Gregory Enns

All Publications

• Efficacy and safety of pegzilarginase in arginase 1 deficiency (PEACE): a phase 3, randomized, double-blind, placebo-controlled, multi-centre trial. EClinicalMedicine Russo, R. S., Gasperini, S., Bubb, G., Neuman, L., Sloan, L. S., Diaz, G. A., Enns, G. M. 2024; 68: 102405

  Abstract

  Arginase 1 Deficiency (ARG1-D) is a rare debilitating, progressive, inherited, metabolic disease characterized by marked increases in plasma arginine (pArg) and its metabolites, with increased morbidity, substantial reductions in quality of life, and premature mortality. Effective treatments that can lower arginine and improve clinical outcomes is currently lacking. Pegzilarginase is a novel human arginase 1 enzyme therapy. The present trial aimed to demonstrate efficacy of pegzilarginase on pArg and key mobility outcomes.This Phase 3 randomized, double-blind, placebo-controlled, parallel-group clinical trial (clinicaltrials.govNCT03921541, EudraCT 2018-004837-34), randomized patients with ARG1-D 2:1 to intravenously/subcutaneously once-weekly pegzilarginase or placebo in conjunction with their individualized disease management. It was conducted in 7 countries; United States, United Kingdom, Canada, Austria, France, Germany, Italy. Primary endpoint was change from baseline in pArg after 24 weeks; key secondary endpoints were change from baseline at Week 24 in Gross Motor Function Measure part E (GMFM-E) and 2-min walk test (2MWT). Full Analysis Set was used for the analyses.From 01 May 2019 to 29 March 2021, 32 patients were enrolled and randomized (pegzilarginase, n = 21; placebo, n = 11). Pegzilarginase lowered geometric mean pArg from 354.0 μmol/L to 86.4 μmol/L at Week 24 vs 464.7 to 426.6 μmol/L for placebo (95% CI: -67.1%, -83.5%; p < 0.0001) and normalized levels in 90.5% of patients (vs 0% with placebo). In addition, clinically relevant functional mobility improvements were demonstrated with pegzilarginase treatment. These effects were sustained long-term through additional 24 weeks of subsequent exposure. Pegzilarginase was well-tolerated, with adverse events being mostly transient and mild/moderate in severity.These results support pegzilarginase as the first potential treatment to normalize pArg in ARG1-D and achieve clinically meaningful improvements in functional mobility.Aeglea BioTherapeutics.

  View details for DOI 10.1016/j.eclinm.2023.102405

  View details for PubMedID 38292042

  View details for PubMedCentralID PMC10825663

• Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial. Neurology Karaa, A., Bertini, E., Carelli, V., Cohen, B. H., Enns, G. M., Falk, M. J., Goldstein, A., Gorman, G. S., Haas, R., Hirano, M., Klopstock, T., Koenig, M. K., Kornblum, C., Lamperti, C., Lehman, A., Longo, N., Molnar, M. J., Parikh, S., Phan, H., Pitceathly, R. D., Saneto, R., Scaglia, F., Servidei, S., Tarnopolsky, M., Toscano, A., Van Hove, J. L., Vissing, J., Vockley, J., Finman, J. S., Brown, D. A., Shiffer, J. A., Mancuso, M., MMPOWER-3 Trial Investigators 2023

