Tina Duong MPT, PhD

All Publications

• 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

• Understanding the relationship between the 32-item motor function measure and daily activities from an individual with spinal muscular atrophy and their caregivers' perspective: a two-part study BMC NEUROLOGY Duong, T., Braid, J., Staunton, H., Barriere, A., Petridis, F., Reithinger, J., Cruz, R., Jarecki, J., De Lemus, M., Gusset, N., Broekgaarden, R., Randhawa, S., Flynn, J., Arbuckle, R., Reif, S., Yang, L., De Martini, A., Vuillerot, C. 2021; 21 (1): 143

  Abstract

  The 32-item Motor Function Measure (MFM32) is a clinician-reported outcome measure used to assess the functional abilities of individuals with neuromuscular diseases, including those with spinal muscular atrophy (SMA). This two-part study explored the relationship between the functional abilities assessed in the MFM32 and activities of daily living (ADLs) from the perspective of individuals with Type 2 and Type 3 (non-ambulant and ambulant) SMA and their caregivers through qualitative interviews and a quantitative online survey.In-depth, semi-structured, qualitative interviews were conducted with individuals with SMA and caregivers from the US. Subsequently, a quantitative online survey was completed by individuals with SMA or their caregivers from France, Germany, Italy, Poland, Spain, Canada, the United States (US) and the UK. In both parts of the study, participants were asked to describe the ADLs considered to be related to the functional abilities assessed in the MFM32. Results from the qualitative interviews informed the content of the quantitative online survey.Qualitative interviews were conducted with 15 adult participants, and 217 participants completed the quantitative online survey. From the qualitative interviews, all of the functional abilities assessed in the patient-friendly MFM32 were deemed as related to one or more ADL. The specific ADLs that participants considered related to the patient-friendly MFM32 items could be grouped into 10 key ADL domains: dressing, mobility/transferring, self-care, self-feeding, reaching, picking up and holding objects, physical activity, writing and technology use, social contact/engagement, toileting and performing work/school activities. These results were confirmed by the quantitative online survey whereby the ADLs reported to be related to each patient-friendly MFM32 item were consistent and could be grouped into the same 10 ADL domains.This study provides in-depth evidence from the patient/caregiver perspective supporting the relevance of the patient-friendly MFM32 items to the ADLs of individuals with Type 2 and Type 3 SMA.

  View details for DOI 10.1186/s12883-021-02166-z

  View details for Web of Science ID 000636352600002

  View details for PubMedID 33789607

  View details for PubMedCentralID PMC8011105

• The Minimal Clinical Important Difference (MCID) in Annual Rate of Change of Timed Function Tests in Boys with DMD. Journal of neuromuscular diseases Duong, T., Canbek, J., Birkmeier, M., Nelson, L., Siener, C., Fernandez-Fernandez, A., Henricson, E., McDonald, C. M., Gordish-Dressman, H. 2021

  Abstract

  Duchenne muscular dystrophy (DMD) is a rare x-linked recessive genetic disorder affecting 1 in every 5000-10000 [1, 2]. This disease leads to a variable but progressive sequential pattern of muscle weakness that eventually causes loss of important functional milestones such as the ability to walk. With promising drugs in development to ameliorate the effects of muscle weakness, these treatments must be associated with a clinically meaningful functional change.The objective of this analysis is to determine both distribution, minimal detectable change (MDC), and anchor-based, minimal clinically important difference, (MCID) of 12 month change values in standardized time function tests (TFT) used to monitor disease progression in DMD.This is a retrospective analysis of prospectively collected data from a multi-center prospective natural history study with the Cooperative International Neuromuscular Research Group (CINRG). This study calculated MDC and MCID values for 3 commonly used timed function tests typically used to monitor disease progression; supine to stand (STS), 10 meter walk/run (10MWT), and 4 stair climb (4SC). MDC used standard error of measurement (SEM) while MCID measurements used the Vignos scale as an anchor to determine clinical change in functional status.All 3 TFT were significantly important clinical endpoints to detect MDC and MCID changes. MDC and MCID 12 month changes were significant in 10MWT (-0.138, -0.212), Supine to Stand (-0.026, -0.023) and 4 stair climb (-0.034, -0.035) with an effect size greater or close to 0.2.The 3 TFT are clinically meaningful endpoints used to establish change in DMD. MCID values were higher than MDC values indicating that an anchor-based approach using Vignos as a clinically meaningful loss of lower extremity abilities is appropriate to assess change in boys with DMD.

  View details for DOI 10.3233/JND-210646

  View details for PubMedID 34151852

• Use of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) in X-Linked Myotubular Myopathy: Content Validity and Psychometric Performance JOURNAL OF NEUROMUSCULAR DISEASES Duong, T., Harding, G., Mannix, S., Abel, C., Phillips, D., Alfano, L. N., Bonnemann, C. G., Lilien, C., Lowes, L. P., Servais, L., Warken-Madelung, B., Bergman, S., James, E. S., Noursalehi, M., Prasad, S., Rico, S., Bilder, D. A. 2021; 8 (1): 63-77

  Abstract

  X-linked myotubular myopathy (XLMTM) is a life-threatening, congenital myopathy characterized by extreme hypotonia, weakness, delayed motor milestones, and respiratory failure, often resulting in pediatric mortality. This study evaluated the content validity and psychometric performance of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders as a measure of neuromuscular functioning in children with X-linked myotubular myopathy. This study was conducted in two phases. Phase I assessed the content validity of the measure for use in an XLMTM pediatric population through: literature review, clinical expert interviews, caregiver interviews, and a modified-Delphi panel among clinicians. Phase II assessed psychometric performance based on the INCEPTUS observational clinical study and the ASPIRO interventional gene therapy study, including tests of reliability (internal consistency, test-retest, and interrater), validity (construct and criterion), and responsiveness based on observational and interventional clinical trial data analyses. Data established construct validity and reliability of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders among XLMTM patients before administration of resamirigene bilparvovec, and sensitivity to study drug administration as evidenced by the significant post-administration response in ASPIRO. Findings support the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders as an appropriate neuromuscular functioning assessment in a pediatric X-linked myotubular myopathy patient population.

  View details for DOI 10.3233/JND-200479

  View details for Web of Science ID 000684019000005

  View details for PubMedID 32925083

  View details for PubMedCentralID PMC7902972

• Knee Strength and Ankle Range of Motion Impacts on Timed Function Tests in Duchenne Muscular Dystrophy: In the Era of Glucocorticoids. Journal of neuromuscular diseases Duong, T., Canbek, J., Fernandez-Fernandez, A., Henricson, E., Birkmeier, M., Siener, C., Rocha, C. T., McDonald, C., Gordish-Dressman, H. 2021

  Abstract

  Duchenne Muscular Dystrophy (DMD) is a neuromuscular disorder that presents in childhood and is characterized by slowly progressive proximal weakness and lower extremity contractures that limit ambulatory ability [1, 2]. Contractures develop in the ankles, knees, and hips due to muscle imbalances, fibrotic changes, loss of strength, and static positioning [2, 5]. Currently, standards of care guidelines emphasize the importance of maintaining good musculoskeletal alignment through stretching, bracing, and glucocorticoid (GC) therapy to preserve strength and function.This is a retrospective analysis of prospectively collected data through the CINRG Duchenne Natural history study (DNHS). The objectives of this analysis are to understand the progression of ankle contractures for individuals with DMD and to investigate the relationship between progressive lower limb contractures, knee strength, and Timed Function Tests.A collection of TFTs including supine to stand (STS), 10 meter walk test (10MWT), and timed stair climbing (4SC) have been used to monitor disease progression and are predictive of loss of ambulation in these patients [4]. Multiple factors contribute to loss of ambulation, including progressive loss of strength and contracture development that leads to changing biomechanical demands for ambulation. A better understanding of the changes in strength and range of motion (ROM) that contribute to loss of function is important in a more individualized rehabilitation management plan. In this longitudinal study, we measured strength using quantitative muscle testing (QMT) with the CINRG Quantitative Measurement System (CQMS)), ROM was measuresed with a goniometer and TFTs were measured using a standard stopwatch and methodology.We enrolled 440 participants; mean baseline age was 8.9 (2.1, 28.0) years with 1321 observations used for analysis. GC use was stratified based on duration on drug with 18.7%at <  6 months or naïve; 4.3%<1 year; 58.0%1 <  10 years; and 19.3%between 10-25 years of GC use. Ankle ROM was better for those on GC compared to GC naive but did not significantly influence long-term progression rates. QMT, ROM, age and GCs contribute to speed of TFTs. Knee extension (KE) strength and Dorsiflexion (DF) ROM are significant predictors of speed for all TFTs (p <  0.001). Of the variables used in this analysis, KE strength is the primary predictor of walking speed, estimating that every pound increase in KE results in a 0.042 m/s improvement in 10MWT, and a smaller similar increase of 0.009 m/s with every degree of ankle DF ROM.GC use provides an improvement in strength and ROM but does not affect rate of change. Knee strength has a greater influence on speed of TFTs than DF ROM, although both are statistically significant predictors of speed. Results show that retaining knee strength [1, 2], along with joint flexibility, may be important factors in the ability to perform walking, climbing and supine to stand activities.

