATIONS Freyermuth, F., Rau, F., Kokunai, Y., Linke, T., Sellier, C., Nakamori, M., Kino, Y., Arandel, L., Jollet, A., Thibault, C., Philipps, M., Vicaire, S., Jost, B., Udd, B., Day, J. W., Duboc, D., Wahbi, K., Matsumura, T., Fujimura, H., Mochizuki, H., Deryckere, F., Kimura, T., Nukina, N., Ishiura, S., Lacroix, V., Campan-Fournier, A., Navratil, V., Chautard, E., Auboeuf, D., Horie, M., Imoto, K., Lee, K., Swanson, M. S., Lopez de Munain, A., Inada, S., Itoh, H., Nakazawa, K., Ashihara, T., Wang, E., Zimmer, T., Furling, D., Takahashi, M. P., Charlet-Berguerand, N. 2016; 7

  Abstract

  Myotonic dystrophy (DM) is caused by the expression of mutant RNAs containing expanded CUG repeats that sequester muscleblind-like (MBNL) proteins, leading to alternative splicing changes. Cardiac alterations, characterized by conduction delays and arrhythmia, are the second most common cause of death in DM. Using RNA sequencing, here we identify novel splicing alterations in DM heart samples, including a switch from adult exon 6B towards fetal exon 6A in the cardiac sodium channel, SCN5A. We find that MBNL1 regulates alternative splicing of SCN5A mRNA and that the splicing variant of SCN5A produced in DM presents a reduced excitability compared with the control adult isoform. Importantly, reproducing splicing alteration of Scn5a in mice is sufficient to promote heart arrhythmia and cardiac-conduction delay, two predominant features of myotonic dystrophy. In conclusion, misregulation of the alternative splicing of SCN5A may contribute to a subset of the cardiac dysfunctions observed in myotonic dystrophy.

  View details for DOI 10.1038/ncomms11067

  View details for PubMedID 27063795

• Precise Correction of Disease Mutations in Induced Pluripotent Stem Cells Derived From Patients With Limb Girdle Muscular Dystrophy. Molecular therapy : the journal of the American Society of Gene Therapy Turan, S., Farruggio, A. P., Srifa, W., Day, J. W., Calos, M. P. 2016; 24 (4): 685-696

  Abstract

  Limb girdle muscular dystrophies types 2B (LGMD2B) and 2D (LGMD2D) are degenerative muscle diseases caused by mutations in the dysferlin and alpha-sarcoglycan genes, respectively. Using patient-derived induced pluripotent stem cells (iPSC), we corrected the dysferlin nonsense mutation c.5713C>T; p.R1905X and the most common alpha-sarcoglycan mutation, missense c.229C>T; p.R77C, by single-stranded oligonucleotide-mediated gene editing, using the CRISPR/Cas9 gene-editing system to enhance the frequency of homology-directed repair. We demonstrated seamless, allele-specific correction at efficiencies of 0.7-1.5%. As an alternative, we also carried out precise gene addition strategies for correction of the LGMD2B iPSC by integration of wild-type dysferlin cDNA into the H11 safe harbor locus on chromosome 22, using dual integrase cassette exchange (DICE) or TALEN-assisted homologous recombination for insertion precise (THRIP). These methods employed TALENs and homologous recombination, and DICE also utilized site-specific recombinases. With DICE and THRIP, we obtained targeting efficiencies after selection of ~20%. We purified iPSC corrected by all methods and verified rescue of appropriate levels of dysferlin and alpha-sarcoglycan protein expression and correct localization, as shown by immunoblot and immunocytochemistry. In summary, we demonstrate for the first time precise correction of LGMD iPSC and validation of expression, opening the possibility of cell therapy utilizing these corrected iPSC.

  View details for DOI 10.1038/mt.2016.40

  View details for PubMedID 26916285

• INFUSION-ASSOCIATED REACTIONS AND IMMUNOGENICITY IN THE ADVANCE STUDY OF ALGLUCOSIDASE ALFA PRODUCED AT 4000 L SCALE IN PATIENTS WITH POMPE DISEASE Kishnani, P. S., Hahn, S., Day, J. W., Gambello, M. J., Gibson, J. B., Hillman, R., Kronn, D., Stockton, D. W., Leslie, N., Tanpaiboon, P., Wang, R., Haack, K., Shafi, R., Sparks, S., Zhao, Y., Pena, L., Pompe ADVANCE Study Consortium ACADEMIC PRESS INC ELSEVIER SCIENCE. 2016: 265

  View details for Web of Science ID 000372683600080

• The revised Hammersmith scale for spinal muscular atrophy: reliability, validity and results from a large international pilot Ramsey, D., Scoto, M., Mayhew, A., Main, M., Mazzone, E., Montes, J., Dunaway, S., Salazar, R., Glanzman, A. M., Pasternak, A., De Sanctis, R., Fanelli, L., Quigley, J., Mirek, E., Duong, T., Gee, R., Lofra, R., Civitello, M., Ramdharry, G., Wallace, A., Bushby, K., Day, J., Darras, B., De Vivo, D., Finkel, R., Mercuri, E., Muntoni, F. PERGAMON-ELSEVIER SCIENCE LTD. 2016: S40

  View details for Web of Science ID 000558787300129

• Clinical characteristics and genotypes in the ADVANCE baseline dataset, a comprehensive cohort of us children and youth with Pompe disease Kishnani, P. S., Day, J. W., Gambello, M., Gibson, J. B., Hillman, R., Kronn, D., Leslie, N., Pena, L., Stockton, D. W., Tanpaiboon, P., Wang, R., Haack, K., Sparks, S., Zhao, Y., Hahn, S., Pompe ADVANCE Study Consortium ACADEMIC PRESS INC ELSEVIER SCIENCE. 2016: S68

  View details for DOI 10.1016/j.ymgme.2015.12.323

  View details for Web of Science ID 000370888100166

• 52-week efficacy and safety profile of alglucosidase alfa produced at 4000 liter scale in US patients with Pompe disease: ADVANCE, a phase 4 open-label prospective study Hahn, S., Pena, L., Day, J. W., Gambello, M., Gibson, J. B., Hillman, R., Kronn, D., Stockton, D., Leslie, N., Tanpaiboon, P., Wang, R., Haack, K., Sparks, S., Zhao, Y., Kishnani, P. S., Pompe ADVANCE Study Consortium ACADEMIC PRESS INC ELSEVIER SCIENCE. 2016: S54

  View details for DOI 10.1016/j.ymgme.2015.12.281

  View details for Web of Science ID 000370888100124

• Novel mutations highlight the key role of the ankyrin repeat domain in TRPV4-mediated neuropathy. Neurology. Genetics Sullivan, J. M., Zimanyi, C. M., Aisenberg, W., Bears, B., Chen, D., Day, J. W., Bird, T. D., Siskind, C. E., Gaudet, R., Sumner, C. J. 2015; 1 (4)

  Abstract

  To characterize 2 novel TRPV4 mutations in 2 unrelated families exhibiting the Charcot-Marie-Tooth disease type 2C (CMT2C) phenotype.Direct CMT gene testing was performed on 2 unrelated families with CMT2C. A 4-fold symmetric tetramer model of human TRPV4 was generated to map the locations of novel TRPV4 mutations in these families relative to previously identified disease-causing mutations (neuropathy, skeletal dysplasia, and osteoarthropathy). Effects of the mutations on TRPV4 expression, localization, and channel activity were determined by immunocytochemical, immunoblotting, Ca(2+) imaging, and cytotoxicity assays.Previous studies suggest that neuropathy-causing mutations occur primarily at arginine residues on the convex face of the TRPV4 ankyrin repeat domain (ARD). Further highlighting the key role of this domain in TRPV4-mediated hereditary neuropathy, we report 2 novel heterozygous missense mutations in the TRPV4-ARD convex face (p.Arg237Gly and p.Arg237Leu). Generation of a model of the TRPV4 homotetramer revealed that while ARD residues mutated in neuropathy (including Arg237) are likely accessible for intermolecular interactions, skeletal dysplasia-causing TRPV4 mutations occur at sites suggesting disruption of intramolecular and/or intersubunit interactions. Like previously described neuropathy-causing mutations, the p.Arg237Gly and p.Arg237Leu substitutions do not alter TRPV4 subcellular localization in transfected cells but cause elevations of cytosolic Ca(2+) levels and marked cytotoxicity.These findings expand the number of ARD residues mutated in TRPV4-mediated neuropathy, providing further evidence of the central importance of this domain to TRPV4 function in peripheral nerve.

  View details for DOI 10.1212/NXG.0000000000000029

  View details for PubMedID 27066566

  View details for PubMedCentralID PMC4811381

• Genotype-phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene BRAIN Sanmaneechai, O., Feely, S., Scherer, S. S., Herrmann, D. N., Burns, J., Muntoni, F., Li, J., Siskind, C. E., Day, J. W., Laura, M., Sumner, C. J., Lloyd, T. E., Ramchandren, S., Shy, R. R., Grider, T., Bacon, C., Finkel, R. S., Yum, S. W., Moroni, I., Piscosquito, G., Pareyson, D., Reilly, M. M., Shy, M. E. 2015; 138

  Abstract

  We aimed to characterize genotype-phenotype correlations and establish baseline clinical data for peripheral neuropathies caused by mutations in the myelin protein zero (MPZ) gene. MPZ mutations are the second leading cause of Charcot-Marie-Tooth disease type 1. Recent research makes clinical trials for patients with MPZ mutations a realistic possibility. However, the clinical severity varies with different mutations and natural history data on progression is sparse. We present cross-sectional data to begin to define the phenotypic spectrum and clinical baseline of patients with these mutations. A cohort of patients with MPZ gene mutations was identified in 13 centres of the Inherited Neuropathies Consortium - Rare Disease Clinical Research Consortium (INC-RDCRC) between 2009 and 2012 and at Wayne State University between 1996 and 2009. Patient phenotypes were quantified by the Charcot-Marie-Tooth disease neuropathy score version 1 or 2 and the Charcot-Marie-Tooth disease paediatric scale outcome instruments. Genetic testing was performed in all patients and/or in first- or second-degree relatives to document mutation in MPZ gene indicating diagnosis of Charcot-Marie-Tooth disease type 1B. There were 103 patients from 71 families with 47 different MPZ mutations with a mean age of 40 years (range 3-84 years). Patients and mutations were separated into infantile, childhood and adult-onset groups. The infantile onset group had higher Charcot-Marie-Tooth disease neuropathy score version 1 or 2 and slower nerve conductions than the other groups, and severity increased with age. Twenty-three patients had no family history of Charcot-Marie-Tooth disease. Sixty-one patients wore foot/ankle orthoses, 19 required walking assistance or support, and 10 required wheelchairs. There was hearing loss in 21 and scoliosis in 17. Forty-two patients did not begin walking until after 15 months of age. Half of the infantile onset patients then required ambulation aids or wheelchairs for ambulation. Our results demonstrate that virtually all MPZ mutations are associated with specific phenotypes. Early onset (infantile and childhood) phenotypes likely represent developmentally impaired myelination, whereas the adult-onset phenotype reflects axonal degeneration without antecedent demyelination. Data from this cohort of patients will provide the baseline data necessary for clinical trials of patients with Charcot-Marie-Tooth disease caused by MPZ gene mutations.

  View details for DOI 10.1093/brain/awv241

  View details for PubMedID 26310628

• MBNL Sequestration by Toxic RNAs and RNA Misprocessing in the Myotonic Dystrophy Brain CELL REPORTS Goodwin, M., Mohan, A., Batra, R., Lee, K., Charizanis, K., Gomez, F. J., Eddarkaoui, S., Sergeant, N., Buee, L., Kimura, T., Clark, H. B., Dalton, J., Takamura, K., Weyn-Vanhentenryck, S. M., Zhang, C., Reid, T., Ranum, L. P., Day, J. W., Swanson, M. S. 2015; 12 (7): 1159-1168

  Abstract

  For some neurological disorders, disease is primarily RNA mediated due to expression of non-coding microsatellite expansion RNAs (RNA(exp)). Toxicity is thought to result from enhanced binding of proteins to these expansions and depletion from their normal cellular targets. However, experimental evidence for this sequestration model is lacking. Here, we use HITS-CLIP and pre-mRNA processing analysis of human control versus myotonic dystrophy (DM) brains to provide compelling evidence for this RNA toxicity model. MBNL2 binds directly to DM repeat expansions in the brain, resulting in depletion from its normal RNA targets with downstream effects on alternative splicing and polyadenylation. Similar RNA processing defects were detected in Mbnl compound-knockout mice, highlighted by dysregulation of Mapt splicing and fetal tau isoform expression in adults. These results demonstrate that MBNL proteins are directly sequestered by RNA(exp) in the DM brain and introduce a powerful experimental tool to evaluate RNA-mediated toxicity in other expansion diseases.

  View details for DOI 10.1016/j.celrep.2015.07.029

  View details for Web of Science ID 000360130900010

  View details for PubMedCentralID PMC4545389

• MBNL Sequestration by Toxic RNAs and RNA Misprocessing in the Myotonic Dystrophy Brain. Cell reports Goodwin, M., Mohan, A., Batra, R., Lee, K. Y., Charizanis, K., Fernández Gómez, F. J., Eddarkaoui, S., Sergeant, N., Buée, L., Kimura, T., Clark, H. B., Dalton, J., Takamura, K., Weyn-Vanhentenryck, S. M., Zhang, C., Reid, T., Ranum, L. P., Day, J. W., Swanson, M. S. 2015; 12 (7): 1159-68

  Abstract

  For some neurological disorders, disease is primarily RNA mediated due to expression of non-coding microsatellite expansion RNAs (RNA(exp)). Toxicity is thought to result from enhanced binding of proteins to these expansions and depletion from their normal cellular targets. However, experimental evidence for this sequestration model is lacking. Here, we use HITS-CLIP and pre-mRNA processing analysis of human control versus myotonic dystrophy (DM) brains to provide compelling evidence for this RNA toxicity model. MBNL2 binds directly to DM repeat expansions in the brain, resulting in depletion from its normal RNA targets with downstream effects on alternative splicing and polyadenylation. Similar RNA processing defects were detected in Mbnl compound-knockout mice, highlighted by dysregulation of Mapt splicing and fetal tau isoform expression in adults. These results demonstrate that MBNL proteins are directly sequestered by RNA(exp) in the DM brain and introduce a powerful experimental tool to evaluate RNA-mediated toxicity in other expansion diseases.