  Abstract

  BACKGROUND AND OBJECTIVES: Primary Mitochondrial Myopathies (PMMs) encompass a group of genetic disorders that impair mitochondrial oxidative phosphorylation, adversely impacting physical function, exercise capacity, and quality of life (QoL). Current PMM standards-of-care address symptoms, with limited clinical impact, constituting a significant therapeutic unmet need. We present data from MMPOWER-3, a pivotal, phase-3, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of elamipretide in participants with genetically-confirmed PMM.METHODS: Following screening, eligible participants were randomized 1:1 to receive either 24weeks of elamipretide 40mg/day or placebo subcutaneously. Primary efficacy endpoints included change from baseline to Week 24 on the distance walked on the 6-minute Walk Test (6MWT), and Total Fatigue on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA). Secondary endpoints included Most Bothersome Symptom Score on the PMMSA, NeuroQoL Fatigue Short Form scores, and the Patient- and Clinician-Global Impression of PMM Symptoms.RESULTS: Participants (N=218) were randomized (n=109 elamipretide; n=109 placebo). Mean age was 45.6 year (64% women; 94% white). The majority of participants (n=162 [74%]) had mitochondrial DNA (mtDNA) mutations, with the remainder having nuclear DNA (nDNA) defects. At screening, the most frequent bothersome PMM symptom on the PMMSA was tiredness during activities (28.9%). At baseline, mean distance walked on the 6MWT was 336.7±81.2 meters, mean score for Total Fatigue on the PMMSA was 10.6±2.5, and mean T-score for the Neuro-QoL Fatigue Short Form was 54.7±7.5. The study did not meet its primary endpoints assessing changes in the 6MWT and PMMSA Total Fatigue Score (TFS). Between the participants receiving elamipretide versus placebo, the difference in the Least Squares Mean (SE) from baseline to Week 24 on distance walked on the 6MWT was -3.2 (95% confidence interval,-18.7,12.3; p=0.69) meters and on the PMMSA Total Fatigue Score was -0.07 (95% confidence interval,-0.10,0.26; p=0.37). Elamipretide treatment was well-tolerated with most adverse events being mild to moderate in severity.DISCUSSION: Subcutaneous elamipretide treatment did not improve outcomes in the 6MWT and PMMSA TFS in patients with PMM. However, this phase-3 study demonstrated that subcutaneous elamipretide is well-tolerated.TRIAL REGISTRATION INFORMATION: Trial registered with clinicaltrials.gov, Clinical Trials Identifier: NCT03323749; submitted on October 12, 2017;first patient enrolled October 9, 2017. https://clinicaltrials.gov/ct2/show/NCT03323749?term=elamipretide&draw=2&rank=9 CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that elamipretide does not improve the 6 minute walk test or fatigue at 24 weeks compared to placebo in patients with primary mitochondrial myopathy.

  View details for DOI 10.1212/WNL.0000000000207402

  View details for PubMedID 37268435

• The Present and Future of Mitochondrial-Based Therapeutics for Eye Disease. Translational vision science & technology Ji, M. H., Kreymerman, A., Belle, K., Ghiam, B. K., Muscat, S. P., Mahajan, V. B., Enns, G. M., Mercola, M., Wood, E. H. 2021; 10 (8): 4

  Abstract

  Translational Relevance: Mitochondria are viable therapeutic targets for a broad spectrum of ocular diseases.

  View details for DOI 10.1167/tvst.10.8.4

  View details for PubMedID 34232272

• Mitochondrial diseases in North America: An analysis of the NAMDC Registry. Neurology. Genetics Barca, E., Long, Y., Cooley, V., Schoenaker, R., Emmanuele, V., DiMauro, S., Cohen, B. H., Karaa, A., Vladutiu, G. D., Haas, R., Van Hove, J. L., Scaglia, F., Parikh, S., Bedoyan, J. K., DeBrosse, S. D., Gavrilova, R. H., Saneto, R. P., Enns, G. M., Stacpoole, P. W., Ganesh, J., Larson, A., Zolkipli-Cunningham, Z., Falk, M. J., Goldstein, A. C., Tarnopolsky, M., Gropman, A., Camp, K., Krotoski, D., Engelstad, K., Rosales, X. Q., Kriger, J., Grier, J., Buchsbaum, R., Thompson, J. L., Hirano, M. 2020; 6 (2): e402

  Abstract

  Objective: To describe clinical, biochemical, and genetic features of participants with mitochondrial diseases (MtDs) enrolled in the North American Mitochondrial Disease Consortium (NAMDC) Registry.Methods: This cross-sectional, multicenter, retrospective database analysis evaluates the phenotypic and molecular characteristics of participants enrolled in the NAMDC Registry from September 2011 to December 2018. The NAMDC is a network of 17 centers with expertise in MtDs and includes both adult and pediatric specialists.Results: One thousand four hundred ten of 1,553 participants had sufficient clinical data for analysis. For this study, we included only participants with molecular genetic diagnoses (n = 666). Age at onset ranged from infancy to adulthood. The most common diagnosis was multisystemic disorder (113 participants), and only a minority of participants were diagnosed with a classical mitochondrial syndrome. The most frequent classical syndromes were Leigh syndrome (97 individuals) and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (71 individuals). Pathogenic variants in the mitochondrial DNA were more frequently observed (414 participants) than pathogenic nuclear gene variants (252 participants). Pathogenic variants in 65 nuclear genes were identified, with POLG1 and PDHA1 being the most commonly affected. Pathogenic variants in 38 genes were reported only in single participants.Conclusions: The NAMDC Registry data confirm the high variability of clinical, biochemical, and genetic features of participants with MtDs. This study serves as an important resource for future enhancement of MtD research and clinical care by providing the first comprehensive description of participant with MtD in North America.