  View details for DOI 10.3233/JND-210724

  View details for PubMedID 34719507

• A Patient-Centered Evaluation of Meaningful Change on the 32-Item Motor Function Measure in Spinal Muscular Atrophy Using Qualitative and Quantitative Data. Frontiers in neurology Duong, T., Staunton, H., Braid, J., Barriere, A., Trzaskoma, B., Gao, L., Willgoss, T., Cruz, R., Gusset, N., Gorni, K., Randhawa, S., Yang, L., Vuillerot, C. 1800; 12: 770423

  Abstract

  The 32-item Motor Function Measure (MFM32) is an assessment of motor function used to evaluate fine and gross motor ability in patients with neuromuscular disorders, including spinal muscular atrophy (SMA). Reliability and validity of the MFM32 have been documented in individuals with SMA. Through semi-structured qualitative interviews (N = 40) and an online survey in eight countries (N = 217) with individuals with Types 2 and 3 SMA aged 2-59 years old and caregivers, the meaning of changes on a patient-friendly version of the MFM32 was explored. In an independent analysis of clinical trial data, anchor- and distribution-based analyses were conducted in a sample of individuals with Type 2 and non-ambulant Type 3 SMA to estimate patient-centered quantitative MFM32 meaningful change thresholds. The results from this study demonstrate that, based on patient and caregiver insights, maintaining functional ability as assessed by a patient-friendly version of the MFM32 is an important outcome. Quantitative analyses using multiple anchors (median age range of 5-8 years old across anchor groups) indicated that an ~3-point improvement in MFM32 total score represents meaningful change at the individual patient level. Overall, the qualitative and quantitative findings from this study support the importance of examining a range of meaningful change thresholds on the MFM32 including ≥0 points change reflecting stabilization or improvement and ≥3 points change reflecting a higher threshold of improvement. Future research is needed to explore quantitative differences in meaningful change on the MFM32 based on age and functional subgroups.

  View details for DOI 10.3389/fneur.2021.770423

  View details for PubMedID 35111124

• Consensus Guidelines for Improving Quality of Assessment and Training for Neuromuscular Diseases. Frontiers in genetics Duong, T., Krosschell, K. J., James, M. K., Nelson, L., Alfano, L. N., Eichinger, K., Mazzone, E., Rose, K., Lowes, L. P., Mayhew, A., Florence, J., King, W., Senesac, C. R., Eagle, M. 2021; 12: 735936

  Abstract

  Critical components of successful evaluation of clinical outcome assessments (COAs) in multisite clinical trials and clinical practice are standardized training, administration, and documented reliability of scoring. Experiences of evaluators, alongside patient differences from regional standards of care, may contribute to heterogeneity in clinical center's expertise. Achieving low variability and high reliability of COA is fundamental to clinical research and to give confidence in our ability to draw rational, interpretable conclusions from the data collected. The objective of this manuscript is to provide a framework to guide the learning process for COAs for use in clinics and clinical trials to maximize reliability and validity of COAs in neuromuscular disease (NMD). This is a consensus-based guideline with contributions from fourteen leading experts in clinical outcomes and the field of clinical outcome training in NMD. This framework should guide reliable and valid assessments in NMD specialty clinics and clinical trials. This consensus aims to expedite study start up with a progressive training pathway ranging from research naive to highly experienced clinical evaluators. This document includes recommendations for education guidelines and roles and responsibilities of key stakeholders in COA assessment and implementation to ensure quality and consistency of outcome administration across different settings.

  View details for DOI 10.3389/fgene.2021.735936

  View details for PubMedID 34858470

• Correction to: Understanding the relationship between the 32-item motor function measure and daily activities from an individual with spinal muscular atrophy and their caregivers' perspective: a two-part study. BMC neurology Duong, T., Braid, J., Staunton, H., Barriere, A., Petridis, F., Reithinger, J., Cruz, R., Jarecki, J., De Lemus, M., Gusset, N., Broekgaarden, R., Randhawa, S., Flynn, J., Arbuckle, R., Reif, S., Yang, L., De Martini, A., Vuillerot, C. 2021; 21 (1): 354

  View details for DOI 10.1186/s12883-021-02307-4

  View details for PubMedID 34517827

• 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

• 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

• Safety and efficacy of gene replacement therapy for X-linked myotubular myopathy (ASPIRO): a multinational, open-label, dose-escalation trial. The Lancet. Neurology Shieh, P. B., Kuntz, N. L., Dowling, J. J., Muller-Felber, W., Bonnemann, C. G., Seferian, A. M., Servais, L., Smith, B. K., Muntoni, F., Blaschek, A., Foley, A. R., Saade, D. N., Neuhaus, S., Alfano, L. N., Beggs, A. H., Buj-Bello, A., Childers, M. K., Duong, T., Graham, R. J., Jain, M., Coats, J., MacBean, V., James, E. S., Lee, J., Mavilio, F., Miller, W., Varfaj, F., Murtagh, M., Han, C., Noursalehi, M., Lawlor, M. W., Prasad, S., Rico, S. 2023; 22 (12): 1125-1139

  Abstract

  BACKGROUND: X-linked myotubular myopathy is a rare, life-threatening, congenital muscle disease observed mostly in males, which is caused by mutations in MTM1. No therapies are approved for this disease. We aimed to assess the safety and efficacy of resamirigene bilparvovec, which is an adeno-associated viral vector serotype 8 delivering human MTM1.METHODS: ASPIRO is an open-label, dose-escalation trial at seven academic medical centres in Canada, France, Germany, and the USA. We included boys younger than 5 years with X-linked myotubular myopathy who required mechanical ventilator support. The trial was initially in two parts. Part 1 was planned as a safety and dose-escalation phase in which participants were randomly allocated (2:1) to either the first dose level (1·3 * 1014 vector genomes [vg]/kg bodyweight) of resamirigene bilparvovec or delayed treatment, then, for later participants, to either a higher dose (3·5 * 1014 vg/kg bodyweight) of resamirigene bilparvovec or delayed treatment. Part 2 was intended to confirm the dose selected in part 1. Resamirigene bilparvovec was administered as a single intravenous infusion. An untreated control group comprised boys who participated in a run-in study (INCEPTUS; NCT02704273) or those in the delayed treatment cohort who did not receive any dose. The primary efficacy outcome was the change from baseline to week 24 in hours of daily ventilator support. After three unexpected deaths, dosing at the higher dose was stopped and the two-part feature of the study design was eliminated. Because of changes to the study design during its implementation, analyses were done on an as-treated basis and are deemed exploratory. All treated and control participants were included in the safety analysis. The trial is registered with ClinicalTrials.gov, NCT03199469. Outcomes are reported as of Feb 28, 2022. ASPIRO is currently paused while deaths in dosed participants are investigated.FINDINGS: Between Aug 3, 2017 and June 1, 2021, 30 participants were screened for eligibility, of whom 26 were enrolled; six were allocated to the lower dose, 13 to the higher dose, and seven to delayed treatment. Of the seven children whose treatment was delayed, four later received the higher dose (n=17 total in the higher dose cohort), one received the lower dose (n=7 total in the lower dose cohort), and two received no dose and joined the control group (n=14 total, including 12 children from INCEPTUS). Median age at dosing or enrolment was 12·1 months (IQR 10·0-30·9; range 9·5-49·7) in the lower dose cohort, 31·1 months (16·0-64·7; 6·8-72·7) in the higher dose cohort, and 18·7 months (10·1-31·5; 5·9-39·3) in the control cohort. Median follow-up was 46·1 months (IQR 41·0-49·5; range 2·1-54·7) for lower dose participants, 27·6 months (24·6-29·1; 3·4-41·0) for higher dose participants, and 28·3 months (9·7-46·9; 5·7-32·7) for control participants. At week 24, lower dose participants had an estimated 77·7 percentage point (95% CI 40·22 to 115·24) greater reduction in least squares mean hours per day of ventilator support from baseline versus controls (p=0·0002), and higher dose participants had a 22·8 percentage point (6·15 to 39·37) greater reduction from baseline versus controls (p=0·0077). One participant in the lower dose cohort and three in the higher dose cohort died; at the time of death, all children had cholestatic liver failure following gene therapy (immediate causes of death were sepsis; hepatopathy, severe immune dysfunction, and pseudomonal sepsis; gastrointestinal haemorrhage; and septic shock). Three individuals in the control group died (haemorrhage presumed related to hepatic peliosis; aspiration pneumonia; and cardiopulmonary failure).INTERPRETATION: Most children with X-linked myotubular myopathy who received MTM1 gene replacement therapy had important improvements in ventilator dependence and motor function, with more than half of dosed participants achieving ventilator independence and some attaining the ability to walk independently. Investigations into the risk for underlying hepatobiliary disease in X-linked myotubular myopathy, and the need for monitoring of liver function before gene replacement therapy, are ongoing.FUNDING: Astellas Gene Therapies.