  View details for DOI 10.1016/j.celrep.2015.07.029

  View details for PubMedID 26257173

  View details for PubMedCentralID PMC4545389

• CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY Fridman, V., Bundy, B., Reilly, M. M., Pareyson, D., Bacon, C., Burns, J., Day, J., Feely, S., Finkel, R. S., Grider, T., Kirk, C. A., Herrmann, D. N., Laura, M., Li, J., Lloyd, T., Sumner, C. J., Muntoni, F., Piscosquito, G., Ramchandren, S., Shy, R., Siskind, C. E., Yum, S. W., Moroni, I., Pagliano, E., Zuchner, S., Scherer, S. S., Shy, M. E. 2015; 86 (8): 873-878

  Abstract

  The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them.We analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES).997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported.Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT.ID number NCT01193075.

  View details for DOI 10.1136/jnnp-2014-308826

  View details for PubMedID 25430934

• PHENOTYPE-GENOTYPE CHARACTERISTICS AND BASELINE NATURAL HISTORY OF HERITABLE NEUROPATHIES CAUSED BY MUTATIONS IN THE MYELIN PROTEIN ZERO GENE Sanmaneechai, O., Feely, S., Scherer, S. S., Herrmann, D. N., Burns, J., Muntoni, F., Li, J., Siskind, C. S., Day, J. W., Laura, M., Sumner, C. J., Lloyd, T. E., Ramchandren, S., Shy, R. R., Grider, T., Bacon, C., Finkel, R. S., Yum, S., Moroni, Piscosquito, G., Pareyson, D., Reilly, M. M., Shy, M. E., INC-RDCRC WILEY-BLACKWELL. 2015: 225–26

  View details for Web of Science ID 000360214600358

• DISEASE PROGRESSION IN HEREDITARY NEUROPATHY: A LONGITUDINAL ANALYSIS OF DATA CONTAINED WITH THE INHERITED NEUROPATHIES CONSORTIUM NATURAL HISTORY STUDY Fridman, Sadjadi, R., Bundy, B., Sillau, S., Bacon, C., Burns, J., Day, J., Feely, S., Finkel, R. S., Grider, T., Kirk, Herrmann, D. N., Laura, M., Li, J., Lloyd, T., Muntoni, F., Pareyson, D., Ramchandren, S., Reilly, M. M., Scherer, S., Shy, R., Sumner, C., Yum, S., Zuchner, S., Shy, M. E., Inherited Neuropathies Consortium WILEY-BLACKWELL. 2015: 143–44

  View details for Web of Science ID 000360214600146

• PULMONARY FUNCTION AND CMT: RESULTS FROM STANFORD HEALTHCARE Siskind, C. E., Day, J. W., Zekos-Ortiz, K. WILEY-BLACKWELL. 2015: 231

  View details for Web of Science ID 000360214600373

• OUTCOME RELIABILITY IN NON-AMBULATORY BOYS/MEN WITH DUCHENNE MUSCULAR DYSTROPHY MUSCLE & NERVE Connolly, A. M., Malkus, E. C., Mendell, J. R., Flanigan, K. M., Miller, J. P., Schierbecker, J. R., Siener, C. A., Golumbek, P. T., Zaidman, C. M., McDonald, C. M., Johnson, L., Nicorici, A., Karachunski, P. I., Day, J. W., Kelecic, J. M., Lowes, L. P., Alfano, L. N., Darras, B. T., Kang, P. B., Quigley, J., Pasternak, A. E., Florence, J. M. 2015; 51 (4): 522-532

  Abstract

  Background: Therapeutic trials in Duchenne muscular dystrophy (DMD) often exclude non-ambulatory individuals. Here we establish optimal and reliable assessments in a multicenter trial. Methods: Non-ambulatory boys/men with DMD (n=91;16.7± 4.5 years) were assessed by trained clinical evaluators. Feasibility (percentage completing task) and reliability [intra-class correlation coefficients (ICCs) between AM and PM tests] were measured. Results: Forced Vital Capacity (FVC, 100% of subjects) showed a mean 47.8 ± 22% predicted (ICC 0.98). Brooke upper extremity functional rating (Brooke) and Egen Klassifikation (EK) scales in 100% of subjects showed ICCs from 0.93-0.99. Manual muscle testing, range of motion, nine-hole peg, and Jebsen-Taylor Hand function testing (JHFT) had variable feasibility (99% to 70%) with ICC also ranging from 0.99 to 0.64. We found beneficial effects of different forms of corticosteroids for Brooke Scale, %predicted FVC, and hand and finger strength. Conclusion: Reliable assessment of non-ambulatory boys/men with DMD is possible. Clinical trials will have to consider corticosteroid use. © 2014 Wiley Periodicals, Inc.

  View details for DOI 10.1002/mus.24346

  View details for Web of Science ID 000351679400009

  View details for PubMedID 25056178

• Clinical Phenotypes as Predictors of the Outcome of Skipping around DMD Exon 45 ANNALS OF NEUROLOGY Findlay, A. R., Wein, N., Kaminoh, Y., Taylor, L. E., Dunn, D. M., Mendell, J. R., King, W. M., Pestronk, A., Florence, J. M., Mathews, K. D., Finkel, R. S., Swoboda, K. J., Howard, M. T., Day, J. W., McDonald, C., Nicolas, A., Le Rumeur, E., Weiss, R. B., Flanigan, K. M. 2015; 77 (4): 668-674

  Abstract

  Exon-skipping therapies aim to convert Duchenne muscular dystrophy (DMD) into less severe Becker muscular dystrophy (BMD) by altering pre-mRNA splicing to restore an open reading frame, allowing translation of an internally deleted and partially functional dystrophin protein. The most common single exon deletion-exon 45 (Δ45)-may theoretically be treated by skipping of either flanking exon (44 or 46). We sought to predict the impact of these by assessing the clinical severity in dystrophinopathy patients.Phenotypic data including clinical diagnosis, age at wheelchair use, age at loss of ambulation, and presence of cardiomyopathy were analyzed from 41 dystrophinopathy patients containing equivalent in-frame deletions.As expected, deletions of either exons 45 to 47 (Δ45-47) or exons 45 to 48 (Δ45-48) result in BMD in 97% (36 of 37) of subjects. Unexpectedly, deletion of exons 45 to 46 (Δ45-46) is associated with the more severe DMD phenotype in 4 of 4 subjects despite an in-frame transcript. Notably, no patients with a deletion of exons 44 to 45 (Δ44-45) were found within the United Dystrophinopathy Project database, and this mutation has only been reported twice before, which suggests an ascertainment bias attributable to a very mild phenotype.The observation that Δ45-46 patients have typical DMD suggests that the conformation of the resultant protein may result in protein instability or altered binding of critical partners. We conclude that in DMD patients with Δ45, skipping of exon 44 and multiexon skipping of exons 46 and 47 (or exons 46-48) are better potential therapies than skipping of exon 46 alone.

  View details for DOI 10.1002/ana.24365

  View details for Web of Science ID 000352102500011

  View details for PubMedID 25612243

  View details for PubMedCentralID PMC4376581

• ATALUREN TREATMENT OF PATIENTS WITH NONSENSE MUTATION DYSTROPHINOPATHY MUSCLE & NERVE Bushby, K., Finkel, R., Wong, B., Barohn, R., Campbell, C., Comi, G. P., Connolly, A. M., Day, J. W., Flanigan, K. M., Goemans, N., Jones, K. J., Mercuri, E., Quinlivan, R., Renfroe, J. B., Russman, B., Ryan, M. M., Tulinius, M., Voit, T., Moore, S. A., Sweeney, H. L., Abresch, R. T., Coleman, K. L., Eagle, M., Florence, J., Gappmaier, E., Glanzman, A. M., Henricson, E., Barth, J., Elfring, G. L., Reha, A., Spiegel, R. J., O'Donnell, M. W., Peltz, S. W., McDonald, C. M. 2014; 50 (4): 477-487

  Abstract

  Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop codons in nonsense mutation (nm) genetic disorders.Randomized, double-blind, placebo-controlled study; males ≥5 years with nm-dystrophinopathy received study drug orally 3 times daily, ataluren 10, 10, 20 mg/kg (N = 57); ataluren 20, 20, 40 mg/kg (N = 60); or placebo (N = 57) for 48 weeks. The primary endpoint was change in 6-Minute Walk Distance (6MWD) at Week 48.Ataluren was generally well tolerated. The primary endpoint favored ataluren 10, 10, 20 mg/kg versus placebo; the week 48 6MWD Δ = 31.3 meters, post hoc P = 0.056. Secondary endpoints (timed function tests) showed meaningful differences between ataluren 10, 10, 20 mg/kg, and placebo.As the first investigational new drug targeting the underlying cause of nm-dystrophinopathy, ataluren offers promise as a treatment for this orphan genetic disorder with high unmet medical need. Muscle Nerve 50: 477-487, 2014.

  View details for DOI 10.1002/mus.24332

  View details for Web of Science ID 000342634100002

  View details for PubMedID 25042182

• Clinical trial readiness for non-ambulatory boys and men with Duchenne muscular dystrophy: 12 and 24 month follow-up from the MDA-DMD Network Connolly, A. M., Malkus, E. C., Schierbecker, J. R., Siener, C. A., Anand, P., Mendell, J. R., Flanigan, K. M., Golumbek, P. T., Zaidman, C. M., McDonald, C. M., Henricson, E., Johnson, L., Nicorici, A., Karachunski, P. I., Day, J. W., Kelecic, J. M., Lowes, L. P., Alfano, L. N., Darras, B. T., Kang, P. B., Florence, J. M. PERGAMON-ELSEVIER SCIENCE LTD. 2014: 855–56

  View details for DOI 10.1016/j.nmd.2014.06.209

  View details for Web of Science ID 000342870200206

• Results of a phase 2 open-label study of ISIS-SMNRx in patients with infantile (Type 1) spinal muscular atrophy Finkel, R. S., Day, J., Chiriboga, C., Vasjar, J., Cook, D., Watson, K., Paulose, S., McMillian, L., Cruz, R., Montes, J., De Vivo, D. C., Yamashita, M., McGuire, D., Alexander, K., Norris, D., Bennett, C. F., Bishop, K. PERGAMON-ELSEVIER SCIENCE LTD. 2014: 920

  View details for DOI 10.1016/j.nmd.2014.06.416

  View details for Web of Science ID 000342870200413

• COMPLICATIONS OF PREGNANCY IN MYOTONIC DYSTROPHY Johnson, N. E., Franklin, J. D., Nasser, E., Luebbe, E., Hilbert, J., Hagerman, K. A., Day, J. W., Ciafaloni, E., Hung, M., Heatwole, C. R. WILEY-BLACKWELL. 2014: S3

  View details for Web of Science ID 000342178600009

• Congenital muscular dystrophy and generalized epilepsy caused by GMPPB mutations. Brain research Raphael, A. R., Couthouis, J., Sakamuri, S., Siskind, C., Vogel, H., Day, J. W., Gitler, A. D. 2014; 1575: 66-71

  Abstract

  The alpha-dystroglycanopathies are genetically heterogeneous muscular dystrophies that result from hypoglycosylation of alpha-dystroglycan (α-DG). Alpha-dystroglycan is an essential link between the extracellular matrix and the muscle fiber sarcolemma, and proper glycosylation is critical for its ability to bind to ligands in the extracellular matrix. We sought to identify the genetic basis of alpha-dystroglycanopathy in a family wherein the affected individuals presented with congenital muscular dystrophy, brain abnormalities and generalized epilepsy. We performed whole exome sequencing and identified compound heterozygous GMPPB mutations in the affected children. GMPPB is an enzyme in the glycosylation pathway, and GMPPB mutations were recently linked to eight cases of alpha-dystroglycanopathy with a range of symptoms. We identified a novel mutation in GMPPB (p.I219T) as well as a previously published mutation (p.R287Q). Thus, our work further confirms a role for GMPPB defects in alpha-dystroglycanopathy, and suggests that glycosylation may play a role in the neuronal membrane channels or networks involved in the physiology of generalized epilepsy syndromes. This article is part of a Special Issue entitled RNA Metabolism 2013.

  View details for DOI 10.1016/j.brainres.2014.04.028

  View details for PubMedID 24780531

• Tractography reveals diffuse white matter abnormalities in Myotonic Dystrophy Type 1 JOURNAL OF THE NEUROLOGICAL SCIENCES Wozniak, J. R., Mueller, B. A., Lim, K. O., Hemmy, L. S., Day, J. W. 2014; 341 (1-2): 73-78

  Abstract

  Cerebral involvement in Myotonic Dystrophy Type 1 (DM1) is well-established but not well characterized. This study applied new Diffusion Tensor Imaging (DTI) tractography to characterize white matter disturbance in adults with DM1. Forty-five participants with DM1 and 44 control participants had MRIs on a Siemens 3T TIM Trio scanner. Data were processed with TRActs Constrained by UnderLying Anatomy (TRACULA) and 7 tracts were evaluated. Bilateral disturbances in white matter integrity were seen in all tracts in participants with DM1 compared to controls. There were no right-left hemisphere differences. The resulting DTI metrics were correlated with cognitive functioning, particularly working memory and processing speed. Motor speed was not significantly correlated with white matter microstructural integrity and, thus, was not the core explanation for the working memory and processing speed findings. White matter integrity was correlated with important clinical variables including the muscular impairment rating scale (MIRS). CTG repeat length was moderately associated with white matter status in corticospinal tract and cingulum. Sleepiness (Epworth Sleepiness Scale) was moderately associated with white matter status in the superior longitudinal fasciculus and cingulum. Overall, the results add to an emerging literature showing widespread white matter disturbances in both early-onset and adult-onset DM1. Results suggest that further investigation of white matter pathology is warranted in DM1 and that non-invasive measures such as DTI have a potentially important clinical value in characterizing the status of individuals with DM1.