  View details for DOI 10.1212/NXG.0000000000000402

  View details for PubMedID 32337332

• AMP-independent activator of AMPK for treatment of mitochondrial disorders. PloS one Moore, T., Yanes, R. E., Calton, M. A., Vollrath, D., Enns, G. M., Cowan, T. M. 2020; 15 (10): e0240517

  Abstract

  Mitochondrial diseases are a clinically heterogenous group of disorders caused by respiratory chain dysfunction and associated with progressive, multi-systemic phenotype. There is no effective treatment or cure, and no FDA-approved drug for treating mitochondrial disease. To identify and characterize potential therapeutic compounds, we developed an in vitro screening assay and identified a group of direct AMP-activated protein kinase (AMPK) activators originally developed for the treatment of diabetes and metabolic syndrome. Unlike previously investigated AMPK agonists such as AICAR, these compounds allosterically activate AMPK in an AMP-independent manner, thereby increasing specificity and decreasing pleiotropic effects. The direct AMPK activator PT1 significantly improved mitochondrial function in assays of cellular respiration, energy status, and cellular redox. PT1 also protected against retinal degeneration in a mouse model of photoreceptor degeneration associated with mitochondrial dysfunction and oxidative stress, further supporting the therapeutic potential of AMP-independent AMPK agonists in the treatment of mitochondrial disease.

  View details for DOI 10.1371/journal.pone.0240517

  View details for PubMedID 33052980

• Successful liver transplantation in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Molecular genetics and metabolism Kripps, K. n., Nakayuenyongsuk, W. n., Shayota, B. J., Berquist, W. n., Gomez-Ospina, N. n., Esquivel, C. O., Concepcion, W. n., Sampson, J. B., Cristin, D. J., Jackson, W. E., Gilliland, S. n., Pomfret, E. A., Kueht, M. L., Pettit, R. W., Sherif, Y. A., Emrick, L. T., Elsea, S. H., Himes, R. n., Hirano, M. n., Van Hove, J. L., Scaglia, F. n., Enns, G. M., Larson, A. A. 2020

  Abstract

  Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a fatal disorder characterized by progressive gastrointestinal dysmotility, peripheral neuropathy, leukoencephalopathy, skeletal myopathy, ophthalmoparesis, and ptosis. MNGIE stems from deficient thymidine phosphorylase activity (TP) leading to toxic elevations of plasma thymidine. Hematopoietic stem cell transplant (HSCT) restores TP activity and halts disease progression but has high transplant-related morbidity and mortality. Liver transplant (LT) was reported to restore TP activity in two adult MNGIE patients. We report successful LT in four additional MNGIE patients, including a pediatric patient. Our patients were diagnosed between ages 14 months and 36 years with elevated thymidine levels and biallelic pathogenic variants in TYMP. Two patients presented with progressive gastrointestinal dysmotility, and three demonstrated progressive peripheral neuropathy with two suffering limitations in ambulation. Two patients, including the child, had liver dysfunction and cirrhosis. Following LT, thymidine levels nearly normalized in all four patients and remained low for the duration of follow-up. Disease symptoms stabilized in all patients, with some manifesting improvements, including intestinal function. No patient died, and LT appeared to have a more favorable safety profile than HSCT, especially when liver disease is present. Follow-up studies will need to document the long-term impact of this new approach on disease outcome. Take Home Message: Liver transplantation is effective in stabilizing symptoms and nearly normalizing thymidine levels in patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and may have an improved safety profile over hematopoietic stem cell transplant.

  View details for DOI 10.1016/j.ymgme.2020.03.001

  View details for PubMedID 32173240

• Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy PLOS ONE Kahn-Kirby, A. H., Amagata, A., Maeder, C. I., Mei, J. J., Sideris, S., Kosaka, Y., Hinman, A., Malone, S. A., Bruegger, J. J., Wang, L., Kim, V., Shrader, W. D., Hoff, K. G., Latham, J. C., Ashley, E. A., Wheeler, M. T., Bertini, E., Carrozzo, R., Martinelli, D., Dionisi-Vici, C., Chapman, K. A., Enns, G. M., Gahl, W., Wolfe, L., Saneto, R. P., Johnson, S. C., Trimmer, J. K., Klein, M. B., Holst, C. R. 2019; 14 (3)