  View details for DOI 10.1016/S1474-4422(23)00313-7

  View details for PubMedID 37977713

• 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

• Patient reported outcome measure for upper limb in Duchenne muscular dystrophy: correlation with PUL2.0. Neuromuscular disorders : NMD Cicala, G., Pane, M., Coratti, G., Brogna, C., Fanelli, L., Norcia, G., Forcina, N., Mazzone, E., Stanca, G., Ferrante, R., Vento, A., Ferraroli, E., Ricci, M., Capasso, A., Leone, D., Palermo, C., Berti, B., Cutrona, C., Mahyew, A., Duong, T., Goemans, N., Vroom, E., Mercuri, E. 2023

  Abstract

  The increasing pressure to include non ambulant Duchenne muscular dystrophy (DMD) boys in clinical trials has highlighted the need for outcome measures that could address the impact of upper limb function on activities of daily living. The aim of the present study was to establish the correlation between the recently developed Patient Reported Outcome Measure for the upper limb (PROM UL) and the observer rated functional scale Performance of Upper Limb (PUL 2.0) in a large cohort of DMD boys and young adults. As part of a larger natural history study, non ambulant DMD patients were assessed using PUL2.0 and PROM UL. One hundred and twenty-five concurrent PUL 2.0 and PROM UL evaluations from 60 non ambulant DMD boys were taken into consideration. The total PROM UL scores showed a strong correlation with both PUL 2.0 total scores and with PUL 2.0 entry item score. The strong correlation between the two tools confirms the clinical meaningfulness of the PUL2.0 and that the PROM UL can help to detect the gradient of progression of upper limb involvement.

  View details for DOI 10.1016/j.nmd.2023.07.003

  View details for PubMedID 37612177

• 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

• Major Adverse Dystrophinopathy Events (MADE) Score as Marker of Cumulative Morbidity and Risk for Mortality in Boys with Duchenne Muscular Dystrophy. Progress in pediatric cardiology Kaufman, B. D., Garcia, A., He, Z., Tesi-Rocha, C., Buu, M., Rosenthal, D., Gordish-Dressman, H., Almond, C. S., Duong, T. 2023; 69

  Abstract

  Overlapping symptoms from cardiomyopathy, respiratory insufficiency, and skeletal myopathy confound assessment of heart failure in Duchenne Muscular Dystrophy. We developed an ordinal scale of multiorgan clinical variables that reflect cumulative disease burden-the Major Adverse Dystrophinopathy Event (MADE) Score. We hypothesized that a higher MADE score would be associated with increased mortality in boys with Duchenne Muscular Dystrophy. The Cooperative International Neuromuscular Research Group Duchenne Natural History Study dataset was utilized for validation.Duchenne Natural History Study variables were selected based on clinical relevance to prespecified domains: Cardiac, Pulmonary, Myopathy, Nutrition. Severity points (0-4) were assigned and summed for study visits. MADE score for cohorts defined by age, ambulatory status, and survival were compared at enrollment and longitudinally.Associations between MADE score and mortality were examined.Duchenne Natural History Study enrolled 440 males, 12.6 ±6.1 years old, with 3,559 visits over 4.6 ±2.8 years, 45 deaths. MADE score increased with age and nonambulatory status. Mean MADE score per visit was 19 ±10 for those who died vs. 9.8 ±9.3 in survivors p=0.03. Baseline MADE score >12 predicted mortality independent of age (78% sensitivity, CPE.70). Rising MADE score trajectory was associated with mortality in models adjusted for enrollment age, follow-up time, and ambulatory status, all p<.001.A multiorgan severity score, MADE, was developed to track cumulative morbidities that impact heart failure in Duchenne muscular dystrophy. MADE score predicted Duchenne Natural History Study mortality. MADE score can be used for serial heart failure assessment in males and may serve as an endpoint for Duchenne muscular dystrophy clinical research.

  View details for DOI 10.1016/j.ppedcard.2023.101639

  View details for PubMedID 37990740

  View details for PubMedCentralID PMC10659574

• Major Adverse Dystrophinopathy Events (MADE) score as marker of cumulative morbidity and risk for mortality in boys with Duchenne muscular dystrophy PROGRESS IN PEDIATRIC CARDIOLOGY Kaufman, B. D., Garcia, A., He, Z., Tesi-Rocha, C., Buu, M., Rosenthal, D., Gordish-Dressman, H., Almond, C. S., Duong, T., CINRG DUCHENNE NAT HIST STUDY 2023; 69

  View details for DOI 10.1016/j.ppedcard.2023.101639

  View details for Web of Science ID 000984595500001

• Development of an International SMA Bulbar Assessment for Inter-professional Administration. Journal of neuromuscular diseases Young, S. D., McGrattan, K., Johnson, E., van der Heul, M., Duong, T., Bakke, M., Werlauff, U., Pasternak, A., Cattaneo, C., Hoffman, K., Fanelli, L., Breaks, A., Allison, K., Baranello, G., Finkel, R., Coratti, G., Lofra, R. M. 2023

  Abstract

  Progressive weakness can affect bulbar muscles in individuals with moderate to severe forms of spinal muscular atrophy (SMA). The paucity of standardized, valid bulbar assessments capturing clinically significant deficits in SMA impedes the ability to monitor function, facilitate intervention, or detect treatment response.To fill this void, an international multidisciplinary team gathered to develop an agreed upon consensus-derived assessment of bulbar function in SMA for inter-professional administration to enhance our ability to monitor disease progression, support clinical management, and evaluate treatment effects.Fifty-six international clinicians experienced in SMA were invited and engaged using the Delphi method over multiple rounds of web-based surveys to establish consensus.Serial virtual meetings occurred with 42 clinicians (21 speech and language therapists, 11 physical therapists, 5 neurologists, 4 occupational therapists, and 1 dentist). Seventy-two validated assessments of bulbar function were identified for potential relevance to individuals with SMA (32 accessible objective, 11 inaccessible objective, 29 patient-reported outcomes). Delphi survey rounds (n = 11, 15, 15) achieved consensus on individual items with relevance and wording discussed. Key aspects of bulbar function identified included: oral intake status, oral facial structure and motor strength, swallowing physiology, voice & speech, and fatigability.Multidisciplinary clinicians with expertise in bulbar function and SMA used Delphi methodology to reach consensus on assessments/items considered relevant for SMA across all age groups. Future steps include piloting the new scale moving towards validation/reliability. This work supports the advancement of assessing bulbar function in children and adults with SMA by a variety of professionals.

  View details for DOI 10.3233/JND-221672

  View details for PubMedID 37212069

• JEWELFISH: 24-month Safety, Pharmacodynamic and Exploratory Efficacy Data in Non-Treatment-Naive Patients with Spinal Muscular Atrophy (SMA) Receiving Treatment with Risdiplam Chiriboga, C., Bruno, C., Duong, T., Fischer, D., Kirschner, J., Scoto, M., Mercuri, E., Gerber, M., Gorni, K., Kletzl, H., Carruthers, I., Martin, C., Gidaro, T., Muntoni, F. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for DOI 10.1212/WNL.0000000000203609

  View details for Web of Science ID 001053672105258

• 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

• 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

• Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomised, double-blind, multi-centre, placebo-controlled phase 2-3 trial. The Lancet. Neurology Kohler, W., Engelen, M., Eichler, F., Lachmann, R., Fatemi, A., Sampson, J., Salsano, E., Gamez, J., Molnar, M. J., Pascual, S., Rovira, M., Vila, A., Pina, G., Martin-Ugarte, I., Mantilla, A., Pizcueta, P., Rodriguez-Pascau, L., Traver, E., Vilalta, A., Pascual, M., Martinell, M., Meya, U., Mochel, F., ADVANCE Study Group, Mc Govern, E., Yazbeck, E., Barbier, M., Luton, M., Pousset, F., Hogrel, J., Adanyeguh, I., Then Bergh, F., Bergner, C., Unterlauft, A., Roicke, H., Hoffmann, K., Scherlach, C., Kalb, A., Meilick, B., Reuschel, M., Fenu, S., Mauro, E., Murphy, E., Krishna, G., Beyene, T., Sierra, A., Quinoa, S., Belen Canovas, A., Grosz, Z., Gyorgyi, B., van de Stadt, S. I., Huffnagel, I. C., van Ballegoij, W. J., Voermans, M. M., Seyedsadjadi, R., Corre, C., Godbole, N., Grant, N. R., Brito Pires, C. M., Trovato, M., Yeh, N., Goodman, J., Keller, J., Joseph, C., Van Haren, K., Sakamuri, S., Duong, T., Perrone, L., Tran, S., Dunaway Young, S., Hashmi, S. 2023; 22 (2): 127-136