  View details for DOI 10.1016/j.jns.2014.04.005

  View details for PubMedID 24768314

• One Year Outcome of Boys With Duchenne Muscular Dystrophy Using the Bayley-III Scales of Infant and Toddler Development PEDIATRIC NEUROLOGY Connolly, A. M., Florence, J. M., Cradock, M. M., Eagle, M., Flanigan, K. M., McDonald, C. M., Karachunski, P. I., Darras, B. T., Bushby, K., Malkus, E. C., Golumbek, P. T., Zaidman, C. M., Miller, J. P., Mendell, J. R. 2014; 50 (6): 557-563

  Abstract

  The pathogenesis of Duchenne muscular dystrophy starts before birth. Despite this, clinical trials exclude young boys because traditional outcome measures rely on cooperation. We recently used the Bayley-III Scales of Infant and Toddler Development to study 24 infants and boys with Duchenne muscular dystrophy. Clinical evaluators at six centers were trained and certified to perform the Bayley-III. Here, we report 6- and 12-month follow-up of two subsets of these boys.Nineteen boys (1.9 ± 0.8 years) were assessed at baseline and 6 months. Twelve boys (1.5 ± 0.8 years) were assessed at baseline, 6, and 12 months.Gross motor scores were lower at baseline compared with published controls (6.2 ± 1.7; normal 10 ± 3; P < 0.0001) and revealed a further declining trend to 5.7 ± 1.7 (P = 0.20) at 6 months. Repeated measures analysis of the 12 boys monitored for 12 months revealed that gross motor scores, again low at baseline (6.6 ± 1.7; P < 0.0001), declined at 6 months (5.9 ± 1.8) and further at 12 months (5.3 ± 2.0) (P = 0.11). Cognitive and language scores were lower at baseline compared with normal children (range, P = 0.002-<0.0001) and did not change significantly at 6 or 12 months (range, P = 0.89-0.09). Fine motor skills, also low at baseline, improved >1 year (P = 0.05).Development can reliably be measured in infants and young boys with Duchenne muscular dystrophy across time using the Bayley-III. Power calculations using these data reveal that motor development may be used as an outcome measure.

  View details for DOI 10.1016/j.pediatrneurol.2014.02.006

  View details for Web of Science ID 000336643700004

  View details for PubMedID 24842254

• Exome sequencing identifies a DNAJB6 mutation in a family with dominantly-inherited limb-girdle muscular dystrophy. Neuromuscular disorders Couthouis, J., Raphael, A. R., Siskind, C., Findlay, A. R., Buenrostro, J. D., Greenleaf, W. J., Vogel, H., Day, J. W., Flanigan, K. M., Gitler, A. D. 2014; 24 (5): 431-435

  Abstract

  Limb-girdle muscular dystrophy primarily affects the muscles of the hips and shoulders (the "limb-girdle" muscles), although it is a heterogeneous disorder that can present with varying symptoms. There is currently no cure. We sought to identify the genetic basis of limb-girdle muscular dystrophy type 1 in an American family of Northern European descent using exome sequencing. Exome sequencing was performed on DNA samples from two affected siblings and one unaffected sibling and resulted in the identification of eleven candidate mutations that co-segregated with the disease. Notably, this list included a previously reported mutation in DNAJB6, p.Phe89Ile, which was recently identified as a cause of limb-girdle muscular dystrophy type 1D. Additional family members were Sanger sequenced and the mutation in DNAJB6 was only found in affected individuals. Subsequent haplotype analysis indicated that this DNAJB6 p.Phe89Ile mutation likely arose independently of the previously reported mutation. Since other published mutations are located close by in the G/F domain of DNAJB6, this suggests that the area may represent a mutational hotspot. Exome sequencing provided an unbiased and effective method for identifying the genetic etiology of limb-girdle muscular dystrophy type 1 in a previously genetically uncharacterized family. This work further confirms the causative role of DNAJB6 mutations in limb-girdle muscular dystrophy type 1D.

  View details for DOI 10.1016/j.nmd.2014.01.014

  View details for PubMedID 24594375

• Diagnostic odyssey of patients with myotonic dystrophy JOURNAL OF NEUROLOGY Hilbert, J. E., Ashizawa, T., Day, J. W., Luebbe, E. A., Martens, W. B., McDermott, M. P., Tawil, R., Thornton, C. A., Moxley, R. T. 2013; 260 (10): 2497-2504

  Abstract

  The onset and symptoms of the myotonic dystrophies are diverse, complicating their diagnoses and limiting a comprehensive approach to their clinical care. This report analyzes the diagnostic delay (time from onset of first symptom to diagnosis) in a large sample of myotonic dystrophy (DM) patients enrolled in the US National Registry [679 DM type 1 (DM1) and 135 DM type 2 (DM2) patients]. Age of onset averaged 34.0 ± 14.1 years in DM2 patients compared to 26.1 ± 13.2 years in DM1 (p < 0.0001). The most common initial symptom in DM2 patients was leg weakness (32.6 %) compared to grip myotonia in DM1 (38.3 %). Pain was reported as the first symptom in 11.1 % of DM2 and 3.0 % of DM1 patients (p < 0.0001). Reaching the correct diagnosis in DM2 took 14 years on average (double the time compared to DM1) and a significantly higher percentage of patients underwent extended workup including electromyography, muscle biopsies, and finally genetic testing. DM patients who were index cases experienced similar diagnostic delays to non-index cases of DM. Further evaluation of how to shorten these diagnostic delays and limit their impact on burdens of disease, family planning, and symptom management is needed.

  View details for DOI 10.1007/s00415-013-6993-0

  View details for Web of Science ID 000325639400006

  View details for PubMedID 23807151

• Role of telomere dysfunction in cardiac failure in Duchenne muscular dystrophy. Nature cell biology Mourkioti, F., Kustan, J., Kraft, P., Day, J. W., Zhao, M., Kost-Alimova, M., Protopopov, A., DePinho, R. A., Bernstein, D., Meeker, A. K., Blau, H. M. 2013; 15 (8): 895-904

  Abstract

  Duchenne muscular dystrophy (DMD), the most common inherited muscular dystrophy of childhood, leads to death due to cardiorespiratory failure. Paradoxically, mdx mice with the same genetic deficiency of dystrophin exhibit minimal cardiac dysfunction, impeding the development of therapies. We postulated that the difference between mdx and DMD might result from differences in telomere lengths in mice and humans. We show here that, like DMD patients, mice that lack dystrophin and have shortened telomeres (mdx/mTR(KO)) develop severe functional cardiac deficits including ventricular dilation, contractile and conductance dysfunction, and accelerated mortality. These cardiac defects are accompanied by telomere erosion, mitochondrial fragmentation and increased oxidative stress. Treatment with antioxidants significantly retards the onset of cardiac dysfunction and death of mdx/mTR(KO) mice. In corroboration, all four of the DMD patients analysed had 45% shorter telomeres in their cardiomyocytes relative to age- and sex-matched controls. We propose that the demands of contraction in the absence of dystrophin coupled with increased oxidative stress conspire to accelerate telomere erosion culminating in cardiac failure and death. These findings provide strong support for a link between telomere length and dystrophin deficiency in the etiology of dilated cardiomyopathy in DMD and suggest preventive interventions.

  View details for DOI 10.1038/ncb2790

  View details for PubMedID 23831727

  View details for PubMedCentralID PMC3774175

• Role of telomere dysfunction in cardiac failure in Duchenne muscular dystrophy NATURE CELL BIOLOGY Mourkioti, F., Kustan, J., Kraft, P., Day, J. W., Zhao, M., Kost-Alimova, M., Protopopov, A., DePinho, R. A., Bernstein, D., Meeker, A. K., Blau, H. M. 2013; 15 (8): 895-U300

  Abstract

  Duchenne muscular dystrophy (DMD), the most common inherited muscular dystrophy of childhood, leads to death due to cardiorespiratory failure. Paradoxically, mdx mice with the same genetic deficiency of dystrophin exhibit minimal cardiac dysfunction, impeding the development of therapies. We postulated that the difference between mdx and DMD might result from differences in telomere lengths in mice and humans. We show here that, like DMD patients, mice that lack dystrophin and have shortened telomeres (mdx/mTR(KO)) develop severe functional cardiac deficits including ventricular dilation, contractile and conductance dysfunction, and accelerated mortality. These cardiac defects are accompanied by telomere erosion, mitochondrial fragmentation and increased oxidative stress. Treatment with antioxidants significantly retards the onset of cardiac dysfunction and death of mdx/mTR(KO) mice. In corroboration, all four of the DMD patients analysed had 45% shorter telomeres in their cardiomyocytes relative to age- and sex-matched controls. We propose that the demands of contraction in the absence of dystrophin coupled with increased oxidative stress conspire to accelerate telomere erosion culminating in cardiac failure and death. These findings provide strong support for a link between telomere length and dystrophin deficiency in the etiology of dilated cardiomyopathy in DMD and suggest preventive interventions.

  View details for DOI 10.1038/ncb2790

  View details for Web of Science ID 000322570900006

  View details for PubMedID 23831727

  View details for PubMedCentralID PMC3774175

• Motor and cognitive assessment of infants and young boys with Duchenne Muscular Dystrophy: results from the Muscular Dystrophy Association DMD Clinical Research Network NEUROMUSCULAR DISORDERS Connolly, A. M., Florence, J. M., Cradock, M. M., Malkus, E. C., Schierbecker, J. R., Siener, C. A., Wulf, C. O., Anand, P., Golumbek, P. T., Zaidman, C. M., Miller, J. P., Lowes, L. P., Alfano, L. N., Viollet-Callendret, L., Flanigan, K. M., Mendell, J. R., McDonald, C. M., Goude, E., Johnson, L., Nicorici, A., Karachunski, P. I., Day, J. W., Dalton, J. C., Farber, J. M., Buser, K. K., Darras, B. T., Kang, P. B., Riley, S. O., Shriber, E., Parad, R., Bushby, K., Eagle, M. 2013; 23 (7): 529-539

  Abstract

  Therapeutic trials in Duchenne Muscular Dystrophy (DMD) exclude young boys because traditional outcome measures rely on cooperation. The Bayley III Scales of Infant and Toddler Development (Bayley III) have been validated in developing children and those with developmental disorders but have not been studied in DMD. Expanded Hammersmith Functional Motor Scale (HFMSE) and North Star Ambulatory Assessment (NSAA) may also be useful in this young DMD population. Clinical evaluators from the MDA-DMD Clinical Research Network were trained in these assessment tools. Infants and boys with DMD (n=24; 1.9±0.7years) were assessed. The mean Bayley III motor composite score was low (82.8±8; p⩽.0001) (normal=100±15). Mean gross motor and fine motor function scaled scores were low (both p⩽.0001). The mean cognitive comprehensive (p=.0002), receptive language (p⩽.0001), and expressive language (p=.0001) were also low compared to normal children. Age was negatively associated with Bayley III gross motor (r=-0.44; p=.02) but not with fine motor, cognitive, or language scores. HFMSE (n=23) showed a mean score of 31±13. NSAA (n=18 boys; 2.2±0.4years) showed a mean score of 12±5. Outcome assessments of young boys with DMD are feasible and in this multicenter study were best demonstrated using the Bayley III.

  View details for DOI 10.1016/j.nmd.2013.04.005

  View details for Web of Science ID 000321997800002

  View details for PubMedID 23726376

• LTBP4 genotype predicts age of ambulatory loss in duchenne muscular dystrophy ANNALS OF NEUROLOGY Flanigan, K. M., Ceco, E., Lamar, K., Kaminoh, Y., Dunn, D. M., Mendell, J. R., King, W. M., Pestronk, A., Florence, J. M., Mathews, K. D., Finkel, R. S., Swoboda, K. J., Gappmaier, E., Howard, M. T., Day, J. W., McDonald, C., McNally, E. M., Weiss, R. B. 2013; 73 (4): 481-488

  Abstract

  OBJECTIVE: Duchenne muscular dystrophy (DMD) displays a clinical range that is not fully explained by the primary DMD mutations. Ltbp4, encoding latent transforming growth factor-β binding protein 4, was previously discovered in a genome-wide scan as a modifier of murine muscular dystrophy. We sought to determine whether LTBP4 genotype influenced DMD severity in a large patient cohort. METHODS: We analyzed nonsynonymous single nucleotide polymorphisms (SNPs) from human LTBP4 in 254 nonambulatory subjects with known DMD mutations. These SNPs, V194I, T787A, T820A, and T1140M, form the VTTT and IAAM LTBP4 haplotypes. RESULTS: Individuals homozygous for the IAAM LTBP4 haplotype remained ambulatory significantly longer than those heterozygous or homozygous for the VTTT haplotype. Glucocorticoid-treated patients who were IAAM homozygotes lost ambulation at 12.5 ± 3.3 years compared to 10.7 ± 2.1 years for treated VTTT heterozygotes or homozygotes. IAAM fibroblasts exposed to transforming growth factor (TGF) β displayed reduced phospho-SMAD signaling compared to VTTT fibroblasts, consistent with LTBP4' role as a regulator of TGFβ. INTERPRETATION: LTBP4 haplotype influences age at loss of ambulation, and should be considered in the management of DMD patients. ANN NEUROL 2013.