  View details for DOI 10.1371/journal.pone.0214250

  View details for Web of Science ID 000462594000047

• Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder AMERICAN JOURNAL OF HUMAN GENETICS Olahova, M., Yoon, W., Thompson, K., Jangam, S., Fernandez, L., Davidson, J. M., Kyle, J. E., Grove, M. E., Fisk, D. G., Kohler, J. N., Holmes, M., Dries, A. M., Huang, Y., Zhao, C., Contrepois, K., Zappala, Z., Fresard, L., Waggott, D., Zink, E. M., Kim, Y., Heyman, H. M., Stratton, K. G., Webb-Robertson, B. M., Snyder, M., Merker, J. D., Montgomery, S. B., Fisher, P. G., Feichtinger, R. G., Mayr, J. A., Hall, J., Barbosa, I. A., Simpson, M. A., Deshpande, C., Waters, K. M., Koeller, D. M., Metz, T. O., Morris, A. A., Schelley, S., Cowan, T., Friederich, M. W., McFarland, R., Van Hove, J. K., Enns, G. M., Yamamoto, S., Ashley, E. A., Wangler, M. F., Taylor, R. W., Bellen, H. J., Bernstein, J. A., Wheeler, M. T., Undiagnosed Diseases Network 2018; 102 (3): 494–504

  Abstract

  ATP synthase, H+ transporting, mitochondrial F1 complex, δ subunit (ATP5F1D; formerly ATP5D) is a subunit of mitochondrial ATP synthase and plays an important role in coupling proton translocation and ATP production. Here, we describe two individuals, each with homozygous missense variants in ATP5F1D, who presented with episodic lethargy, metabolic acidosis, 3-methylglutaconic aciduria, and hyperammonemia. Subject 1, homozygous for c.245C>T (p.Pro82Leu), presented with recurrent metabolic decompensation starting in the neonatal period, and subject 2, homozygous for c.317T>G (p.Val106Gly), presented with acute encephalopathy in childhood. Cultured skin fibroblasts from these individuals exhibited impaired assembly of F1FO ATP synthase and subsequent reduced complex V activity. Cells from subject 1 also exhibited a significant decrease in mitochondrial cristae. Knockdown of Drosophila ATPsynδ, the ATP5F1D homolog, in developing eyes and brains caused a near complete loss of the fly head, a phenotype that was fully rescued by wild-type human ATP5F1D. In contrast, expression of the ATP5F1D c.245C>T and c.317T>G variants rescued the head-size phenotype but recapitulated the eye and antennae defects seen in other genetic models of mitochondrial oxidative phosphorylation deficiency. Our data establish c.245C>T (p.Pro82Leu) and c.317T>G (p.Val106Gly) in ATP5F1D as pathogenic variants leading to a Mendelian mitochondrial disease featuring episodic metabolic decompensation.

  View details for PubMedID 29478781

• Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society GENETICS IN MEDICINE Parikh, S., Goldstein, A., Karaa, A., Koenig, M., Anselm, I., Brunel-Guitton, C., Christodoulou, J., Cohen, B. H., Dimmock, D., Enns, G. M., Falk, M. J., Feigenbaum, A., Frye, R. E., Ganesh, J., Griesemer, D., Haas, R., Horvath, R., Korson, M., Kruer, M. C., Mancuso, M., McCormack, S., Raboisson, M., Reimschisel, T., Salvarinova, R., Saneto, R. P., Scaglia, F., Shoffner, J., Stacpoole, P. W., Sue, C. M., Tarnopolsky, M., Van Karnebeek, C., Wolfe, L. A., Cunningham, Z., Rahman, S., Chinnery, P. F. 2017; 19 (12)

  View details for DOI 10.1038/gim.2017.107

  View details for Web of Science ID 000468456200002

• Glutathione as a Redox Biomarker in Mitochondrial Disease-Implications for Therapy. Journal of clinical medicine Enns, G. M., Cowan, T. M. 2017; 6 (5)

  Abstract

  Technical advances in the ability to measure mitochondrial dysfunction are providing new insights into mitochondrial disease pathogenesis, along with new tools to objectively evaluate the clinical status of mitochondrial disease patients. Glutathione (l-ϒ-glutamyl-l-cysteinylglycine) is the most abundant intracellular thiol, and the intracellular redox state, as reflected by levels of oxidized (GSSG) and reduced (GSH) glutathione, as well as the GSH/GSSG ratio, is considered to be an important indication of cellular health. The ability to quantify mitochondrial dysfunction in an affected patient will not only help with routine care, but also improve rational clinical trial design aimed at developing new therapies. Indeed, because multiple disorders have been associated with either primary or secondary deficiency of the mitochondrial electron transport chain and redox imbalance, developing mitochondrial therapies that have the potential to improve the intracellular glutathione status has been a focus of several clinical trials over the past few years. This review will also discuss potential therapies to increase intracellular glutathione with a focus on EPI-743 (α-tocotrienol quinone), a compound that appears to have the ability to modulate the activity of oxidoreductases, in particular NAD(P)H:quinone oxidoreductase 1.