  Abstract

  BACKGROUND: Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop life-threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator-activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy.METHODS: ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2-3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18-65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 mug·h/mL [SD 20%]) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing.FINDINGS: Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 [81%] of 77 patients receiving leriglitazone and 34 [87%] of 39 receiving placebo completed treatment. There was no between-group difference in the primary endpoint (mean [SD] change from baseline leriglitazone: -27·7 [41·4] m; placebo: -30·3 [60·5] m; least-squares mean difference -1·2 m; 95% CI -22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 [70%] of 77 vs nine [23%] of 39 patients, respectively) and peripheral oedema (49 [64%] of 77 vs seven [18%] of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six [5%] of 116 patients, all of whom were in the placebo group.INTERPRETATION: The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy.FUNDING: Minoryx Therapeutics.

  View details for DOI 10.1016/S1474-4422(22)00495-1

  View details for PubMedID 36681445

• Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomised, double-blind, multi-centre, placebo-controlled phase 2-3 trial LANCET NEUROLOGY Koehler, W., Engelen, M., Eichler, F., Lachmann, R., Fatemi, A., Sampson, J., Salsano, E., Gamez, J., Molnar, M., Pascual, S., Rovira, M., Vila, A., Pina, G., Martin-Ugarte, I., Mantilla, A., Pizcueta, P., Rodriguez-Pascau, L., Traver, E., Vilalta, A., Pascual, M., Martinell, M., Meya, U., Mochel, F., Adv Study Grp 2023; 22 (2): 127-136

  View details for Web of Science ID 000926094700001

• 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

• 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

• Emerging therapies for Duchenne muscular dystrophy LANCET NEUROLOGY Markati, T., Oskoui, M., Farrar, M. A., Duong, T., Goemans, N., Servais, L. 2022; 21 (9): 814-829

  View details for Web of Science ID 000965574400022

• Emerging therapies for Duchenne muscular dystrophy. The Lancet. Neurology Markati, T., Oskoui, M., Farrar, M. A., Duong, T., Goemans, N., Servais, L. 2022

  Abstract

  Duchenne muscular dystrophy is an X-linked disease caused by the absence of functional dystrophin in the muscle cells. Major advances have led to the development of gene therapies, tools that induce exon skipping, and other therapeutic approaches, including treatments targeting molecular pathways downstream of the absence of functional dystrophin. However, glucocorticoids remain the only treatment unequivocally shown to slow disease progression, despite the adverse effects associated with their long-term use. Besides glucocorticoids, which are standard care, five compounds have received regulatory approval in some but not all jurisdictions, with further efficacy results being awaited. Several compounds with promising results in early-phase clinical trials have not met their efficacy endpoints in late-phase trials, but the clinical development of many other compounds is ongoing. The current landscape is complicated by the number of compounds in various stages of development, their various mechanisms of action, and their genotype-specific applicability. The difficulties of clinical development that arise from both the rarity and variability of Duchenne muscular dystrophy might be overcome in the future by use of sensitive biomarkers, natural history data, and ameliorated trial designs.

  View details for DOI 10.1016/S1474-4422(22)00125-9

  View details for PubMedID 35850122

• INCEPTUS Natural History, Run-in Study for Gene Replacement Clinical Trial in X-Linked Myotubular Myopathy. Journal of neuromuscular diseases Dowling, J. J., Muller-Felber, W., Smith, B. K., Bonnemann, C. G., Kuntz, N. L., Muntoni, F., Servais, L., Alfano, L. N., Beggs, A. H., Bilder, D. A., Blaschek, A., Duong, T., Graham, R. J., Jain, M., Lawlor, M. W., Lee, J., Coats, J., Lilien, C., Lowes, L. P., MacBean, V., Neuhaus, S., Noursalehi, M., Pitts, T., Finlay, C., Christensen, S., Rafferty, G., Seferian, A. M., Tsuchiya, E., James, E. S., Miller, W., Sepulveda, B., Vila, M. C., Prasad, S., Rico, S., Shieh, P. B., INCEPTUS investigators 2022

  Abstract

  BackgroundX-linked myotubular myopathy (XLMTM) is a life-threatening congenital myopathy that, in most cases, is characterized by profound muscle weakness, respiratory failure, need for mechanical ventilation and gastrostomy feeding, and early death.ObjectiveWe aimed to characterize the neuromuscular, respiratory, and extramuscular burden of XLMTM in a prospective, longitudinal study.MethodsThirty-four participants <  4 years old with XLMTM and receiving ventilator support enrolled in INCEPTUS, a prospective, multicenter, non-interventional study. Disease-related adverse events, respiratory and motor function, feeding, secretions, and quality of life were assessed.ResultsDuring median (range) follow-up of 13.0 (0.5, 32.9) months, there were 3 deaths (aspiration pneumonia; cardiopulmonary failure; hepatic hemorrhage with peliosis) and 61 serious disease-related events in 20 (59%) participants, mostly respiratory (52 events, 18 participants). Most participants (80%) required permanent invasive ventilation (>16 hours/day); 20% required non-invasive support (6-16 hours/day). Median age at tracheostomy was 3.5 months (95% CI: 2.5, 9.0). Thirty-three participants (97%) required gastrostomy. Thirty-one (91%) participants had histories of hepatic disease and/or prospectively experienced related adverse events or laboratory or imaging abnormalities. CHOP INTEND scores ranged from 19-52 (mean: 35.1). Seven participants (21%) could sit unsupported for≥30 seconds (one later lost this ability); none could pull to stand or walk with or without support. These parameters remained static over time across the INCEPTUS cohort.ConclusionsINCEPTUS confirmed high medical impact, static respiratory, motor and feeding difficulties, and early death in boys with XLMTM. Hepatobiliary disease was identified as an under-recognized comorbidity. There are currently no approved disease-modifying treatments.

  View details for DOI 10.3233/JND-210781

  View details for PubMedID 35694931

• Genetic modifiers of upper limb function in Duchenne muscular dystrophy. Journal of neurology Sabbatini, D., Fusto, A., Vianello, S., Villa, M., Janik, J., D'Angelo, G., Diella, E., Magri, F., Comi, G. P., Panicucci, C., Bruno, C., D'Amico, A., Bertini, E., Astrea, G., Battini, R., Politano, L., Masson, R., Baranello, G., Previtali, S. C., Messina, S., Vita, G., Berardinelli, A., Mongini, T., Pini, A., Pane, M., Mercuri, E., Hoffman, E. P., Morgenroth, L., Gordish-Dressman, H., Duong, T., McDonald, C. M., Bello, L., Pegoraro, E. 2022

  Abstract

  Genetic modifiers of Duchenne muscular dystrophy (DMD) are variants located in genes different from the disease-causing gene DMD, but associated with differences in disease onset, progression, or response to treatment. Modifiers described so far have been tested mainly for associations with ambulatory function, while their effect on upper limb function, which is especially relevant for quality of life and independence in non-ambulatory patients, is unknown. We tested genotypes at several known modifier loci (SPP1, LTBP4, CD40, ACTN3) for association with Performance Upper Limb version 1.2 score in an Italian multicenter cohort, and with Brooke scale score in the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS), using generalized estimating equation (GEE) models of longitudinally collected data, with age and glucocorticoid treatment as covariates. CD40 rs1883832, previously linked to earlier loss of ambulation, emerged as a modifier of upper limb function, negatively affecting shoulder and distal domains of PUL (p=0.023 and 0.018, respectively) in the Italian cohort, as well as of Brooke score (p=0.018) in the CINRG-DNHS. These findings will be useful for the design and interpretation of clinical trials in DMD, especially for non-ambulatory populations.