  View details for DOI 10.1002/ana.23819

  View details for Web of Science ID 000319523800009

  View details for PubMedID 23440719

• Diffusion tensor imaging reveals widespread white matter abnormalities in children and adolescents with myotonic dystrophy type 1 JOURNAL OF NEUROLOGY Wozniak, J. R., Mueller, B. A., Bell, C. J., Muetzel, R. L., Lim, K. O., Day, J. W. 2013; 260 (4): 1122-1131

  Abstract

  Diffusion tensor imaging was used to evaluate cerebral white matter in 16 patients (ages 9-18) with myotonic dystrophy type 1 compared to 15 matched controls. Patients with myotonic dystrophy showed abnormalities in mean diffusivity compared to controls in frontal, temporal, parietal, and occipital white matter and in all individual tracts examined. Whole cerebrum mean diffusivity was 8.6 % higher overall in patients with myotonic dystrophy compared to controls. Whole cerebrum fractional anisotropy was also abnormal (10.8 % low overall) in all regions and tracts except corticospinal tracts. Follow-up analysis of parallel and perpendicular diffusivity suggests possible relative preservation of myelin in corticospinal tracts. Correlations between Wechsler working memory performance and mean diffusivity were strong for all regions. Frontal and temporal fractional anisotropy were correlated with working memory as well. Results are consistent with earlier studies demonstrating that significant white matter disturbances are characteristic in young patients with myotonic dystrophy and that these abnormalities are associated with the degree of working memory impairment seen in this disease.

  View details for DOI 10.1007/s00415-012-6771-4

  View details for Web of Science ID 000317351900022

  View details for PubMedID 23192171

  View details for PubMedCentralID PMC3609908

• A focal domain of extreme demethylation within D4Z4 in FSHD2 NEUROLOGY Hartweck, L. M., Anderson, L. J., Lemmers, R. J., Dandapat, A., Toso, E. A., Dalton, J. C., Tawil, R., Day, J. W., Van der Maarel, S. M., Kyba, M. 2013; 80 (4): 392-399

  Abstract

  Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disease with an unclear genetic mechanism. Most patients have a contraction of the D4Z4 macrosatellite repeat array at 4qter, which is thought to cause partial demethylation (FSHD1) of the contracted allele. Demethylation has been surveyed at 3 restriction enzyme sites in the first repeat and only a single site across the entire array, and current models postulate that a generalized D4Z4 chromatin alteration causes FSHD. The background of normal alleles has confounded the study of epigenetic alterations; however, rare patients (FSHD2) have a form of the disease in which demethylation is global, i.e., on all D4Z4 elements throughout the genome. Our objective was to take advantage of the global nature of FSHD2 to identify where disease-relevant methylation changes occur within D4Z4.Using bisulfite sequencing of DNA from blood and myoblast cells, methylation levels at 74 CpG sites across 3 disparate regions within D4Z4 were measured in FSHD2 patients and controls.We found that rates of demethylation caused by FSHD2 are not consistent across D4Z4. We identified a focal region of extreme demethylation within a 5' domain, which we named DR1. Other D4Z4 regions, including the DUX4 ORF, were hypomethylated but to a much lesser extent.These data challenge the simple view that FSHD is caused by a broad "opening" of D4Z4 and lead us to postulate that the region of focal demethylation is the site of action of the key D4Z4 chromatin regulatory factors that go awry in FSHD.

  View details for Web of Science ID 000313961000018

  View details for PubMedID 23284062

  View details for PubMedCentralID PMC3589240

• A randomized, double-blind trial of lisinopril and losartan for the treatment of cardiomyopathy in duchenne muscular dystrophy. PLoS currents Allen, H. D., Flanigan, K. M., Thrush, P. T., Dvorchik, I., Yin, H., Canter, C., Connolly, A. M., Parrish, M., McDonald, C. M., Braunlin, E., Colan, S. D., Day, J., Darras, B., Mendell, J. R. 2013; 5

  Abstract

  This study sought to compare the effectiveness and safety of an angiotensin converting enzyme inhibitor (ACE-I) (lisinopril) vs. an angiotensin receptor blocker (ARB) (losartan) for the treatment of cardiomyopathy (CM) in boys with Duchenne muscular dystrophy (DMD).Development of CM is universal in boys with DMD. ACE-I and ARB have both been suggested as effective treatment options. ARBs have been associated with skeletal muscle regeneration in a mouse model of DMD. The question of which, if either, is more effective for CM treatment in DMD remains. The purpose of this multicenter double-blind prospective study was to compare efficacy and safety of lisinopril versus losartan in the treatment of newly diagnosed CM in boys with DMD.Echocardiographic technician inter- and intraobserver variability were tested on 2 separate days on 2 different boys with DMD CM. Results were compared with paired t-testing. Twenty-two boys with newly diagnosed DMD CM (echocardiographic ejection fraction (EF) 10% EF drop. Three boys in the aCE-I group had 3 visits, due to study funding termination. Two were withdrawn because of low EF. All their data are included in the analysis for as long as they remained in the study. Mean EF's were similar at baseline (47.5%- ACE-I, 48.4%- ARB). After 1 year each group significantly improved to 54.6% and 55.2% respectively (p=.02). There was no difference between the 2 treatment groups at 1 year.Inter-observer and intra-observer reliability studies showed no differences between echocardiographers on serial examinations. EF improved equally in the two groups. There is no therapeutic difference in EF improvement between lisinopril and losartan over the one-year duration for treatment of boys with DMD-related CM.ClinicalTrials.gov NCT01982695.

  View details for DOI 10.1371/currents.md.2cc69a1dae4be7dfe2bcb420024ea865

  View details for PubMedID 24459612

  View details for PubMedCentralID PMC3871420

• Cerebral and muscle MRI abnormalities in myotonic dystrophy NEUROMUSCULAR DISORDERS Franc, D. T., Muetzel, R. L., Robinson, P. R., Rodriguez, C. P., Dalton, J. C., Naughton, C. E., Mueller, B. A., Wozniak, J. R., Lim, K. O., Day, J. W. 2012; 22 (6): 483-491

  Abstract

  Pathophysiological mechanisms underlying the clinically devastating CNS features of myotonic dystrophy (DM) remain more enigmatic and controversial than do the muscle abnormalities of this common form of muscular dystrophy. To better define CNS and cranial muscle changes in DM, we used quantitative volumetric and diffusion tensor MRI methods to measure cerebral and masticatory muscle differences between controls (n=5) and adults with either congenital (n=5) or adult onset (n=5) myotonic dystrophy type 1 and myotonic dystrophy type 2 (n=5). Muscle volumes were diminished in DM1 and strongly correlated with reduced white matter integrity and gray matter volume. Moreover, correlation of reduced fractional anisotropy (white matter integrity) and gray matter volume in both DM1 and DM2 suggests that these abnormalities may share a common underlying pathophysiological mechanism. Further quantitative temporal and spatial characterization of these features will help delineate developmental and progressive neurological components of DM, and help determine the causative molecular and cellular mechanisms.

  View details for DOI 10.1016/j.nmd.2012.01.003

  View details for Web of Science ID 000305164900002

  View details for PubMedID 22290140

  View details for PubMedCentralID PMC3350604

• Clinical and genetic features of spinocerebellar ataxia type 8. Handbook of clinical neurology Ikeda, Y., Ranum, L. P., Day, J. W. 2012; 103: 493-505

  View details for DOI 10.1016/B978-0-444-51892-7.00031-0

  View details for PubMedID 21827909

• Spinocerebellar ataxia type 5. Handbook of clinical neurology Dick, K. A., Ikeda, Y., Day, J. W., Ranum, L. P. 2012; 103: 451-459

  Abstract

  In 1994, Ranum and colleagues identified a ten-generation American kindred with a relatively mild autosomal dominant form of spinocerebellar ataxia (Ranum et al., 1994). The mutation was mapped to the centromeric region of chromosome 11, and the disorder designated SCA5 (Ranum et al., 1994). Using a multifaceted mapping approach, Ikeda et al. (2006) discovered that β-III spectrin (SPTBN2) mutations cause spinocerebellar ataxia type 5 (SCA5) in the American kindred and two additional independently reported SCA5 families. The American and French families have separate in-frame deletions of 39 and 15 bp, respectively, in the third of 17 spectrin repeat motifs. A third mutation, found in a German family, is located in the second calponin homology domain, a region known to bind actin and Arp1. Consistent with Purkinje cell degeneration in SCA5, β-III spectrin is highly expressed in cerebellar Purkinje cells. TIRF microscopy performed on cell lines transiently transfected with mutant or wild-type spectrin shows that mutant β-III spectrin fails to stabilize the glutamate transporter EAAT4 at the plasma membrane. Additionally, marked differences in EAAT4 and GluRδ2 were found by protein blot and cell fractionation in SCA5 autopsy tissue. This review summarizes data showing that β-III spectrin mutations are a novel cause of neurodegenerative disease, which may affect the stabilization or trafficking of membrane proteins.

  View details for DOI 10.1016/B978-0-444-51892-7.00028-0

  View details for PubMedID 21827906

• 2010 Marigold therapeutic strategies for myotonic dystrophy. Neuromuscular disorders Blonsky, K., Monckton, D., Wieringa, B., Schoser, B., Day, J. W., Engelen, B. v. 2012; 22 (1): 87-94

  View details for DOI 10.1016/j.nmd.2011.06.747

  View details for PubMedID 21852134

• Randomized, blinded trial of weekend vs daily prednisone in Duchenne muscular dystrophy NEUROLOGY Escolar, D. M., Hache, L. P., Clemens, P. R., Cnaan, A., McDonald, C. M., Viswanathan, V., Kornberg, A. J., Bertorini, T. E., Nevo, Y., Lotze, T., Pestronk, A., Ryan, M. M., Monasterio, E., Day, J. W., Zimmerman, A., Arrieta, A., Henricson, E., Mayhew, J., Florence, J., Hu, F., Connolly, A. M. 2011; 77 (5): 444-452

  Abstract

  To perform a double-blind, randomized study comparing efficacy and safety of daily and weekend prednisone in boys with Duchenne muscular dystrophy (DMD).A total of 64 boys with DMD who were between 4 and 10 years of age were randomized at 1 of 12 centers of the Cooperative International Neuromuscular Research Group. Efficacy and safety of 2 prednisone schedules (daily 0.75 mg/kg/day and weekend 10 mg/kg/wk) were evaluated over 12 months.Equivalence was met for weekend and daily dosing of prednisone for the primary outcomes of quantitative muscle testing (QMT) arm score and QMT leg score. Secondary strength scores for QMT elbow flexors also showed equivalence between the 2 treatment groups. Overall side effect profiles of height and weight, bone density, cataract formation, blood pressure, and behavior, analyzed at 12 months, did not differ between weekend and daily dosing of prednisone.Weekend dosing of prednisone is equally beneficial to the standard daily dosing of prednisone. Analysis of side effect profiles demonstrated overall tolerability of both dosing regimens.This study provides Class I evidence that weekend prednisone dosing is as safe and effective as daily prednisone in preserving muscle strength and preventing body mass index increases in boys with DMD over a 12-month period.

  View details for DOI 10.1212/WNL.0b013e318227b164

  View details for Web of Science ID 000293383100012

  View details for PubMedID 21753160

  View details for PubMedCentralID PMC3146308

• Misregulation of miR-1 processing is associated with heart defects in myotonic dystrophy NATURE STRUCTURAL & MOLECULAR BIOLOGY Rau, F., Freyermuth, F., Fugier, C., Villemin, J., Fischer, M., Jost, B., Dembele, D., Gourdon, G., Nicole, A., Duboc, D., Wahbi, K., Day, J. W., Fujimura, H., Takahashi, M. P., Auboeuf, D., Dreumont, N., Furling, D., Charlet-Berguerand, N. 2011; 18 (7): 840-U120

  Abstract

  Myotonic dystrophy is an RNA gain-of-function disease caused by expanded CUG or CCUG repeats, which sequester the RNA binding protein MBNL1. Here we describe a newly discovered function for MBNL1 as a regulator of pre-miR-1 biogenesis and find that miR-1 processing is altered in heart samples from people with myotonic dystrophy. MBNL1 binds to a UGC motif located within the loop of pre-miR-1 and competes for the binding of LIN28, which promotes pre-miR-1 uridylation by ZCCHC11 (TUT4) and blocks Dicer processing. As a consequence of miR-1 loss, expression of GJA1 (connexin 43) and CACNA1C (Cav1.2), which are targets of miR-1, is increased in both DM1- and DM2-affected hearts. CACNA1C and GJA1 encode the main calcium- and gap-junction channels in heart, respectively, and we propose that their misregulation may contribute to the cardiac dysfunctions observed in affected persons.

  View details for DOI 10.1038/nsmb.2067

  View details for Web of Science ID 000292507500013

  View details for PubMedID 21685920

• Nonsense Mutation-Associated Becker Muscular Dystrophy: Interplay Between Exon Definition and Splicing Regulatory Elements within the DMD Gene HUMAN MUTATION Flanigan, K. M., Dunn, D. M., von Niederhausern, A., Soltanzadeh, P., Howard, M. T., Sampson, J. B., Swoboda, K. J., Bromberg, M. B., Mendell, J. R., Taylor, L. E., Anderson, C. B., Pestronk, A., Florence, J. M., Connolly, A. M., Mathews, K. D., Wong, B., Finkel, R. S., Bonnemann, C. G., Day, J. W., McDonald, C., Weiss, R. B. 2011; 32 (3): 299-308

  Abstract

  Nonsense mutations are usually predicted to function as null alleles due to premature termination of protein translation. However, nonsense mutations in the DMD gene, encoding the dystrophin protein, have been associated with both the severe Duchenne Muscular Dystrophy (DMD) and milder Becker Muscular Dystrophy (BMD) phenotypes. In a large survey, we identified 243 unique nonsense mutations in the DMD gene, and for 210 of these we could establish definitive phenotypes. We analyzed the reading frame predicted by exons flanking those in which nonsense mutations were found, and present evidence that nonsense mutations resulting in BMD likely do so by inducing exon skipping, confirming that exonic point mutations affecting exon definition have played a significant role in determining phenotype. We present a new model based on the combination of exon definition and intronic splicing regulatory elements for the selective association of BMD nonsense mutations with a subset of DMD exons prone to mutation-induced exon skipping.