  View details for DOI 10.3390/jcm6050050

  View details for PubMedID 28467362

• Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nature communications Gomez-Ospina, N., Potter, C. J., Xiao, R., Manickam, K., Kim, M., Kim, K. H., Shneider, B. L., Picarsic, J. L., Jacobson, T. A., Zhang, J., He, W., Liu, P., Knisely, A. S., Finegold, M. J., Muzny, D. M., Boerwinkle, E., Lupski, J. R., Plon, S. E., Gibbs, R. A., Eng, C. M., Yang, Y., Washington, G. C., Porteus, M. H., Berquist, W. E., Kambham, N., Singh, R. J., Xia, F., Enns, G. M., Moore, D. D. 2016; 7: 10713-?

  Abstract

  Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.

  View details for DOI 10.1038/ncomms10713

  View details for PubMedID 26888176

• A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency NEW ENGLAND JOURNAL OF MEDICINE Burton, B. K., Balwani, M., Feillet, F., Baric, I., Burrow, T. A., Camarena Grande, C., Coker, M., Consuelo-Sanchez, A., Deegan, P., Di Rocco, M., Enns, G. M., Erbe, R., Ezgu, F., Ficicioglu, C., Furuya, K. N., Kane, J., Laukaitis, C., Mengel, E., Neilan, E. G., Nightingale, S., Peters, H., Scarpa, M., Schwab, K. O., Smolka, V., Valayannopoulos, V., Wood, M., Goodman, Z., Yang, Y., Eckert, S., Rojas-Caro, S., Quinn, A. G. 2015; 373 (11): 1010-1020

  Abstract

  Lysosomal acid lipase is an essential lipid-metabolizing enzyme that breaks down endocytosed lipid particles and regulates lipid metabolism. We conducted a phase 3 trial of enzyme-replacement therapy in children and adults with lysosomal acid lipase deficiency, an underappreciated cause of cirrhosis and severe dyslipidemia.In this multicenter, randomized, double-blind, placebo-controlled study involving 66 patients, we evaluated the safety and effectiveness of enzyme-replacement therapy with sebelipase alfa (administered intravenously at a dose of 1 mg per kilogram of body weight every other week); the placebo-controlled phase of the study was 20 weeks long and was followed by open-label treatment for all patients. The primary end point was normalization of the alanine aminotransferase level. Secondary end points included additional disease-related efficacy assessments, safety, and side-effect profile.Substantial disease burden at baseline included a very high level of low-density lipoprotein cholesterol (≥190 mg per deciliter) in 38 of 66 patients (58%) and cirrhosis in 10 of 32 patients (31%) who underwent biopsy. A total of 65 of the 66 patients who underwent randomization completed the double-blind portion of the trial and continued with open-label treatment. At 20 weeks, the alanine aminotransferase level was normal in 11 of 36 patients (31%) in the sebelipase alfa group and in 2 of 30 (7%) in the placebo group (P=0.03), with mean changes from baseline of -58 U per liter versus -7 U per liter (P<0.001). With respect to prespecified key secondary efficacy end points, we observed improvements in lipid levels and reduction in hepatic fat content (P<0.001 for all comparisons, except P=0.04 for triglycerides). The number of patients with adverse events was similar in the two groups; most events were mild and were considered by the investigator to be unrelated to treatment.Sebelipase alfa therapy resulted in a reduction in multiple disease-related hepatic and lipid abnormalities in children and adults with lysosomal acid lipase deficiency. (Funded by Synageva BioPharma and others; ARISE ClinicalTrials.gov number, NCT01757184.).