  View details for DOI 10.1007/s00415-022-11133-8

  View details for PubMedID 35513612

• Comparison of strength testing modalities in dysferlinopathy. Muscle & nerve Reash, N. F., James, M. K., Alfano, L. N., Mayhew, A. G., Jacobs, M., Iammarino, M. A., Holsten, S., Sakamoto, C., Tateishi, T., Yajima, H., Duong, T., de Wolf, B., Gee, R., Bharucha-Goebel, D. X., Bravver, E., Mori-Yoshimura, M., Bushby, K., Rufibach, L. E., Straub, V., Lowes, L. P., Jain COS Consortium 2022

  Abstract

  INTRODUCTION/AIMS: Dysferlinopathy demonstrates heterogeneity in muscle weakness between patients which can progress at different rates over time. Changing muscle strength due to disease progression or from an investigational product is associated with changing functional ability. The purpose of this study was to compare 3 methods of strength testing used in the Clinical Outcome Study (COS) for dysferlinopathy to understand which method and which muscle groups were most sensitive to change over time.METHODS: Patients were evaluated at each study visit using functional scales, manual muscle testing, and handheld dynamometry (HHD) at all 15 sites. A fixed-frame system (Fixed) was used at a subset of 7 sites. Screening and Baseline visits were evaluated for reliability. Data over a 1-year period were analyzed to determine sensitivity to change among strength modalities and individual muscle groups.RESULTS: HHD and Fixed captured significant change across 1 year in summed muscle strength score of four muscle groups (P<0.01). Strength summed scores were significantly correlated with functional scales (rho=0.68 - 0.92, P<0.001). Individual muscle groups, however, showed high levels of variability between visits.DISCUSSION: Although both HHD and Fixed demonstrate change over 12 months, HHD is a less expensive option that provides data on a continuous scale and may be easier to implement. Due to variability in strength measures, researchers should carefully consider use of strength testing as an outcome and may wish to select functional measures with less variability as clinical trial endpoints. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/mus.27570

  View details for PubMedID 35506767

• 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

• MANATEE: A Study of R07204239 in Combination with Risdiplam Treatment in Pediatric Patients with SMA Duong, T., Darras, B. T., Morrow, J., Muntoni, F., Servais, L., Carruthers, I., Gerber, M., Kletzl, H., Martin, C., Zhang, B. B., Scalco, R. S., Mercuri, E. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000894020500146

• JEWELFISH: Safety, Pharmacodynamic and Exploratory Efficacy Data in Non -Na ve Patients with Spinal Muscular Atrophy (SMA) Receiving Treatment with Risdiplam Chiriboga, C. A., Bruno, C., Duong, T., Fischer, D., Kirschner, J., Mercuri, E., Gerber, M., Gorni, K., Kletzl, H., Carruthers, I., Martin, C., Warren, F., Scoto, M. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000894020500061

• 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

• 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

• 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

• 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

• Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls NEW ENGLAND JOURNAL OF MEDICINE Darras, B. T., Masson, R., Mazurkiewicz-Beldzinska, M., Rose, K., Xiong, H., Zanoteli, E., Baranello, G., Bruno, C., Vlodavets, D., Wang, Y., El-Khairi, M., Gerber, M., Gorni, K., Khwaja, O., Kletzl, H., Scalco, R. S., Fontoura, P., Servais, L., FIREFISH Working Grp 2021; 385 (5): 427-435

  Abstract

  Type 1 spinal muscular atrophy (SMA) is a progressive neuromuscular disease characterized by an onset at 6 months of age or younger, an inability to sit without support, and deficient levels of 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 in blood.We conducted an open-label study of risdiplam in infants with type 1 SMA who were 1 to 7 months of age at enrollment. Part 1 of the study (published previously) determined the dose to be used in part 2 (reported here), which assessed the efficacy and safety of daily risdiplam as compared with no treatment in historical controls. The primary end point was the ability to sit without support for at least 5 seconds after 12 months of treatment. Key secondary end points were a score of 40 or higher on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND; range, 0 to 64, with higher scores indicating better motor function), an increase of at least 4 points from baseline in the CHOP-INTEND score, a motor-milestone response as measured by Section 2 of the Hammersmith Infant Neurological Examination (HINE-2), and survival without permanent ventilation. For the secondary end points, comparisons were made with the upper boundary of 90% confidence intervals for natural-history data from 40 infants with type 1 SMA.A total of 41 infants were enrolled. After 12 months of treatment, 12 infants (29%) were able to sit without support for at least 5 seconds, a milestone not attained in this disorder. The percentages of infants in whom the key secondary end points were met as compared with the upper boundary of confidence intervals from historical controls were 56% as compared with 17% for a CHOP-INTEND score of 40 or higher, 90% as compared with 17% for an increase of at least 4 points from baseline in the CHOP-INTEND score, 78% as compared with 12% for a HINE-2 motor-milestone response, and 85% as compared with 42% for survival without permanent ventilation (P<0.001 for all comparisons). The most common serious adverse events were pneumonia, bronchiolitis, hypotonia, and respiratory failure.In this study involving infants with type 1 SMA, risdiplam resulted in higher percentages of infants who met motor milestones and who showed improvements in motor function than the percentages observed in historical cohorts. Longer and larger trials are required to determine the long-term safety and efficacy of risdiplam in infants with type 1 SMA. (Funded by F. Hoffmann-La Roche; FIREFISH ClinicalTrials.gov number, NCT02913482.).

  View details for DOI 10.1056/NEJMoa2102047

  View details for Web of Science ID 000684497600011

  View details for PubMedID 34320287

• 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

• KonectomTM Smartphone-based Digital Outcome Assessments for Adults Living with Spinal Muscular Atrophy (SMA): A Conceptual Framework Arteaga-Bracho, E. E., Dai, Y., Drory, V., Duong, T., Kleinschnitz, C., Rodrigue, X., Sacconi, S., Sansone, V. A., Valente, M., Guymard, T., Belachew, S., Guo, C. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for Web of Science ID 000729283603035

• JEWELFISH: Safety and Pharmacodynamic Data in Non-Naive Patients with Spinal Muscular Atrophy (SMA) Receiving Treatment with Risdiplam Chiriboga, C. A., Bruno, C., Duong, T., Fischer, D., Kirschner, J., Mercuri, E., Gerber, M., Gorni, K., Kletzl, H., McIver, T., Scalco, R. S., Warren, F., Scoto, M. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for Web of Science ID 000729283602089

• 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

• Gaussian Process Regression for COP Trajectory Estimation in Healthy and Pathological Gait Using Instrumented Insoles Duong, T. H., Uher, D., Young, S., Duong, T., Sangco, M., Cornett, K., Montes, J., Zanotto, D., IEEE IEEE. 2021: 9548-9553

  View details for DOI 10.1109/IROS51168.2021.9636562

  View details for Web of Science ID 000755125507065

• 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

• Improving Care and Empowering Adults Living with SMA: A Call to Action in the New Treatment Era JOURNAL OF NEUROMUSCULAR DISEASES Walter, M. C., Chiriboga, C., Duong, T., Goemans, N., Mayhew, A., Ouillade, L., Oskoui, M., Quinlivan, R., Vazquez-Costa, J. F., Vissing, J., Servais, L. 2021; 8 (4): 543-551

  Abstract

  While Spinal Muscular Atrophy (SMA) has historically been managed with supportive measures, the emergence of innovative medicines has given those living with SMA hope for improved quality of life and has revolutionized care. Despite these advances, the use of therapies and changes in disease management strategies have focused on pediatric populations, leaving adults living with SMA, and those transitioning into adulthood, relatively neglected. Through a multi-faceted approach that gathered unbiased perspectives from clinical experts, validated insights from individuals with lived experiences, and substantiated findings with evidence from the literature, we have exposed unmet needs that are hindering the field and, ultimately, impacting care and quality of life for adults living with SMA. Here, we set new aspirations and calls to action to inspire continued research in this field, stimulate dialogue across the SMA community and inform policies that deliver effective management and care throughout an adult's journey living with SMA.

  View details for DOI 10.3233/JND-200611

  View details for Web of Science ID 000680742800011

  View details for PubMedID 33646175

  View details for PubMedCentralID PMC8385518

• E-Health & Innovation to Overcome Barriers in Neuromuscular Diseases. Report from the 1st eNMD Congress: Nice, France, March 22-23, 2019 JOURNAL OF NEUROMUSCULAR DISEASES Pini, J., Siciliano, G., Lahaut, P., Braun, S., Segovia-Kueny, S., Kole, A., Hernando, I., Selb, J., Schirinzi, E., Duong, T., Hogrel, J., Serrano Olmedo, J., Vissing, J., Servais, L., Vincent-Genod, D., Vuillerot, C., Bannwarth, S., Eggenspieler, D., Vicart, S., Diaz-Manera, J., Lochmueller, H., Sacconi, S., eNMD Grp 2021; 8 (4): 743-754

  Abstract

  By definition, neuromuscular diseases are rare and fluctuating in terms of symptoms; patients are often lately diagnosed, do not have enough information to understand their condition and be proactive in their management. Usually, insufficient resources or services are available, leading to patients' social burden. From a medical perspective, the rarity of such diseases leads to the unfamiliarity of the medical staff and caregiver and an absence of consensus in disease assessment, treatment, and management. Innovations have to be developed in response to patients' and physicians' unmet needs.It is vital to improve several aspects of patients' quality of life with a better comprehension of their disease, simplify their management and follow-up, help their caregiver, and reduce the social and economic burden for living with a rare debilitating disease. Database construction regrouping patients' data and symptoms according to specific country registration on data privacy will be critical in establishing a clear consensus on neuromuscular disease treatment.Clinicians also need technological innovations to help them recognize neuromuscular diseases, find the best therapeutic approach based on medical consensus, and tools to follow patients' states regularly. Diagnosis also has to be improved by implementing automated systems to analyze a considerable amount of data, representing a significant step forward to accelerate the diagnosis and the patients' follow up. Further, the development of new tools able to precisely measure specific outcomes reliably is of the matter of importance in clinical trials to assess the efficacy of a newly developed compound.In this context, creation of an expert community is essential to communicate and share ideas. To this end, 97 clinicians, healthcare professionals, researchers, and representatives of private companies from 9 different countries met to discuss the new perspective and challenges to develop and implement innovative tools in the field of neuromuscular diseases.