  View details for DOI 10.1002/humu.21426

  View details for Web of Science ID 000288034100007

  View details for PubMedID 21972111

• White matter abnormalities and neurocognitive correlates in children and adolescents with myotonic dystrophy type 1: A diffusion tensor imaging study NEUROMUSCULAR DISORDERS Wozniak, J. R., Mueller, B. A., Ward, E. E., Lim, K. O., Day, J. W. 2011; 21 (2): 89-96

  Abstract

  Diffusion tensor imaging was used to evaluate cerebral white matter in eight patients (ages 10-17), with myotonic dystrophy type 1 (3 congenital-onset, 5 juvenile-onset) compared to eight controls matched for age and sex. Four regions of interest were examined: inferior frontal, superior frontal, supracallosal, and occipital. The myotonic dystrophy group showed white matter abnormalities compared to controls in all regions. All indices of white matter integrity were abnormal: fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. With no evidence of regional variation, correlations between whole cerebrum white matter fractional anisotropy and neurocognitive functioning were examined in the patients. Strong correlations were observed between whole cerebrum fractional anisotropy and full-scale intelligence and a measure of executive functioning. Results indicate that significant white matter abnormality is characteristic of young patients with myotonic dystrophy type 1 and that the white matter abnormality seen with neuroimaging has implications for cognitive functioning.

  View details for DOI 10.1016/j.nmd.2010.11.013

  View details for Web of Science ID 000290245200002

  View details for PubMedID 21169018

  View details for PubMedCentralID PMC3026055

• TRAUMA, TDP-43, AND AMYOTROPHIC LATERAL SCLEROSIS MUSCLE & NERVE Appel, S. H., Cwik, V. A., Day, J. W. 2010; 42 (6): 851-852

  View details for DOI 10.1002/mus.21939

  View details for Web of Science ID 000285172400001

  View details for PubMedID 21104858

• Targeting parents for the treatment of pediatric obesity in boys with Duchenne muscular dystrophy: A case series EATING AND WEIGHT DISORDERS-STUDIES ON ANOREXIA BULIMIA AND OBESITY Arikian, A., Boutelle, K., Peterson, C. B., Dalton, J., Day, J. W., Crow, S. J. 2010; 15 (3): E161-E165

  Abstract

  Obesity is a major public health concern in children. Obesity occurs frequently in boys with Duchenne muscular dystrophy (DMD), complicating treatment and impairing functioning. Parent-focused interventions to facilitate weight loss have been successful in other pediatric samples but have not been studied with this population. The current investigation examined the feasibility and potential efficacy of parent-focused treatment to improve healthy eating and physical activity of parents and eating and weight in their sons with DMD. Three families participated in this case series. Resulting changes in body weight among boys with DMD were an outcome variable. Findings indicate inconsistent changes in boys' weight, decreases in parent weight, increases in healthy foods available in the home, and increases in children's perceived quality of life. Participant ratings of treatment suitability and satisfaction were generally favorable. These preliminary findings support the use of parent-focused psychoeducation for the treatment of obesity in children with DMD.

  View details for Web of Science ID 000286027100006

  View details for PubMedID 21150251

• Mutational Spectrum of DMD Mutations in Dystrophinopathy Patients: Application of Modern Diagnostic Techniques to a Large Cohort HUMAN MUTATION Flanigan, K. M., Dunn, D. M., von Niederhausern, A., Soltanzadeh, P., Gappmaier, E., Howard, M. T., Sampson, J. B., Mendell, J. R., Wall, C., King, W. M., Pestronk, A., Florence, J. M., Connolly, A. M., Mathews, K. D., Stephan, C. M., Laubenthal, K. S., Wong, B. L., Morehart, P. J., Meyer, A., Finkel, R. S., Bonnemann, C. G., Medne, L., Day, J. W., Dalton, J. C., Margolis, M. K., Hinton, V. J., Weiss, R. B. 2009; 30 (12): 1657-1666

  Abstract

  Mutations in the DMD gene, encoding the dystrophin protein, are responsible for the dystrophinopathies Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), and X-linked Dilated Cardiomyopathy (XLDC). Mutation analysis has traditionally been challenging, due to the large gene size (79 exons over 2.2 Mb of genomic DNA). We report a very large aggregate data set comprised of DMD mutations detected in samples from patients enrolled in the United Dystrophinopathy Project, a multicenter research consortium, and in referral samples submitted for mutation analysis with a diagnosis of dystrophinopathy. We report 1,111 mutations in the DMD gene, including 891 mutations with associated phenotypes. These results encompass 506 point mutations (including 294 nonsense mutations) and significantly expand the number of mutations associated with the dystrophinopathies, highlighting the utility of modern diagnostic techniques. Our data supports the uniform hypermutability of CGA>TGA mutations, establishes the frequency of polymorphic muscle (Dp427m) protein isoforms and reveals unique genomic haplotypes associated with "private" mutations. We note that 60% of these patients would be predicted to benefit from skipping of a single DMD exon using antisense oligonucleotide therapy, and 62% would be predicted to benefit from an inclusive multiexonskipping approach directed toward exons 45 through 55.

  View details for DOI 10.1002/humu.21114

  View details for Web of Science ID 000272796400007

  View details for PubMedID 19937601

  View details for PubMedCentralID PMC3404892

• SNP Haplotype Mapping in a Small ALS Family PLOS ONE Krueger, K. A., Tsuji, S., Fukuda, Y., Takahashi, Y., Goto, J., Mitsui, J., Ishiura, H., Dalton, J. C., Miller, M. B., Day, J. W., Ranum, L. P. 2009; 4 (5)

  Abstract

  The identification of genes for monogenic disorders has proven to be highly effective for understanding disease mechanisms, pathways and gene function in humans. Nevertheless, while thousands of Mendelian disorders have not yet been mapped there has been a trend away from studying single-gene disorders. In part, this is due to the fact that many of the remaining single-gene families are not large enough to map the disease locus to a single site in the genome. New tools and approaches are needed to allow researchers to effectively tap into this genetic gold-mine. Towards this goal, we have used haploid cell lines to experimentally validate the use of high-density single nucleotide polymorphism (SNP) arrays to define genome-wide haplotypes and candidate regions, using a small amyotrophic lateral sclerosis (ALS) family as a prototype. Specifically, we used haploid-cell lines to determine if high-density SNP arrays accurately predict haplotypes across entire chromosomes and show that haplotype information significantly enhances the genetic information in small families. Panels of haploid-cell lines were generated and a 5 centimorgan (cM) short tandem repeat polymorphism (STRP) genome scan was performed. Experimentally derived haplotypes for entire chromosomes were used to directly identify regions of the genome identical-by-descent in 5 affected individuals. Comparisons between experimentally determined and in silico haplotypes predicted from SNP arrays demonstrate that SNP analysis of diploid DNA accurately predicted chromosomal haplotypes. These methods precisely identified 12 candidate intervals, which are shared by all 5 affected individuals. Our study illustrates how genetic information can be maximized using readily available tools as a first step in mapping single-gene disorders in small families.

  View details for DOI 10.1371/journal.pone.0005687

  View details for Web of Science ID 000266331700014

  View details for PubMedID 19479031

  View details for PubMedCentralID PMC2682655

• Congenital muscular dystrophy in a new age NEUROLOGY Day, J. W. 2008; 71 (5): 308-309

  View details for Web of Science ID 000257998800001

  View details for PubMedID 18663176

• Myotonic dystrophy type 2 in Japan: ancestral origin distinct from Caucasian families NEUROGENETICS Saito, T., Amakusa, Y., Kimura, T., Yahara, O., Aizawa, H., Ikeda, Y., Day, J. W., Ranum, L. P., Ohno, K., Matsuura, T. 2008; 9 (1): 61-63

  Abstract

  Myotonic dystrophy type 2 (DM2) is caused by expansion of a tetranucleotide CCTG repeat in intron 1 of the ZNF9 gene on chromosome 3q21. All studied DM2 mutations have been reported in Caucasians and share an identical haplotype, suggesting a common founder. We identified a Japanese patient with DM2 and showed that the affected haplotype is distinct from the previously identified DM2 haplotype shared among Caucasians. These data strongly suggest that DM2 expansion mutations originate from separate founders in Europe and Japan and are more widely distributed than previously recognized.

  View details for DOI 10.1007/s10048-007-0110-4

  View details for Web of Science ID 000252638800007

  View details for PubMedID 18057971

• Heterozygosity for a protein truncation mutation of sodium channel SCN8A in a patient with cerebellar atrophy, ataxia, and mental retardation JOURNAL OF MEDICAL GENETICS Trudeau, M. M., DALTON, J. C., Day, J. W., Ranum, L. P., Meisler, M. H. 2006; 43 (6): 527-530

  Abstract

  The SCN8A gene on chromosome 12q13 encodes the voltage gated sodium channel Na(v)1.6, which is widely expressed in neurons of the CNS and PNS. Mutations in the mouse ortholog of SCN8A result in ataxia and other movement disorders.We screened the 26 coding exons of SCN8A in 151 patients with inherited or sporadic ataxia.A 2 bp deletion in exon 24 was identified in a 9 year old boy with mental retardation, pancerebellar atrophy, and ataxia. This mutation, Pro1719ArgfsX6, introduces a translation termination codon into the pore loop of domain 4, resulting in removal of the C-terminal cytoplasmic domain and predicted loss of channel function. Three additional heterozygotes in the family exhibit milder cognitive and behavioural deficits including attention deficit hyperactivity disorder (ADHD). No additional occurrences of this mutation were observed in 625 unrelated DNA samples (1250 chromosomes).The phenotypes of the heterozygous individuals suggest that mutations in SCN8A may result in motor and cognitive deficits of variable expressivity, but the study was limited by lack of segregation in the small pedigree and incomplete information about family members. Identification of additional families will be required to confirm the contribution of the SCN8A mutation to the clinical features in ataxia, cognition and behaviour disorders.

  View details for DOI 10.1136/jmg.2005.035667

  View details for Web of Science ID 000237973300011

  View details for PubMedID 16236810

  View details for PubMedCentralID PMC2564538

• DM2 intronic expansions: evidence for CCUG accumulation without flanking sequence or effects on ZNF9 mRNA processing or protein expression HUMAN MOLECULAR GENETICS Margolis, J. M., Schoser, B. G., Moseley, M. L., Day, J. W., Ranum, L. P. 2006; 15 (11): 1808-1815

  Abstract

  Myotonic dystrophy type 2 (DM2) is caused by a CCTG expansion mutation in intron 1 of the zinc finger protein 9 (ZNF9) gene. The mean expansion size in patients is larger than for DM1 or any previously reported disorder (mean=5000 CCTGs; range=75-11 000), and similar to DM1, repeats containing ribonuclear inclusions accumulate in affected DM2 tissue. Although an RNA gain-of-function mechanism involving DM1 CUG or DM2 CCUG expansion transcripts is now well established, still debated are the potential role that flanking sequences within the DMPK 3'-UTR may have on disease pathogenesis and whether or not decreased expression of DMPK, ZNF9 or neighboring genes at these loci contribute to disease. To address these questions in DM2, we have examined the nucleic acid content of the ribonuclear inclusions and the effects of these large expansions on ZNF9 expression. Using cell lines either haploid or homozygous for the expansion, as well as skeletal muscle biopsy tissue, we demonstrate that pre-mRNAs containing large CCUG expansions are normally spliced and exported from the nucleus, that the expansions do not decrease ZNF9 expression at the mRNA or protein level, and that the ribonuclear inclusions are enriched for the CCUG expansion, but not intronic flanking sequences. These data suggest that the downstream molecular effects of the DM2 mutation are triggered by the accumulation of CCUG repeat tract alone.

  View details for DOI 10.1093/hmg/ddl103

  View details for Web of Science ID 000237696700007

  View details for PubMedID 16624843

• Spectrin mutations cause spinocerebellar ataxia type 5 NATURE GENETICS Ikeda, Y., Dick, K. A., Weatherspoon, M. R., Gincel, D., Armbrust, K. R., DALTON, J. C., Stevanin, G., Durr, A., Zuhlke, C., Burk, K., Clark, H. B., Brice, A., Rothstein, J. D., Schut, L. J., Day, J. W., Ranum, L. P. 2006; 38 (2): 184-190

  Abstract

  We have discovered that beta-III spectrin (SPTBN2) mutations cause spinocerebellar ataxia type 5 (SCA5) in an 11-generation American kindred descended from President Lincoln's grandparents and two additional families. Two families have separate in-frame deletions of 39 and 15 bp, and a third family has a mutation in the actin/ARP1 binding region. Beta-III spectrin is highly expressed in Purkinje cells and has been shown to stabilize the glutamate transporter EAAT4 at the surface of the plasma membrane. We found marked differences in EAAT4 and GluRdelta2 by protein blot and cell fractionation in SCA5 autopsy tissue. Cell culture studies demonstrate that wild-type but not mutant beta-III spectrin stabilizes EAAT4 at the plasma membrane. Spectrin mutations are a previously unknown cause of ataxia and neurodegenerative disease that affect membrane proteins involved in glutamate signaling.

  View details for DOI 10.1038/ng1728

  View details for Web of Science ID 000234953200012

  View details for PubMedID 16429157

• Gene symbol: SCN8A. Disease: Ataxia. Accession #Hd0520. Human genetics Meisler, M. H., Trudeau, M. M., DALTON, J. C., Day, J. W., Ranum, L. P. 2006; 118 (6): 776-?

  View details for PubMedID 17297687

• Dominant non-coding repeat expansions in human disease. Genome dynamics Dick, K. A., Margolis, J. M., Day, J. W., Ranum, L. P. 2006; 1: 67-83

  Abstract

  The general model that dominant diseases are caused by mutations that result in a gain or change in function of the corresponding protein was challenged by the discovery that the myotonic dystrophy type 1 mutation is a CTG expansion located in the 3' untranslated portion of a kinase gene. The subsequent discovery that a similar transcribed but untranslated CCTG expansion in an intron causes the same multisystemic features in myotonic dystrophy type 2 (DM2), along with other developments in the DM1 field, demonstrate a mechanism in which these expansion mutations cause disease through a gain of function mechanism triggered by the accumulation of transcripts containing CUG or CCUG repeat expansions. A similar RNA gain of function mechanism has also been implicated in fragile X tremor ataxia syndrome (FXTAS) and may play a role in pathogenesis of other non-coding repeat expansion diseases, including spinocerebellar ataxia type 8 (SCA8), SCA10, SCA12 and Huntington disease-like 2.