  View details for DOI 10.1056/NEJMoa1501365

  View details for Web of Science ID 000360959000006

• Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genetics in medicine Parikh, S., Goldstein, A., Koenig, M. K., Scaglia, F., Enns, G. M., Saneto, R., Anselm, I., Cohen, B. H., Falk, M. J., Greene, C., Gropman, A. L., Haas, R., Hirano, M., Morgan, P., Sims, K., Tarnopolsky, M., van Hove, J. L., Wolfe, L., DiMauro, S. 2015; 17 (9): 689-701

  Abstract

  The purpose of this statement is to review the literature regarding mitochondrial disease and to provide recommendations for optimal diagnosis and treatment. This statement is intended for physicians who are engaged in diagnosing and treating these patients.The Writing Group members were appointed by the Mitochondrial Medicine Society. The panel included members with expertise in several different areas. The panel members utilized a comprehensive review of the literature, surveys, and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve.Consensus-based recommendations are provided for the diagnosis and treatment of mitochondrial disease.The Delphi process enabled the formation of consensus-based recommendations. We hope that these recommendations will help standardize the evaluation, diagnosis, and care of patients with suspected or demonstrated mitochondrial disease.Genet Med 17 9, 689-701.

  View details for DOI 10.1038/gim.2014.177

  View details for PubMedID 25503498

• Treatment of methylmalonic acidemia by liver or combined liver-kidney transplantation. journal of pediatrics Niemi, A., Kim, I. K., Krueger, C. E., Cowan, T. M., Baugh, N., Farrell, R., Bonham, C. A., Concepcion, W., Esquivel, C. O., Enns, G. M. 2015; 166 (6): 1455-61 e1

  Abstract

  To assess biochemical, surgical, and long-term outcomes of liver (LT) or liver-kidney transplantation (LKT) for severe, early-onset methylmalonic acidemia/acid (MMA).A retrospective chart review (December 1997 to May 2012) of patients with MMA who underwent LT or LKT at Lucile Packard Children's Hospital at Stanford.Fourteen patients underwent LT (n = 6) or LKT (n = 8) at mean age 8.2 years (range 0.8-20.7). Eleven (79%) were diagnosed during the neonatal period, including 6 by newborn screening. All underwent deceased donor transplantation; 12 (86%) received a whole liver graft. Postoperative survival was 100%. At a mean follow-up of 3.25 ± 4.2 years, patient survival was 100%, liver allograft survival 93%, and kidney allograft survival 100%. One patient underwent liver re-transplantation because of hepatic artery thrombosis. After transplantation, there were no episodes of hyperammonemia, acidosis, or metabolic decompensation. The mean serum MMA at the time of transplantation was 1648 ± 1492 μmol/L (normal <0.3, range 99-4420). By 3 days, post-transplantation levels fell on average by 87% (mean 210 ± 154 μmol/L), and at 4 months, they were 83% below pre-transplantation levels (mean 305 ± 108 μmol/L). Developmental delay was present in 12 patients (86%) before transplantation. All patients maintained neurodevelopmental abilities or exhibited improvements in motor skills, learning abilities, and social functioning.LT or LKT for MMA eradicates episodes of hyperammonemia, results in excellent long-term survival, and suggests stabilization of neurocognitive development. Long-term follow-up is underway to evaluate whether patients who undergo early LT need kidney transplantation later in life.

  View details for DOI 10.1016/j.jpeds.2015.01.051

  View details for PubMedID 25771389

• Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway. Genetics in medicine Enns, G. M., Shashi, V., Bainbridge, M., Gambello, M. J., Zahir, F. R., Bast, T., Crimian, R., Schoch, K., Platt, J., Cox, R., Bernstein, J. A., Scavina, M., Walter, R. S., Bibb, A., Jones, M., Hegde, M., Graham, B. H., Need, A. C., Oviedo, A., Schaaf, C. P., Boyle, S., Butte, A. J., Chen, R., Clark, M. J., Haraksingh, R., Cowan, T. M., He, P., Langlois, S., Zoghbi, H. Y., Snyder, M., Gibbs, R. A., Freeze, H. H., Goldstein, D. B. 2014; 16 (10): 751-758

  Abstract

  Purpose:The endoplasmic reticulum-associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent degradation by the proteasome. To define the phenotype associated with a novel inherited disorder of cytosolic endoplasmic reticulum-associated degradation pathway dysfunction, we studied a series of eight patients with deficiency of N-glycanase 1.Methods:Whole-genome, whole-exome, or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data.Results:All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypolacrima or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele.Conclusion:NGLY1 deficiency is a novel autosomal recessive disorder of the endoplasmic reticulum-associated degradation pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a broader range of mutations are detected.Genet Med advance online publication 20 March 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.22.