  View details for DOI 10.3233/JND-210655

  View details for Web of Science ID 000680742800029

  View details for PubMedID 33843694

  View details for PubMedCentralID PMC8385527

• 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

• 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

• 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

• ASPIRO Gene Therapy Trial In X-Linked Myotubular Myopathy (XLMTM): Update on Preliminary Safety And Efficacy Findings up to 72 Weeks Post-Treatment Shieh, P. B., Kuntz, N., Smith, B., Dowling, J., Mueller-Felber, W., Boennemann, C. G., Servais, L., Muntoni, F., Blaschek, A., Neuhaus, S., Alfano, L. N., Beggs, A. H., Buj-Bello, A., Childers, M., Duong, T., Graham, R. J., Jain, M., James, E. S., Lawlor, M. W., Lee, J., MacBean, V., Mavilio, F., Murtagh, M., Noursalehi, M., Prasad, S., Rico, S. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058001286

• Neuromuscular disorders in Children. A multidisciplinary approach to management, 1 ed (Book Review) NEUROMUSCULAR DISORDERS Book Review Authored by: Sarkozy, A. 2020; 30 (4): 351

  View details for DOI 10.1016/j.nmd.2020.02.016

  View details for Web of Science ID 000533614400014

• Neuromuscular Disorders in Children: A Multidisciplinary Approach to Management (Book Review) DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Book Review Authored by: Ramdas, S. 2020; 62 (3): 398

  View details for DOI 10.1111/dmcn.14454

  View details for Web of Science ID 000505834100001

• Conference Report on Contractures in Musculoskeletal and Neurological Conditions. Muscle & nerve Nuckolls, G. H., Kinnett, K. n., Dayanidhi, S. n., Domenighetti, A. A., Duong, T. n., Hathout, Y. n., Lawlor, M. W., Lee, S. n., Magnusson, S. P., McDonald, C. M., McNally, E. M., Miller, N. F., Olwin, B. B., Raghavan, P. n., Roberts, T. n., Rutkove, S. n., Sarwark, J. F., Senesac, C. n., Vogel, L. F., Walter, G. A., Willcocks, R. n., Rymer, W. Z., Lieber, R. L. 2020

  Abstract

  Limb contractures are debilitating complications associated with various muscle and nervous system disorders. This report summarizes a conference at the Shirley Ryan AbilityLab in Chicago, IL on April 19-20, 2018 involving researchers and physicians from diverse disciplines convened to discuss current clinical and preclinical understanding of contractures in Duchenne muscular dystrophy, stroke, cerebral palsy and other conditions. Presenters described changes in muscle architecture, activation, extracellular matrix, satellite cells and muscle fiber sarcomeric structure that accompany or predispose muscles to contracture. Participants identified ongoing and future research directions that may lead to understanding of the intersecting factors that trigger contractures. These include additional studies of changes in muscle, tendon, joint and neuronal tissues during contracture development using imaging, molecular and physiologic approaches. Participants identified the need for improved biomarkers and outcome measures to identify patients likely to develop contractures and to accurately measure efficacy of treatments currently available and under development. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/mus.26845

  View details for PubMedID 32108365

• Longitudinal changes in clinical outcome measures in COL6-related dystrophies and LAMA2-related dystrophies NEUROLOGY Jain, M. S., Meilleur, K., Kim, E., Norato, G., Waite, M., Nelson, L., McGuire, M., Duong, T., Keller, K., Lott, D. J., Glanzman, A., Rose, K., Main, M., Fiorini, C., Chrismer, I., Linton, M., Punjabi, M., Elliott, J., Tounkara, F., Vasavada, R., Logaraj, R., Winkert, J., Donkervoort, S., Leach, M., Dastgir, J., Hynan, L., Nichols, C., Hartnett, E., Averion, G. M., Collins, J. C., Kim, E. S., Kokkinis, A., Schindler, A., Zukosky, K., Fee, R., Hinton, V., Mohassel, P., Bharucha-Goebel, D., Vuillerot, C., McGraw, P., Barton, M., Fontana, J., Rutkowski, A., Foley, A., Bonnemann, C. G. 2019; 93 (21): E1932-E1943

  Abstract

  To identify the rate of change of clinical outcome measures in children with 2 types of congenital muscular dystrophy (CMD), COL6-related dystrophies (COL6-RDs) and LAMA2-related dystrophies (LAMA2-RDs).Over the course of 4 years, 47 individuals (23 with COL6-RD and 24 with LAMA2-RD) 4 to 22 years of age were evaluated. Assessments included the Motor Function Measure 32 (MFM32), myometry (knee flexors and extensors, elbow flexors and extensors), goniometry (knee and elbow extension), pulmonary function tests, and quality-of-life measures. Separate linear mixed-effects models were fitted for each outcome measurement, with subject-specific random intercepts.Total MFM32 scores for COL6-RDs and LAMA2-RDs decreased at a rate of 4.01 and 2.60 points, respectively, each year (p < 0.01). All muscle groups except elbow flexors for individuals with COL6-RDs decreased in strength between 1.70% (p < 0.05) and 2.55% (p < 0.01). Range-of-motion measurements decreased by 3.21° (p < 0.05) at the left elbow each year in individuals with LAMA2-RDs and 2.35° (p < 0.01) in right knee extension each year in individuals with COL6-RDs. Pulmonary function demonstrated a yearly decline in sitting forced vital capacity percent predicted of 3.03% (p < 0.01) in individuals with COL6-RDs. There was no significant change in quality-of-life measures analyzed.Results of this study describe the rate of change of motor function as measured by the MFM32, muscle strength, range of motion, and pulmonary function in individuals with COL6-RDs and LAMA2-RDs.

  View details for DOI 10.1212/WNL.0000000000008517

  View details for Web of Science ID 000512631100002

  View details for PubMedID 31653707

  View details for PubMedCentralID PMC6885579

• Consensus-based care recommendations for congenital and childhood-onset myotonic dystrophy type 1. Neurology. Clinical practice Johnson, N. E., Aldana, E. Z., Angeard, N., Ashizawa, T., Berggren, K. N., Marini-Bettolo, C., Duong, T., Ekstrom, A., Sansone, V., Tian, C., Hellerstein, L., Campbell, C. 2019; 9 (5): 443–54

  Abstract

  Purpose of review: Myotonic dystrophy type 1 is a multisystemic disorder caused by a noncoding triplet repeat. The age of onset is variable across the lifespan, but in its most severe form, the symptoms appear at birth (congenital myotonic dystrophy) or in the pediatric age range (childhood-onset myotonic dystrophy). These children have a range of disabilities that reduce the lifespan and cause significant morbidity. Currently, there are no agreed upon recommendations for caring for these children.Recent findings: The Myotonic Dystrophy Foundation recruited 11 international clinicians who are experienced with congenital and childhood-onset myotonic dystrophy to create consensus-based care recommendations. The experts used a 2-step methodology using elements of the single text procedure and nominal group technique. Completion of this process has led to the development of clinical care recommendations for this population.Summary: Children with myotonic dystrophy often require monitoring and interventions to improve the lifespan and quality of life. The resulting recommendations are intended to standardize and improve the care of children with myotonic dystrophy.