  View details for DOI 10.1159/000092501

  View details for PubMedID 18724054

• Genetics and molecular pathogenesis of the myotonic dystrophies. Current neurology and neuroscience reports Day, J. W., Ranum, L. P. 2005; 5 (1): 55-59

  Abstract

  Pathogenic repeat expansions were initially identified as causing either a loss of gene product, such as in fragile X mental retardation, or an expansion of a polyglutamine region of a protein, as was first shown in spinobulbar muscular atrophy (Kennedy's disease). The pathogenic effect of the repeat expansion in myotonic dystrophy type 1, however, has been controversial because it does not encode a protein but nonetheless results in a highly penetrant dominant disease. Clinical and molecular characterization of myotonic dystrophy types 1 and 2 have now demonstrated a novel disease mechanism involving pathogenic effects of repeat expansions that are expressed in RNA but are not translated into protein.

  View details for PubMedID 15676109

• RNA pathogenesis of the myotonic dystrophies NEUROMUSCULAR DISORDERS Day, J. W., Ranum, L. P. 2005; 15 (1): 5-16

  Abstract

  Myotonic dystrophy (dystrophia myotonica, DM) is the most common form of muscular dystrophy in adults. The presence of two genetic forms of this complex multisystemic disease (DM1 and DM2) was unrecognized until the genetic cause of DM1 was identified in 1992. The fact that the DM1 mutation is an untranslated CTG expansion led to extended controversy about the molecular pathophysiology of this disease. When the DM2 mutation was identified in 2001 as being a similarly untranslated CCTG expansion, the molecular and clinical parallels between DM1 and DM2 substantiated the role of a novel mechanism in generating the unusual constellation of clinical features seen in these diseases: the repeat expansions expressed at the RNA level alter RNA processing, at least in part by interfering with alternative splicing of other genes. For example, in both DM1 and DM2, altered splicing of chloride channel and insulin receptor transcripts leads to myotonia and insulin resistance, respectively. Although other mechanisms may underlie the differences between DM1 and DM2, the pathogenic effects of the RNA mechanism are now clear, which will facilitate development of appropriate treatments.

  View details for DOI 10.1016/j.nmd.2004.09.012

  View details for Web of Science ID 000226567900002

  View details for PubMedID 15639115

• Sudden cardiac death in myotonic dystrophy type 2 NEUROLOGY Schoser, B. G., Ricker, K., Schneider-Gold, C., Hengstenberg, C., Durre, J., Bultmann, B., Kress, W., Day, J. W., Ranum, L. P. 2004; 63 (12): 2402-2404

  Abstract

  Medical records and follow-up data were reviewed in 297 genetically proven myotonic dystrophy type 2 (DM2) patients. Patients were selected by the criteria of cardiac sudden death before age 45. Sudden death occurred in four patients, three of whom were cardiological asymptomatic, and one with a history of heart failure. Cardiac histopathology showed dilated cardiomyopathy in all, and conduction system fibrosis in two patients. Pathogenetic CCUG ribonuclear inclusions were demonstrable in cardiomyocytes.

  View details for Web of Science ID 000226010000039

  View details for PubMedID 15623712

• Spinocerebellar ataxia type 8: Molecular genetic comparisons and haplotype analysis of 37 families with ataxia AMERICAN JOURNAL OF HUMAN GENETICS Ikeda, Y., DALTON, J. C., Moseley, M. L., Gardner, K. L., Bird, T. D., Ashizawa, T., Seltzer, W. K., Pandolfo, M., MILUNSKY, A., Potter, N. T., Shoji, M., Vincent, J. B., Day, J. W., Ranum, L. P. 2004; 75 (1): 3-16

  Abstract

  We reported elsewhere that an untranslated CTG expansion causes the dominantly inherited neurodegenerative disorder spinocerebellar ataxia type 8 (SCA8). SCA8 shows a complex inheritance pattern with extremes of incomplete penetrance, in which often only one or two affected individuals are found in a given family. SCA8 expansions have also been found in control chromosomes, indicating that separate genetic or environmental factors increase disease penetrance among SCA8-expansion-carrying patients with ataxia. We describe the molecular genetic features and disease penetrance of 37 different families with SCA8 ataxia from the United States, Canada, Japan, and Mexico. Haplotype analysis using 17 STR markers spanning an approximately 1-Mb region was performed on the families with ataxia, on a group of expansion carriers in the general population, and on psychiatric patients, to clarify the genetic basis of the reduced penetrance and to investigate whether CTG expansions among different populations share a common ancestral background. Two major ancestrally related haplotypes (A and A') were found among white families with ataxia, normal controls, and patients with major psychosis, indicating a common ancestral origin of both pathogenic and nonpathogenic SCA8 expansions among whites. Two additional and distinct haplotypes were found among a group of Japanese families with ataxia (haplotype B) and a Mexican family with ataxia (haplotype C). Our finding that SCA8 expansions on three independently arising haplotypes are found among patients with ataxia and cosegregate with ataxia when multiple family members are affected further supports the direct role of the CTG expansion in disease pathogenesis.

  View details for Web of Science ID 000222031300002

  View details for PubMedID 15152344

  View details for PubMedCentralID PMC1182005

• Myotonic dystrophy: RNA pathogenesis comes into focus AMERICAN JOURNAL OF HUMAN GENETICS Ranum, L. P., Day, J. W. 2004; 74 (5): 793-804

  Abstract

  Myotonic dystrophy (DM)--the most common form of muscular dystrophy in adults, affecting 1/8000 individuals--is a dominantly inherited disorder with a peculiar and rare pattern of multisystemic clinical features affecting skeletal muscle, the heart, the eye, and the endocrine system. Two genetic loci have been associated with the DM phenotype: DM1, on chromosome 19, and DM2, on chromosome 3. In 1992, the mutation responsible for DM1 was identified as a CTG expansion located in the 3' untranslated region of the dystrophia myotonica-protein kinase gene (DMPK). How this untranslated CTG expansion causes myotonic dystrophy type 1(DM1) has been controversial. The recent discovery that myotonic dystrophy type 2 (DM2) is caused by an untranslated CCTG expansion, along with other discoveries on DM1 pathogenesis, indicate that the clinical features common to both diseases are caused by a gain-of-function RNA mechanism in which the CUG and CCUG repeats alter cellular function, including alternative splicing of various genes. We discuss the pathogenic mechanisms that have been proposed for the myotonic dystrophies, the clinical and molecular features of DM1 and DM2, and the characterization of murine and cell-culture models that have been generated to better understand these diseases.

  View details for Web of Science ID 000220926100002

  View details for PubMedID 15065017

  View details for PubMedCentralID PMC1181975

• Rapid resolution of quadriplegic CIDP by combined plasmapheresis and IVIg NEUROLOGY Walk, D., Li, L. Y., Parry, G. J., Day, J. W. 2004; 62 (1): 155-156

  View details for Web of Science ID 000188010100046

  View details for PubMedID 14718727

• Myotonic dystrophy type 2: Human founder haplotype and evolutionary conservation of the repeat tract AMERICAN JOURNAL OF HUMAN GENETICS Liquori, C. L., Ikeda, Y., Weatherspoon, M., Ricker, K., Schoser, B. G., DALTON, J. C., Day, J. W., Ranum, L. P. 2003; 73 (4): 849-862

  Abstract

  Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, can be caused by a mutation on either chromosome 19 (DM1) or 3 (DM2). In 2001, we demonstrated that DM2 is caused by a CCTG expansion in intron 1 of the zinc finger protein 9 (ZNF9) gene. To investigate the ancestral origins of the DM2 expansion, we compared haplotypes for 71 families with genetically confirmed DM2, using 19 short tandem repeat markers that we developed that flank the repeat tract. All of the families are white, with the majority of Northern European/German descent and a single family from Afghanistan. Several conserved haplotypes spanning >700 kb appear to converge into a single haplotype near the repeat tract. The common interval that is shared by all families with DM2 immediately flanks the repeat, extending up to 216 kb telomeric and 119 kb centromeric of the CCTG expansion. The DM2 repeat tract contains the complex repeat motif (TG)(n)(TCTG)(n)(CCTG)(n). The CCTG portion of the repeat tract is interrupted on normal alleles, but, as in other expansion disorders, these interruptions are lost on affected alleles. We examined haplotypes of 228 control chromosomes and identified a potential premutation allele with an uninterrupted (CCTG)(20) on a haplotype that was identical to the most common affected haplotype. Our data suggest that the predominant Northern European ancestry of families with DM2 resulted from a common founder and that the loss of interruptions within the CCTG portion of the repeat tract may predispose alleles to further expansion. To gain insight into possible function of the repeat tract, we looked for evolutionary conservation. The complex repeat motif and flanking sequences within intron 1 are conserved among human, chimpanzee, gorilla, mouse, and rat, suggesting a conserved biological function.

  View details for Web of Science ID 000185676100012

  View details for PubMedID 14505273

  View details for PubMedCentralID PMC1180607

• Autoimmune rippling muscle NEUROLOGY Muley, S. A., Day, J. W. 2003; 61 (6): 869-870

  View details for Web of Science ID 000185460600041

  View details for PubMedID 14504350

• Myotonic dystrophy type 2 - Molecular, diagnostic and clinical spectrum NEUROLOGY Day, J. W., Ricker, K., Jacobsen, J. F., Rasmussen, L. J., Dick, K. A., Kress, W., Schneider, C., Koch, M. C., Beilman, G. J., Harrison, A. R., DALTON, J. C., Ranum, L. P. 2003; 60 (4): 657-664

  Abstract

  Myotonic dystrophy types 1 (DM1) and 2 (DM2/proximal myotonic myopathy PROMM) are dominantly inherited disorders with unusual multisystemic clinical features. The authors have characterized the clinical and molecular features of DM2/PROMM, which is caused by a CCTG repeat expansion in intron 1 of the zinc finger protein 9 (ZNF9) gene.Three-hundred and seventy-nine individuals from 133 DM2/PROMM families were evaluated genetically, and in 234 individuals clinical and molecular features were compared.Among affected individuals 90% had electrical myotonia, 82% weakness, 61% cataracts, 23% diabetes, and 19% cardiac involvement. Because of the repeat tract's unprecedented size (mean approximately 5,000 CCTGs) and somatic instability, expansions were detectable by Southern analysis in only 80% of known carriers. The authors developed a repeat assay that increased the molecular detection rate to 99%. Only 30% of the positive samples had single sizeable expansions by Southern analysis, and 70% showed multiple bands or smears. Among the 101 individuals with single expansions, repeat size did not correlate with age at disease onset. Affected offspring had markedly shorter expansions than their affected parents, with a mean size difference of -17 kb (-4,250 CCTGs).DM2 is present in a large number of families of northern European ancestry. Clinically, DM2 resembles adult-onset DM1, with myotonia, muscular dystrophy, cataracts, diabetes, testicular failure, hypogammaglobulinemia, and cardiac conduction defects. An important distinction is the lack of a congenital form of DM2. The clinical and molecular parallels between DM1 and DM2 indicate that the multisystemic features common to both diseases are caused by CUG or CCUG expansions expressed at the RNA level.

  View details for Web of Science ID 000182948000024

  View details for PubMedID 12601109

• Molecular genetics of spinocerebellar ataxia type 8 (SCA8) CYTOGENETIC AND GENOME RESEARCH Mosemiller, A. K., DALTON, J. C., Day, J. W., Ranum, L. P. 2003; 100 (1-4): 175-183

  Abstract

  We previously reported that a transcribed but untranslated CTG expansion causes a novel form of ataxia, spinocerebellar ataxia type 8 (SCA8) (Koob et al., 1999). SCA8 was the first example of a dominant spinocerebellar ataxia that is not caused by the expansion of a CAG repeat translated into a polyglutamine tract. This slowly progressive form of ataxia is characterized by dramatic repeat instability and a high degree of reduced penetrance. The clinical and genetic features of the disease are discussed below.

  View details for DOI 10.1159/000072852

  View details for Web of Science ID 000186274900018

  View details for PubMedID 14526178

• Randomized, controlled trial of intravenous immunoglobulin in myasthenia gravis MUSCLE & NERVE Wolfe, G. I., Barohn, R. J., Foster, B. M., Jackson, C. E., Kissel, J. T., Day, J. W., Thornton, C. A., Nations, S. P., Bryan, W. W., Amato, A. A., Freimer, M. L., Parry, G. J., Mendell, J. R. 2002; 26 (4): 549-552

  Abstract

  We initiated a randomized, double-blinded, placebo-controlled trial of intravenous immunoglobulin (IVIG) treatment in myasthenia gravis (MG). Patients received IVIG 2 gm/kg at induction and 1 gm/kg after 3 weeks vs. 5% albumin placebo. The primary efficacy measurement was the change in the quantitative MG Score (QMG) at day 42. Fifteen patients were enrolled (6 to IVIG; 9 to placebo) before the study was terminated because of insufficient IVIG inventories. At day 42, there was no significant difference in primary or secondary outcome measurements between the two groups. In a subsequent 6-week open-label study of IVIG, positive trends were observed.

  View details for DOI 10.1002/mus.10224

  View details for Web of Science ID 000178385500016

  View details for PubMedID 12362423

• Myotonic dystrophy: clinical and molecular parallels between myotonic dystrophy type 1 and type 2. Current neurology and neuroscience reports Ranum, L. P., Day, J. W. 2002; 2 (5): 465-470

  Abstract

  Myotonic dystrophy (DM) is a dominantly inherited disorder with a peculiar pattern of multisystemic clinical features affecting skeletal muscle, the heart, the eye, and the endocrine system. Two genetic loci have been associated with the DM phenotype: DM1 on chromosome 19, and DM2 on chromosome 3. In 1992, the mutation responsible for DM1 was identified as a CTG expansion located in the 3' untranslated region of the dystrophica myotonica-protein kinase gene (DMPK). How this untranslated CTG expansion causes DM1 has been a matter of controversy. The recent discovery that DM2 is caused by an untranslated CCTG expansion, along with other discoveries on DM1 pathogenesis, indicate that the clinical features common to both diseases are caused by a gain of function RNA mechanism in which the CUG and CCUG repeats alter cellular function, including alternative splicing of various genes.