  View details for DOI 10.1038/gim.2014.22

  View details for PubMedID 24651605

• Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway GENETICS IN MEDICINE Enns, G. M., Shashi, V., Bainbridge, M., Gambello, M. J., Zahir, F. R., Bast, T., Crimian, R., Schoch, K., Platt, J., Cox, R., Bernstein, J. A., Scavina, M., Walter, R. S., Bibb, A., Jones, M., Hegde, M., Graham, B. H., Need, A. C., Oviedo, A., Schaaf, C. P., Boyle, S., Butte, A. J., Chen, R., Clark, M. J., Haraksingh, R., Cowan, T. M., He, P., Langlois, S., Zoghbi, H. Y., Snyder, M., Gibbs, R. A., Freeze, H. H., Goldstein, D. B. 2014; 16 (10): 751-758

  Abstract

  Purpose:The endoplasmic reticulum-associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent degradation by the proteasome. To define the phenotype associated with a novel inherited disorder of cytosolic endoplasmic reticulum-associated degradation pathway dysfunction, we studied a series of eight patients with deficiency of N-glycanase 1.Methods:Whole-genome, whole-exome, or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data.Results:All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypolacrima or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele.Conclusion:NGLY1 deficiency is a novel autosomal recessive disorder of the endoplasmic reticulum-associated degradation pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a broader range of mutations are detected.Genet Med advance online publication 20 March 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.22.

  View details for DOI 10.1038/gim.2014.22

  View details for Web of Science ID 000342884500005

• Degree of Glutathione Deficiency and Redox Imbalance Depend on Subtype of Mitochondrial Disease and Clinical Status PLOS ONE Enns, G. M., Moore, T., Le, A., Atkuri, K., Shah, M. K., Cusmano-Ozog, K., Niemi, A., Cowan, T. M. 2014; 9 (6)

  Abstract

  Mitochondrial disorders are associated with decreased energy production and redox imbalance. Glutathione plays a central role in redox signaling and protecting cells from oxidative damage. In order to understand the consequences of mitochondrial dysfunction on in vivo redox status, and to determine how this varies by mitochondrial disease subtype and clinical severity, we used a sensitive tandem mass spectrometry assay to precisely quantify whole blood reduced (GSH) and oxidized (GSSG) glutathione levels in a large cohort of mitochondrial disorder patients. Glutathione redox potential was calculated using the Nernst equation. Compared to healthy controls (n = 59), mitochondrial disease patients (n = 58) as a group showed significant redox imbalance (redox potential -251 mV ± 9.7, p<0.0001) with an increased level of oxidation by ∼ 9 mV compared to controls (-260 mV ± 6.4). Underlying this abnormality were significantly lower whole blood GSH levels (p = 0.0008) and GSH/GSSG ratio (p = 0.0002), and significantly higher GSSG levels (p<0.0001) in mitochondrial disease patients compared to controls. Redox potential was significantly more oxidized in all mitochondrial disease subgroups including Leigh syndrome (n = 15), electron transport chain abnormalities (n = 10), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (n = 8), mtDNA deletion syndrome (n = 7), mtDNA depletion syndrome (n = 7), and miscellaneous other mitochondrial disorders (n = 11). Patients hospitalized in metabolic crisis (n = 7) showed the greatest degree of redox imbalance at -242 mV ± 7. Peripheral whole blood GSH and GSSG levels are promising biomarkers of mitochondrial dysfunction, and may give insights into the contribution of oxidative stress to the pathophysiology of the various mitochondrial disorders. In particular, evaluation of redox potential may be useful in monitoring of clinical status or response to redox-modulating therapies in clinical trials.

  View details for DOI 10.1371/journal.pone.0100001

  View details for Web of Science ID 000338508200063

  View details for PubMedCentralID PMC4062483

• CORRELATION OF GLUTATHIONE REDOX POTENTIAL WITH MITOCHONDRIAL DISEASE ETIOLOGY AND CLINICAL SEVERITY Enns, G. M., Moore, T., Le, A., Atkuri, K., Shah, M. K., Cusmano-Ozog, K., Nierni, A., Cowan, T. M. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2014: 268

  View details for Web of Science ID 000332500200086

• Degree of glutathione deficiency and redox imbalance depend on subtype of mitochondrial disease and clinical status. PloS one Enns, G. M., Moore, T., Le, A., Atkuri, K., Shah, M. K., Cusmano-Ozog, K., Niemi, A., Cowan, T. M. 2014; 9 (6)