  View details for DOI 10.1212/CPJ.0000000000000646

  View details for PubMedID 31750030

• 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

• 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

• Patient Reported Quality of Life Measures in Limb-Girdle Muscular Dystrophy: Correlation with Clinical Outcomes Duong, T., Gordish-Dressman, H., Rocha, C., Leshner, R., Sparks, S. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000475965903155

• 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

• 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

• Lower Extremity Functional Outcome Measures in Duchenne Muscular Dystrophy-A Delphi Survey JOURNAL OF NEUROMUSCULAR DISEASES Senesac, C. R., Lott, D. J., Willcocks, R. J., Duong, T., Smith, B. K. 2019; 6 (1): 75-83

  Abstract

  Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease characterized by progressive muscle weakness, multiple system involvement and premature mortality. Effective treatments for DMD through clinical trials and natural history studies are currently underway. Clinical trials in DMD typically include several outcome measures of motor function. Research sites and studies have been found to have slightly different operational definitions for a given functional outcome resulting in different procedures and protocols for these measurements.The goal of this study is to establish agreement among experts in the field around best practices in collecting functional outcome data in DMD providing researchers and clinicians with guidance on best practices.A group of 30 experts in Duchenne Muscular Dystrophy (DMD) with experience in the development and/ or execution of lower extremity outcome measures for this population met face to face to identify incongruences in the collection of this data. This effort was based in the United States (US) and sponsored by Parent Project Muscular Dystrophy. Several discrepancies were categorized for each outcome which included: 6-minute walk test, 10-meter walk/run, supine to stand, ascend 4 stairs, sit to stand, and the NorthStar Ambulatory Assessment. Following this meeting an additional 32 experts in DMD (28 from the United States and 11 international participants) consented to participate in a Delphi Survey to reach consensus on the protocols and execution of lower extremity outcomes.Round one: 70 operationally defined questions were surveyed with 45 (64%) reaching >70% consensus. Round two: 27 questions were operational, with 20 (74%) reaching >70% consensus. Those questions that did not reach consensus appear minor.With minor modifications in the collection of data across sites, outcomes could potentially be normalized across research studies. This would reduce excessive training for evaluators in trials and produce minimal differences between protocols. Consistency in protocols will promote more efficient study start up, less errors between administration of items across studies, and ultimately improve quality and reliability of the functional outcomes. The authors strongly advocate for the establishment of a "research network library" that could be utilized by all those performing clinical assessments and trials in DMD.

  View details for DOI 10.3233/JND-180337

  View details for Web of Science ID 000685097900006

  View details for PubMedID 30562905

  View details for PubMedCentralID PMC6698889

• 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

• 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

• Report on the workshop: Meaningful outcome measures for Duchenne muscular dystrophy, London, UK, 30-31 January 2017 NEUROMUSCULAR DISORDERS Straub, V., Mercuri, E., DMD Outcome Measure Study Grp 2018; 28 (8): 690-701

  View details for DOI 10.1016/j.nmd.2018.05.013

  View details for Web of Science ID 000445982300011

  View details for PubMedID 30033203

• 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

• 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

• 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

• 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

• Muscle Strength and Function Measures in a Multicenter Study of Myotonic Dystrophy Type 1 (DM1): Baseline Impairment and Test-Retest Agreement over 3 Months Eichinger, K., Currence, M., Capron, K., Duong, T., Gee, R., Herbelin, L., Joe, G., King, W., Lott, D. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090804272

• 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

• 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

• ELECTRICAL IMPEDANCE MYOGRAPHY IN INDIVIDUALS WITH COLLAGEN 6 AND LAMININ alpha-2 CONGENITAL MUSCULAR DYSTROPHY: A CROSS-SECTIONAL AND 2-YEAR ANALYSIS MUSCLE & NERVE Nichols, C., Jain, M. S., Meilleur, K. G., Wu, T., Collins, J., Waite, M. R., Dastgir, J., Salman, A., Donkervoort, S., Duong, T., Keller, K., Leach, M. E., Lott, D. J., Mcguire, M. N., Nelson, L., Rutkowski, A., Vuillerot, C., Bonnemann, C. G., Lehky, T. J. 2018; 57 (1): 54–60

  View details for DOI 10.1002/mus.25629

  View details for Web of Science ID 000417762300027

• A multinational study on motor function in early-onset FSHD. Neurology Mah, J. K., Feng, J. n., Jacobs, M. B., Duong, T. n., Carroll, K. n., de Valle, K. n., Carty, C. L., Morgenroth, L. P., Guglieri, M. n., Ryan, M. M., Clemens, P. R., Thangarajh, M. n., Webster, R. n., Smith, E. n., Connolly, A. M., McDonald, C. M., Karachunski, P. n., Tulinius, M. n., Harper, A. n., Cnaan, A. n., Chen, Y. W. 2018; 90 (15): e1333–e1338

  Abstract

  To investigate motor function associations with age, sex, and D4Z4 repeats among participants with early-onset facioscapulohumeral muscular dystrophy (FSHD) type 1 as defined by weakness onset before 10 years of age.We collected standardized motor assessments, including manual muscle testing (MMT), quantitative muscle testing, functional motor evaluations, and clinical severity scores (CSSs), at 12 Cooperative International Neuromuscular Research Group centers. To measure associations, we used linear regression models adjusted for sex, evaluation age, age at onset of weakness, and D4Z4 repeats.Among 52 participants (60% female, mean age 22.9 ± 14.7 years), weakness was most pronounced in the shoulder and abdominal musculature. Older enrollment age was associated with greater CSSs (p = 0.003). When adjusted for enrollment age, sex, and D4Z4 repeats, younger age at onset of facial weakness was associated with greater CSSs, slower velocities in timed function tests, and lower MMT scores (p < 0.05).Significant clinical variability was observed in early-onset FSHD. Earlier age at onset of facial weakness was associated with greater disease severity. Longitudinal assessments are needed to determine the rate of disease progression in this population.

  View details for PubMedID 29540582

  View details for PubMedCentralID PMC5894929

• Motor Function Test Reliability During the NeuroNEXT Spinal Muscular Atrophy Infant Biomarker Study. Journal of neuromuscular diseases Krosschell, K. J., Bosch, M. n., Nelson, L. n., Duong, T. n., Lowes, L. P., Alfano, L. N., Benjamin, D. n., Carry, T. B., Devine, G. n., Kelley, C. n., Gadekan, R. n., Malkus, E. C., Pasternak, A. n., Provance-Orr, S. n., Roemeiser-Logan, L. n., Nicorici, A. n., Trussell, D. n., Young, S. D., Fetterman, J. R., Montes, J. n., Powers, P. J., Quinones, R. n., Quigley, J. n., Coffey, C. S., Yankey, J. W., Bartlett, A. n., Kissel, J. T., Kolb, S. J. 2018; 5 (4): 509–21

  Abstract

  The NeuroNEXT SMA Infant Biomarker Study, a two year, longitudinal, multi-center study of infants with SMA type 1 and healthy infants, presented a unique opportunity to assess multi-site rater reliability on three infant motor function tests (MFTs) commonly used to assess infants with SMA type 1.To determine the effect of prospective MFT rater training and the effect of rater experience on inter-rater and intra-rater reliability for the Test of Infant Motor Performance Screening Items (TIMPSI), the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) and the Alberta Infant Motor Scale (AIMS).Training was conducted utilizing a novel set of motor function test (MFT) videos to optimize accurate MFT administration and reliability for the study duration. Inter- and intra-rater reliability of scoring for the TIMPSI and inter-rater reliability of scoring for the CHOP INTEND and the AIMS was assessed using intraclass correlation coefficients (ICC). Effect of rater experience on reliability was examined using ICC. Agreement with 'expert' consensus scores was examined using Pearson's correlation coefficients.Inter-rater reliability on all MFTs was good to excellent. Intra-rater reliability for the primary MFT, the TIMPSI, was excellent for the study duration. Agreement with 'expert' consensus was within predetermined limits (≥85%) after training. Evaluator experience with SMA and MFTs did not affect reliability.Reliability of scores across evaluators was demonstrated for all three study MFTs and scores were reproducible on repeated administration. Evaluator experience had no effect on reliability.

  View details for PubMedID 30223401

• 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

• Interleukin 1 Receptor-Like 1 Protein (ST2) is a Potential Biomarker for Cardiomyopathy in Duchenne Muscular Dystrophy PEDIATRIC CARDIOLOGY Anderson, J., Seol, H., Gordish-Dressman, H., Hathout, Y., Spurney, C. F., CINRG Investigators 2017; 38 (8): 1606-1612

  Abstract

  Duchenne muscular dystrophy (DMD) is a rare, fatal X-linked disorder characterized by the lack of dystrophin, a key sarcolemma muscle protein. Cardiac failure is a significant cause of death in DMD subjects. The purpose of our research was to identify potential cardiac serum biomarkers associated with DMD cardiomyopathy. This is an observational, case-controlled study using subjects from the CINRG DMD natural history study with cardiomyopathy (ejection fraction (EF) <55%; shortening fraction (SF) <28%), subjects without cardiomyopathy (EF ≥ 55%; SF ≥ 28%) compared to normal healthy volunteer subjects. The DMD with cardiomyopathy group had significantly lower average EF and SF (EF = 45 ± 10/SF = 25 ± 2%) than the DMD without cardiomyopathy group (EF = 58 ± 5% and SF = 32 ± 3%; p < 0.01). Among a selected set of potential biomarkers for cardiomyopathy (MMP9, BNP, GAL3, CRP, LEP, TNC, TLR4 and ST2) we validated ST2 as significantly elevated in the serum of DMD cardiomyopathy group (35,798 ± 4884 pg/mL) compared to normal controls (9940 ± 2680 pg/mL; p < 0.01; n = 6). Matrix metallopeptidase 9 (MMP9) levels were found significantly increased in both DMD groups compared to controls (p < 0.01). No significant differences were seen in BNP, GAL3, CRP, LEP, TNC or TLR4 levels. Increased ST2 levels were found in serum of DMD subjects compared to healthy volunteers and further elevated in DMD subjects with cardiomyopathy. Future studies correlating cardiomyopathy with ST2 levels may allow for improved non-invasive monitoring of cardiac disease in DMD subjects.