  View details for PubMedID 12169228

• Force assessment in periodic paralysis after electrical muscle stimulation MAYO CLINIC PROCEEDINGS Day, J. W., Sakamoto, C., Parry, G. J., Lehmann-Horn, F., Iaizzo, P. A. 2002; 77 (3): 232-240

  Abstract

  To obtain an objective measure of muscle force in periodic paralysis, we studied ankle dorsiflexion torque during induced paralytic attacks in hyperkalemic and hypokalemic patients. SUBJECTS, PATIENTS, AND METHODS: Dorsiflexor torque after peroneal nerve stimulation was recorded during provocative tests on 5 patients with hypokalemic or hyperkalemic disorders and on 2 control subjects (1995-2001). Manual strength assessment was simultaneously performed in a blinded fashion. Standardized provocation procedures were used.The loss of torque in hyperkalemic patients roughly paralleled the loss of clinically detectable strength, whereas in the hypokalemic patients, pronounced torque loss occurred well before observed clinical effects. No dramatic changes occurred in the control subjects. Torque amplitude decreased more than 70% in all patients during the provocation tests; such decreases were associated with alterations induced in serum potassium concentrations.Stimulated torque measurement offers several advantages in characterizing muscle dysfunction in periodic paralysis: (1) it is independent of patient effort; (2) it can show a definitely abnormal response early during provocative maneuvers; and (3) characteristics of muscle contraction can be measured that are unobservable during voluntary contraction. Stimulated torque measurements can characterize phenotypic muscle function in neuromuscular diseases.

  View details for Web of Science ID 000174132800005

  View details for PubMedID 11888026

• Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9 SCIENCE Liquori, C. L., Ricker, K., Moseley, M. L., Jacobsen, J. F., Kress, W., NAYLOR, S. L., Day, J. W., Ranum, L. P. 2001; 293 (5531): 864-867

  Abstract

  Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, can be caused by a mutation on either chromosome 19q13 (DM1) or 3q21 (DM2/PROMM). DM1 is caused by a CTG expansion in the 3' untranslated region of the dystrophia myotonica-protein kinase gene (DMPK). Several mechanisms have been invoked to explain how this mutation, which does not alter the protein-coding portion of a gene, causes the specific constellation of clinical features characteristic of DM. We now report that DM2 is caused by a CCTG expansion (mean approximately 5000 repeats) located in intron 1 of the zinc finger protein 9 (ZNF9) gene. Parallels between these mutations indicate that microsatellite expansions in RNA can be pathogenic and cause the multisystemic features of DM1 and DM2.

  View details for Web of Science ID 000170241000045

  View details for PubMedID 11486088

• Clinical illness due to parvovirus B19 infection after infusion of solvent/detergent-treated pooled plasma TRANSFUSION Koenigbauer, U. F., Eastlund, T., Day, J. W. 2000; 40 (10): 1203-1206

  Abstract

  Lipid-enveloped viruses such as HIV, HBV, and HCV can be inactivated by treatment with solvents and detergents. HAV and human parvovirus B19 lack lipid envelopes and are not inactivated. Solvent/detergent-treated pooled plasma (S/D plasma) contains neutralizing antibodies, but it is not known whether the parvovirus B19 antibody content is sufficient to prevent transmission of the disease. A patient is described who developed a clinical illness due to parvovirus B19 infection after the infusion of S/D plasma.A 36-year-old woman with myasthenia gravis underwent five plasma exchange procedures from January 15 to January 25, 1999, using albumin, except for 5 units of SD plasma given because of a low fibrinogen level. Four of the 5 units were implicated in a recall after high levels of parvovirus B19 DNA were found in several lots. Two weeks after the infusion, the patient developed fatigue, a rash, and severe polyarthralgias. Parvovirus B19 IgG and IgM antibody titers were consistent with an acute infection.Clinically apparent parvovirus B19 infection can follow the use of S/D plasma that contains high levels of parvovirus B19 DNA.

  View details for Web of Science ID 000089844200011

  View details for PubMedID 11061856

• Spinocerebellar ataxia type 8 - Clinical features in a large family NEUROLOGY Day, J. W., Schut, L. J., Moseley, M. L., Durand, A. C., Ranum, L. P. 2000; 55 (5): 649-657

  Abstract

  To compare the clinical and genetic features of the seven-generation family (MN-A) used to define the spinocerebellar ataxia 8 (SCA8) locus.The authors recently described an untranslated CTG expansion that causes a novel form of SCA (SCA8) characterized by reduced penetrance and complex patterns of repeat instability.Clinical and molecular features of 82 members of the MN-A family were evaluated by neurologic examination, quantitative dexterity testing, and, in some individuals, MRI and sperm analyses.SCA8 is a slowly progressive, predominantly cerebellar ataxia with marked cerebellar atrophy, affecting gait, swallowing, speech, and limb and eye movements. CTG tracts are longer in affected (mean = 116 CTG repeats) than in unaffected expansion carriers (mean = 90, p < 10-8). Quantitative dexterity testing did not detect even subtle signs of ataxia in unaffected expansion carriers. Surprisingly, all 21 affected MN-A family members inherited an expansion from their mothers. The maternal penetrance bias is consistent with maternal repeat expansions yielding alleles above the pathogenic threshold in the family (>107 CTG) and paternal contractions resulting in shorter alleles. Consistent with the reduced penetrance of paternal transmissions, CTG tracts in all or nearly all sperm (84 to 99) are significantly shorter than in the blood (116) of an affected man.The biologic relationship between repeat length and ataxia indicates that the CTG repeat is directly involved in SCA8 pathogenesis. Diagnostic testing and genetic counseling are complicated by the reduced penetrance, which often makes the inheritance appear recessive or sporadic, and by interfamilial differences in the length of a stable (CTA)n tract preceding the CTG repeat.

  View details for Web of Science ID 000089484700010

  View details for PubMedID 10980728

• SCA8 CTG repeat: en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance HUMAN MOLECULAR GENETICS Moseley, M. L., Schut, M. J., Bird, T. D., Koob, M. D., Day, J. W., Ranum, L. P. 2000; 9 (14): 2125-2130

  Abstract

  We recently described an untranslated CTG expansion that causes a previously undescribed form of spinocerebellar ataxia (SCA8). The SCA8 CTG repeat is preceded by a polymorphic but stable CTA tract, with the configuration (CTA)(1-21)(CTG)(n). The CTG portion of the repeat is elongated on pathogenic alleles, which nearly always change in size when transmitted from generation to generation. To better understand the reduced penetrance and maternal penetrance bias associated with SCA8 we analyzed the sequence configurations and instability patterns of the CTG repeat in affected and unaffected family members. In contrast to other triplet repeat diseases, expanded alleles found in affected SCA8 individuals can have either a pure uninterrupted CTG repeat tract or an allele with one or more CCG, CTA, CTC, CCA or CTT interruptions. Surprisingly, we found six different sequence configurations of the CTG repeat on expanded alleles in a seven generation family. In two instances duplication of CCG interruptions occurred over a single generation and in other instances duplications that had occurred in different branches of the family could be inferred. We also evaluated SCA8 instability in sperm samples from individuals with expansions ranging in size from 80 to 800 repeats in blood. Surprisingly the SCA8 repeat tract in sperm underwent contractions, with nearly all of the resulting expanded alleles having repeat lengths of <100 CTGs, a size that is not often associated with disease. These en masse repeat contractions in sperm likely underlie the reduced penetrance associated with paternal transmission.

  View details for Web of Science ID 000089181300007

  View details for PubMedID 10958651

• New nomenclature and DNA testing guidelines for myotonic dystrophy type 1(DM1) NEUROLOGY GONZALEZ, I., Ohsawa, N., Singer, R. H., Devillers, M., Ashizawa, T., Balasubramanyam, A., Cooper, T. A., Khajavi, M., Lia-Baldini, A. S., Miller, G., Philips, A. V., Timchenko, L. T., Waring, J., Yamagata, H., Barbet, J. P., Klesert, T. R., Tapscott, S. J., Roses, A. D., Wagner, M., Baiget, M., Martorell, L., Browne, G. B., Eymard, B., Gourdon, G., JUNIEN, C., Seznec, H., Carey, N., Gosling, M., Maire, P., Gennarelli, M., Sato, S., Ansved, T., Kvist, U., Eriksson, M., Furling, D., Chen, E. J., Housman, D. E., Luciano, B., Siciliano, M., Spring, N., Shimizu, M., Eddy, E., Morris, G. E., Krahe, R., FURUYA, H., Adelman, J., Pribnow, D., Furutama, D., Mathieu, J., Hilton-Jones, D., Kinoshita, M., Abbruzzese, C., Sinden, R. R., Wells, R. D., Pearson, C. E., Kobayashi, T., Johansson, A., Salvatori, S., Perryman, B., Swanson, M. S., Gould, F. K., Harris, S. E., Johnson, K., Mitchell, A. M., Monckton, D. G., Winchester, C. L., Antonini, G., Day, J. W., Liquori, C., Ranum, L. P., Westerlaken, J., Wieringa, B., Griffith, J. D., Michalowski, S., Moore, H., Hamshere, M., Korade, Z., Thornton, C. A., Jaeger, H., Lehmann, F., Moorman, J. R., Mounsey, J. P., Mahadevan, M. S. 2000; 54 (6): 1218-1221

  View details for Web of Science ID 000086109300004

• Adult-onset "infant" botulism: An unusual cause of weakness in the intensive care unit NEUROLOGY Li, L. Y., Kelkar, P., Exconde, R. E., Day, J., Parry, G. J. 1999; 53 (4): 891-891

  View details for Web of Science ID 000082518300048

  View details for PubMedID 10489068

• Clinical and genetic characteristics of a five-generation family with a novel form of myotonic dystrophy (DM2) NEUROMUSCULAR DISORDERS Day, J. W., Roelofs, R., Leroy, B., Pech, I., Benzow, K., Ranum, L. P. 1999; 9 (1): 19-27

  Abstract

  We report the clinical and genetic characteristics of a five-generation family (MN1) with an unusual form of myotonic dystrophy (DM). Affected individuals have clinical features that are similar to DM including myotonia, distal weakness, frontal balding, polychromatic cataracts, infertility and cardiac arrhythmias. Genetic analyses reveal that affected individuals do not have the CTG expansion associated with DM, nor is the disease locus linked to the DM region of chromosome 19. We have also excluded the MN1 disease locus from the chromosomal regions containing the genes for the muscle sodium (alpha- and beta-subunits) and chloride channels, both of which are involved in other myotonic disorders. We have recently mapped the disease locus (DM2) in this family to a 10 cM region of chromosome 3q [Ranum LPW, Rasmussen PF, Benzow KA, Koob MD, Day JW. Nat Genet 1998;19:196-198]. The genetically distinct form of myotonic dystrophy in the MN1 kindred shares some of the clinical features of previously reported families with proximal myotonic myopathy (PROMM). The size of the MN1 family (25 affected individuals) makes it a unique resource for both clinical and genetic studies. This second form of myotonic dystrophy may help resolve the confusion that remains about how the CTG repeat expansion in the 3' untranslated portion of the myotonin protein kinase gene causes the multisystem involvement of DM.

  View details for Web of Science ID 000078636800004

  View details for PubMedID 10063831

• Genetic mapping of a second myotonic dystrophy locus NATURE GENETICS Ranum, L. P., Rasmussen, P. F., Benzow, K. A., Koob, M. D., Day, J. W. 1998; 19 (2): 196-198

  Abstract

  We report the mapping of a second myotonic dystrophy locus, myotonic dystrophy type 2 (DM2). Myotonic dystrophy (DM) is a multi-system disease and the most common form of muscular dystrophy in adults. In 1992, DM was shown to be caused by an expanded CTG repeat in the 3' untranslated region of the dystrophia myotonica-protein kinase gene (DMPK) on chromosome 19 (refs 2-6). Although several theories have been put forth to explain how the CTG expansion causes the broad spectrum of clinical features associated with DM, it is not understood how this mutation, which does not alter the protein-coding region of a gene, causes an affect at the cellular level. We have identified a five-generation family (MN1) with a genetically distinct form of myotonic dystrophy. Affected members exhibit remarkable clinical similarity to DM (myotonia, proximal and distal limb weakness, frontal balding, cataracts and cardiac arrhythmias) but do not have the chromosome-19 D CTG expansion. We have mapped the disease locus (DM2) of the MN1 family to a 10-cM region of chromosome 3q. Understanding the common molecular features of two different forms of the disease should shed light on the mechanisms responsible for the broad constellation of seemingly unrelated clinical features present in both diseases.

  View details for Web of Science ID 000073865100032

  View details for PubMedID 9620781

• Genetic manipulation of AChR responses suggests multiple causes of weakness in slow-channel syndrome. Annals of the New York Academy of Sciences GOMEZ, C. M., Maselli, R., Williams, J. M., Bhattacharyya, B. B., Wollmann, R. L., Day, J. W. 1998; 841: 167-180

  View details for PubMedID 9668235

• Rapid cloning of expanded trinucleotide repeat sequences from genomic DNA NATURE GENETICS Koob, M. D., Benzow, K. A., Bird, T. D., Day, J. W., Moseley, M. L., Ranum, L. P. 1998; 18 (1): 72-75

  Abstract

  Trinucleotide repeat expansions have been shown to cause a number of neurodegenerative diseases. A hallmark of most of these diseases is the presence of anticipation, a decrease in the age at onset in consecutive generations due to the tendency of the unstable trinucleotide repeat to lengthen when passed from one generation to the next. The involvement of trinucleotide repeat expansions in a number of other diseases--including familial spastic paraplegia, schizophrenia, bipolar affective disorder and spinocerebellar ataxia type 7 (SCA7; ref. 10)--is suggested both by the presence of anticipation and by repeat expansion detection (RED) analysis of genomic DNA samples. The involvement of trinucleotide expansions in these diseases, however, can be conclusively confirmed only by the isolation of the expansions present in these populations and detailed analysis to assess each expansion as a possible pathogenic mutation. We describe a novel procedure for quick isolation of expanded trinucleotide repeats and the corresponding flanking nucleotide sequence directly from small amounts of genomic DNA by a process of Repeat Analysis, Pooled Isolation and Detection of individual clones containing expanded trinucleotide repeats (RAPID cloning). We have used this technique to clone the pathogenic SCA7 CAG expansion from an archived DNA sample of an individual affected with ataxia and retinal degeneration.

  View details for Web of Science ID 000071259600026

  View details for PubMedID 9425905

• Suggests multiple causes of weakness in slow-channel syndrome MYASTHENIA GRAVIS AND RELATED DISEASES GOMEZ, C. M., Maselli, R., Williams, J. M., Bhattacharyya, B. B., Wollmann, R. L., Day, J. W. 1998; 841: 167-180

  View details for Web of Science ID 000074924900020

• Desensitization of mutant acetylcholine receptors in transgenic mice reduces the amplitude of neuromuscular synaptic currents SYNAPSE Bhattacharyya, B. J., Day, J. W., Gundeck, J. E., Leonard, S., Wollmann, R. L., GOMEZ, C. M. 1997; 27 (4): 367-377

  Abstract

  While the slow onset of desensitization of nicotinic acetylcholine receptors (AChRs), relative to the rate of acetylcholine removal, excludes this kinetic state from shaping synaptic responses in normal neuromuscular transmission, its role in neuromuscular disorders has not been examined. The slow-channel congenital myasthenic syndrome (SCCMS) is a disorder caused by point mutations in the AChR subunit-encoding genes leading to kinetically abnormal (slow) channels, reduced miniature endplate current amplitudes (MEPCs), and degeneration of the postsynaptic membrane. Because of this complicated picture of kinetic and structural change in the neuromuscular junction, it is difficult to assess the importance of the multiple factors that may be responsible for the reduced endplate current amplitudes, and ultimately the clinical syndrome. In order to address this we have used a transgenic mouse model for the SCCMS that has slow AChR ion channels and reduced endplate responsiveness in the absence of any of the degenerative changes. We found that the reduction in MEPC amplitudes in these mice could not be explained by either reduced AChR number or by reduced AChR channel conductance. Rather, we found that the mutant AChRs in situ manifested an activity-dependent reduction in sensitivity that caused diminished MEPC and endplate current amplitude with nerve stimulation. This observation demonstrates that the basis for the reduction in MEPC amplitudes in the SCCMS may be multifactorial. Moreover, these findings demonstrate that, under conditions that alter their rate of desensitization, the kinetic properties of nicotinic AChRs can control the strength of synaptic responses.

  View details for Web of Science ID A1997YE82600010

  View details for PubMedID 9372559

• Slow-channel transgenic mice: A model of postsynaptic organellar degeneration at the neuromuscular junction JOURNAL OF NEUROSCIENCE GOMEZ, C. M., Maselli, R., Gundeck, J. E., Chao, M., Day, J. W., Tamamizu, S., Lasalde, J. A., McNamee, M., Wollmann, R. L. 1997; 17 (11): 4170-4179

  Abstract

  The slow-channel congenital myasthenic syndrome (SCCMS) is a dominantly inherited disorder of neuromuscular transmission characterized by delayed closure of the skeletal muscle acetylcholine receptor (AChR) ion channel and degeneration of the neuromuscular junction. The identification of a series of AChR subunit mutations in the SCCMS supports the hypothesis that the altered kinetics of the endplate currents in this disease are attributable to inherited abnormalities of the AChR. To investigate the role of these mutant AChR subunits in the development of the synaptic degeneration seen in the SCCMS, we have studied the properties of the AChR mutation, epsilonL269F, found in a family with SCCMS, using both in vitro and in vivo expression systems. The mutation causes a sixfold increase in the open time of AChRs expressed in vitro, similar to the phenotype of other reported mutants. Transgenic mice expressing this mutant develop a syndrome that is highly reminiscent of the SCCMS. Mice have fatigability of limb muscles, electrophysiological evidence of slow AChR ion channels, and defective neuromuscular transmission. Pathologically, the motor endplates show focal accumulation of calcium and striking ultrastructural changes, including enlargement and degeneration of the subsynaptic mitochondria and nuclei. These findings clearly demonstrate the role of this mutation in the spectrum of abnormalities associated with the SCCMS and point to the subsynaptic organelles as principal targets in this disease. These transgenic mice provide a useful model for the study of excitotoxic synaptic degeneration.

  View details for Web of Science ID A1997XA05600021

  View details for PubMedID 9151734

• An improved method for muscle force neuromuscular disease assessment JOURNAL OF MEDICAL ENGINEERING & TECHNOLOGY Brass, T. J., Loushin, M. K., Day, J. W., Iaizzo, P. A. 1996; 20 (2): 67-74

  Abstract

  We describe here the reliability and validity of methods to quantify involuntary muscle torque induced by non-invasive nerve stimulation. A rigid apparatus was used to hold the subject's limb in a predetermined position and confine movement to a specific direction (i.e. ankle dorsiflexion or thumb adduction). An incorporated strain gauge was used to measure isometric torque, and all data were recorded by a data acquisition program. The innervating nerves were stimulated by surface electrodes, using either single stimuli to generate a twitch, or short trains of stimuli to produce tetanic contraction of the individual muscle under study. The average peak tetanic torque generated by the dorsiflexor muscles in healthy control was 20.4 +/- 3.8 Nm and varied by 3.7% with repeated testing. The mean torque generated by the adductor pollicis muscle in controls was 1.5 +/- 0.4 Nm and varied by 4.6% with repeated testing. In patient populations significant changes in activated torque were readily quantified, and the effects of treatment can be easily assessed. Furthermore, several specific parameters of recorded isometric contractions were measured; e.g. time between stimulus and torque onset, peak rate of torque development, time to peak torque, half-relaxation time, and others (none of which are measurable when using voluntary contraction of muscle). Compared to current assessment methods, monitoring muscle torque generated by nerve stimulation improves objectivity, reliability, and quantitative capabilities. The presented method has significant potential both in diagnosing neuromuscular disorders and determining treatment efficacy.

  View details for Web of Science ID A1996UY85000003

  View details for PubMedID 8836925

• Transgenic mouse model of the slow-channel syndrome MUSCLE & NERVE GOMEZ, C. M., Bhattacharyya, B. B., Charnet, P., Day, J. W., Labarca, C., Wollmann, R. L., Lambert, E. H. 1996; 19 (1): 79-87

  Abstract

  To investigate the effect of acetylcholine receptor (AChR) mutations on neuromuscular transmission and to develop a model for the human neuromuscular disease, the slow-channel syndrome, we generated transgenic mice with abnormal AChRs using a delta subunit with a mutation in the ion channel domain. In three transgenic lines, nerve-evoked end-plate currents and spontaneous miniature end-plate currents (MEPCs) had prolonged decay phases and MEPC amplitudes were reduced by 33%. Single nerve stimuli elicited repetitive compound muscle action potentials in vivo. Transgenic mice were abnormally sensitive to the neuromuscular blocker, curare. These observations demonstrate that we can predictably alter AChR function, synaptic responses, and muscle fiber excitation in vivo by overexpressing subunits containing well-defined mutations. Furthermore these data support the hypothesis that the electrophysiological findings in the neuromuscular disorder, the slow-channel syndrome, are due to mutant AChRs.

  View details for Web of Science ID A1996TM00100013

  View details for PubMedID 8538674

• NICOTINIC ACETYLCHOLINE-RECEPTOR DESENSITIZATION IS REGULATED BY ACTIVATION-INDUCED EXTRACELLULAR ADENOSINE ACCUMULATION JOURNAL OF NEUROSCIENCE Pitchford, S., Day, J. W., Gordon, A., MOCHLYROSEN, D. 1992; 12 (11): 4540-4544

  Abstract

  Adenosine modulation of nicotinic ACh receptor (nAChR) function was studied in primary cultures of rat skeletal muscle. Activation of the nAChR by carbachol increased extracellular adenosine concentration in a dose-dependent manner. Furthermore, carbachol activation of the nicotinic receptor resulted in a twofold increase in cAMP levels in the muscle cells. The carbachol-dependent increase in cAMP levels was inhibited by adenosine receptor antagonists as well as by nicotinic receptor antagonists. These results suggest that the increased cAMP levels were due to adenosine receptor activation by the extracellular adenosine accumulated on nAChR activation. Others have shown that desensitization of the nAChR by agonist is mediated, in part, by phosphorylation. Since we found that nicotinic cholinergic agonists also cause adenosine accumulation with concomitant cAMP increases, we determined whether the accumulated adenosine has a role in desensitization. We found that the adenosine receptor antagonist, BW1434U, significantly inhibited carbachol-induced nAChR desensitization, indicating that extracellular adenosine is involved in nAChR desensitization. Our data suggest that nAChR function is regulated via a feedback mechanism mediated by adenosine released from muscle on activation of the nAChR.

  View details for Web of Science ID A1992JY18800034

  View details for PubMedID 1331363

• NORMOCALCEMIC TETANY ABOLISHED BY CALCIUM INFUSION ANNALS OF NEUROLOGY Day, J. W., Parry, G. J. 1990; 27 (4): 438-440

  Abstract

  Tetany is a disorder of increased neuronal excitability usually associated with hypocalcemia. We studied a patient with typical tetanic cramps that responded to intravenous infusion of calcium despite normal serum concentrations of total and ionized calcium. Three generations were affected by similar symptoms, suggesting that this is a dominantly inherited disorder of neuronal hyperirritability.

  View details for Web of Science ID A1990CZ77200012

  View details for PubMedID 2353799

• THUNDERCLAP HEADACHE - SYMPTOM OF UNRUPTURED CEREBRAL ANEURYSM LANCET Day, J. W., Raskin, N. H. 1986; 2 (8518): 1247-1248

  Abstract

  Many patients with a ruptured berry aneurysm report an intense sentinel headache of sudden onset in the weeks before rupture. Such headaches have been attributed to a leak of blood, which implies that partial rupture has occurred. A case is reported of a patient who had severe headaches which seemed to be caused by an unruptured cerebral aneurysm, accompanied by diffuse cerebral vasospasm. Headache episodes with the thunderclap profile may require angiography for diagnosis even if the cerebrospinal fluid is bloodless.

  View details for Web of Science ID A1986E984600005

  View details for PubMedID 2878133

• TIME COURSE OF MINIATURE POSTSYNAPTIC POTENTIALS AT THE MAUTHNER FIBER GIANT SYNAPSE OF THE HATCHETFISH BRAIN RESEARCH Day, J. W., Huse, W. D., Bennett, M. V. 1985; 325 (1-2): 115-128

  Abstract

  The hatchetfish Mauthner fiber is presynaptic to 8-14 large myelinated axons in the medulla; the large ('giant') synapses formed by these fibers appear to be nicotinic cholinergic. Miniature postsynaptic potentials (mPSPs) were recorded from single identified synapses. The mPSPs were averaged to more accurately determine their shape; the rise time was approximately 70 microseconds, and the fall usually was biphasic with time constants of decay for the two phases of 280 and 800 microseconds. In 25% of the records analyzed a third, slow tail of decay was seen which had an average decay constant of 4.2 ms. The biphasic decay of mPSPs largely accounts for the similar shape of the postsynaptic current following a presynaptic impulse, which is described in the accompanying paper.

  View details for Web of Science ID A1985ABG2900013

  View details for PubMedID 2983824

• POSTSYNAPTIC CURRENTS AT THE MAUTHNER FIBER GIANT SYNAPSE OF THE HATCHETFISH BRAIN RESEARCH Huse, W. D., Day, J. W., Bennett, M. V. 1985; 325 (1-2): 129-141

  Abstract

  Postsynaptic currents (PSCs) at the giant synapse between Mauthner and giant fibers of the hatchetfish Gasteropelecus were studied under voltage clamp. This axo-axonic synapse lies in the central nervous system beneath the floor of the 4th ventricle where electrodes can be closely positioned both pre- and postsynaptically. Transmission is nicotonic cholinergic. The PSCs produced by Mauthner fiber impulses rise rapidly to a peak and decay in two phases; an early more rapid phase is followed by a late slower phase. The slope conductance of the peak amplitude of the PSCs declines at more inside positive potentials. The late phase of decay is exponential and voltage dependent, becoming faster for PSCs evoked at more inside positive potentials. At potentials positive to about -40 mV the late phase merges with the early phase. The decay rate constant of the slowest phase is exponentially related to voltage for potentials negative to about -10 mV, but becomes less voltage dependent for more positive potentials. The peak current is independent of whether it is evoked during inward or outward active currents of the electrically excitable membrane, and two phase decays are observed in PSCs of reduced quantal content. Thus, changes in slope conductance and two phase decays are not due to series resistance or interactions between quanta. PSCs can be modeled by a 3 state reaction scheme in which closed channels open when they bind transmitter and then can pass to a second closed state with receptor still bound such that they must return through the open state before losing their transmitter and returning to the resting, closed state.

  View details for Web of Science ID A1985ABG2900014

  View details for PubMedID 2983825

• POSTSYNAPTIC DEPRESSION OF MAUTHNER CELL-MEDIATED STARTLE REFLEX, A POSSIBLE CONTRIBUTOR TO HABITUATION BRAIN RESEARCH ALJURE, E., Day, J. W., Bennett, M. V. 1980; 188 (1): 261-268

  View details for Web of Science ID A1980JP12300023

  View details for PubMedID 7370756

• United Dystrophinopathy Project. LTBP4 genotype predicts age of ambulatory loss in duchenne muscular dystrophy JW Day