  View details for DOI 10.1007/s00246-017-1703-9

  View details for Web of Science ID 000415580300011

  View details for PubMedID 28821969

  View details for PubMedCentralID PMC6317901

• Pulmonary Endpoints in Duchenne Muscular Dystrophy A Workshop Summary AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Finder, J., Mayer, O., Sheehan, D., Sawnani, H., Abresch, R., Benditt, J., Birnkrant, D. J., Duong, T., Henricson, E., Kinnett, K., McDonald, C. M., Connlly, A. M. 2017; 196 (4): 512-519

  Abstract

  Development of novel therapeutics for treatment of Duchenne muscular dystrophy (DMD) has led to clinical trials that include pulmonary endpoints that allow assessment of respiratory muscle status, especially in nonambulatory subjects. Parent Project Muscular Dystrophy (PPMD) convened a workshop in Bethesda, Maryland, on April 14 and 15, 2016, to summarize published respiratory data in DMD and give guidance to clinical researchers assessing the effect of interventions on pulmonary outcomes in DMD.

  View details for DOI 10.1164/rccm.201703-0507WS

  View details for Web of Science ID 000407532700018

  View details for PubMedID 28636407

• 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

• Development of a patient-reported outcome measure for upper limb function in Duchenne muscular dystrophy: DMD Upper Limb PROM DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Klingels, K., Mayhew, A. G., Mazzone, E. S., Duong, T., Decostre, V., Werlauff, U., Vroom, E., Mercuri, E., Goemans, N. M., Eagle, M., De Groot, I., Main, M., Messina, S., Campion, G., Servais, L., Van den Hauwe, M., Es, E., Pane, M., Buccella, F., Kuijer, J., Ceradini, F., Henricson, E., McDonald, C., Florence, J., Upper Limb Clinical Outcome Grp 2017; 59 (2): 224-231

  Abstract

  To develop a patient-reported outcome measure (PROM) assessing upper limb function related to activities of daily living (ADL) that cannot be observed in a clinical setting, specifically for patients with Duchenne muscular dystrophy (DMD) across a wide age range, applicable in the different stages of the disease.The developmental process was based on US Food and Drug Administration guidelines. This included item generation from a systematic review of existing tools and expert opinion on task difficulty and relevance, involving individuals with DMD. Cultural aspects affecting ADL were taken into consideration to make this tool applicable to the broad DMD community. Items were selected in relation to a conceptual framework reflecting disease progression covering the full range of upper limb function across different ADL domains.After pilot testing and iterative Rasch analyses, redundant or clinically irrelevant items were removed. The final questionnaire consists of 32 items covering four domains of ADL (food, self-care, household and environment, leisure and communication). Test-retest reliability was excellent.A DMD-specific upper limb PROM was developed on the basis of clinical relevance and psychometric robustness. Its main purpose is to document the patient self-reported natural history of DMD and assess the efficacy of interventions.

  View details for DOI 10.1111/dmcn.13277

  View details for Web of Science ID 000392830000025

  View details for PubMedID 27671699

• 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

• Association Study of Exon Variants in the NF-kappa B and TGF beta Pathways Identifies CD40 as a Modifier of Duchenne Muscular Dystrophy AMERICAN JOURNAL OF HUMAN GENETICS Bello, L., Flanigan, K. M., Weiss, R. B., Spitali, P., Aartsma-Rus, A., Muntoni, F., Zaharieva, I., Ferlini, A., Mercuri, E., Tuffery-Giraud, S., Claustres, M., Straub, V., Lochmuller, H., Barp, A., Vianello, S., Pegoraro, E., Punetha, J., Gordish-Dressman, H., Giri, M., McDonald, C. M., Hoffman, E. P., United Dystrophinopathy Project, Cooperative Int Neuromuscular Res 2016; 99 (5): 1163-1171

  Abstract

  The expressivity of Mendelian diseases can be influenced by factors independent from the pathogenic mutation: in Duchenne muscular dystrophy (DMD), for instance, age at loss of ambulation (LoA) varies between individuals whose DMD mutations all abolish dystrophin expression. This suggests the existence of trans-acting variants in modifier genes. Common single nucleotide polymorphisms (SNPs) in candidate genes (SPP1, encoding osteopontin, and LTBP4, encoding latent transforming growth factor β [TGFβ]-binding protein 4) have been established as DMD modifiers. We performed a genome-wide association study of age at LoA in a sub-cohort of European or European American ancestry (n = 109) from the Cooperative International Research Group Duchenne Natural History Study (CINRG-DNHS). We focused on protein-altering variants (Exome Chip) and included glucocorticoid treatment as a covariate. As expected, due to the small population size, no SNPs displayed an exome-wide significant p value (< 1.8 × 10-6). Subsequently, we prioritized 438 SNPs in the vicinities of 384 genes implicated in DMD-related pathways, i.e., the nuclear-factor-κB and TGFβ pathways. The minor allele at rs1883832, in the 5'-untranslated region of CD40, was associated with earlier LoA (p = 3.5 × 10-5). This allele diminishes the expression of CD40, a co-stimulatory molecule for T cell polarization. We validated this association in multiple independent DMD cohorts (United Dystrophinopathy Project, Bio-NMD, and Padova, total n = 660), establishing this locus as a DMD modifier. This finding points to cell-mediated immunity as a relevant pathogenetic mechanism and potential therapeutic target in DMD.

  View details for DOI 10.1016/j.ajhg.2016.08.023

  View details for Web of Science ID 000387529600013

  View details for PubMedID 27745838

  View details for PubMedCentralID PMC5097949

• 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

• 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

• Genetic Modifiers of Ambulation in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study ANNALS OF NEUROLOGY Bello, L., Kesari, A., Gordish-Dressman, H., Cnaan, A., Morgenroth, L. P., Punetha, J., Duong, T., Henricson, E. K., Pegoraro, E., McDonald, C. M., Hoffman, E. P., Cooperative Int Neuromuscular Res 2015; 77 (4): 684-696

  Abstract

  We studied the effects of LTBP4 and SPP1 polymorphisms on age at loss of ambulation (LoA) in a multiethnic Duchenne muscular dystrophy (DMD) cohort.We genotyped SPP1 rs28357094 and LTBP4 haplotype in 283 of 340 participants in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS). Median ages at LoA were compared by Kaplan-Meier analysis and log-rank test. We controlled polymorphism analyses for concurrent effects of glucocorticoid corticosteroid (GC) treatment (time-varying Cox regression) and for population stratification (multidimensional scaling of genome-wide markers).Hispanic and South Asian participants (n = 18, 41) lost ambulation 2.7 and 2 years earlier than Caucasian subjects (p = 0.003, <0.001). The TG/GG genotype at SPP1 rs28357094 was associated to 1.2-year-earlier median LoA (p = 0.048). This difference was greater (1.9 years, p = 0.038) in GC-treated participants, whereas no difference was observed in untreated subjects. Cox regression confirmed a significant effect of SPP1 genotype in GC-treated participants (hazard ratio = 1.61, p = 0.016). LTBP4 genotype showed a direction of association with age at LoA as previously reported, but it was not statistically significant. After controlling for population stratification, we confirmed a strong effect of LTBP4 genotype in Caucasians (2.4 years, p = 0.024). Median age at LoA with the protective LTBP4 genotype in this cohort was 15.0 years, 16.0 for those who were treated with GC.SPP1 rs28357094 acts as a pharmacodynamic biomarker of GC response, and LTBP4 haplotype modifies age at LoA in the CINRG-DNHS cohort. Adjustment for GC treatment and population stratification appears crucial in assessing genetic modifiers in DMD.

  View details for DOI 10.1002/ana.24370

  View details for Web of Science ID 000352102500013

  View details for PubMedID 25641372

  View details for PubMedCentralID PMC4403971