  Abstract

  Mitochondrial disorders are associated with decreased energy production and redox imbalance. Glutathione plays a central role in redox signaling and protecting cells from oxidative damage. In order to understand the consequences of mitochondrial dysfunction on in vivo redox status, and to determine how this varies by mitochondrial disease subtype and clinical severity, we used a sensitive tandem mass spectrometry assay to precisely quantify whole blood reduced (GSH) and oxidized (GSSG) glutathione levels in a large cohort of mitochondrial disorder patients. Glutathione redox potential was calculated using the Nernst equation. Compared to healthy controls (n = 59), mitochondrial disease patients (n = 58) as a group showed significant redox imbalance (redox potential -251 mV ± 9.7, p<0.0001) with an increased level of oxidation by ∼ 9 mV compared to controls (-260 mV ± 6.4). Underlying this abnormality were significantly lower whole blood GSH levels (p = 0.0008) and GSH/GSSG ratio (p = 0.0002), and significantly higher GSSG levels (p<0.0001) in mitochondrial disease patients compared to controls. Redox potential was significantly more oxidized in all mitochondrial disease subgroups including Leigh syndrome (n = 15), electron transport chain abnormalities (n = 10), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (n = 8), mtDNA deletion syndrome (n = 7), mtDNA depletion syndrome (n = 7), and miscellaneous other mitochondrial disorders (n = 11). Patients hospitalized in metabolic crisis (n = 7) showed the greatest degree of redox imbalance at -242 mV ± 7. Peripheral whole blood GSH and GSSG levels are promising biomarkers of mitochondrial dysfunction, and may give insights into the contribution of oxidative stress to the pathophysiology of the various mitochondrial disorders. In particular, evaluation of redox potential may be useful in monitoring of clinical status or response to redox-modulating therapies in clinical trials.

  View details for DOI 10.1371/journal.pone.0100001

  View details for PubMedID 24941115

• A new LC-MS/MS method for the clinical determination of reduced and oxidized glutathione from whole blood. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences Moore, T., Le, A., Niemi, A., Kwan, T., Cusmano-Ozog, K., Enns, G. M., Cowan, T. M. 2013; 929: 51-55

  Abstract

  Reduced levels of glutathione (γ-glutamylcysteinylglycine, GSH) and the ratio of GSH to glutathione disulfide (GSSG) can serve as important indicators of oxidative stress and disease risk. Measured concentrations of GSH and GSSG vary widely between laboratories, largely due to the instability of GSH during sample handling and variables arising from different analytical methods. We have developed a simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for measuring whole blood GSH and GSSG that minimizes preanalytic and analytic variability, reliably eliminates interference from ion suppression, and can easily be implemented in clinical laboratories. Samples were deproteinized with sulfosalicylic acid (SSA) and derivatized with N-ethylmaleimide (NEM) in a single preparative step, and the resulting supernatants combined with stable-isotope internal standards (GSH-(13)C, (15)N-NEM and GSSG-(13)C,(15)N), subjected to chromatographic separation using a Hypercarb column, and analyzed by MS/MS in the positive-ion mode. Results showed excellent linearity for both GSH and GSSG over the ranges of physiologic normal, with inter- and intra-assay CV's of 3.1-4.3% and accuracy between 95% and 101%. The lower limits of detection (LLOD) were 0.4μM for GSH and 0.1μM for GSSG and the lower limits of quantitation (LLOQ) were 1.5μM for GSH and 0.1μM for GSSG. Derivatized samples are stable for at least 3 years when stored at -80°C, and underivatized samples for at least 24h at either 4°C or room temperature. Reference intervals were determined for 59 control samples, and were (mean±SD): GSH 900±140μM; GSSG 1.17±0.43μM; GSH/GSSG 880±370.

  View details for DOI 10.1016/j.jchromb.2013.04.004

  View details for PubMedID 23660247

• Brain uptake of Tc99m-HMPAO correlates with clinical response to the novel redox modulating agent EPI-743 in patients with mitochondrial disease MOLECULAR GENETICS AND METABOLISM Blankenberg, F. G., Kinsman, S. L., Cohen, B. H., Goris, M. L., Spicer, K. M., Perlman, S. L., Krane, E. J., Kheifets, V., Thoolen, M., Miller, G., Enns, G. M. 2012; 107 (4): 690-699

  Abstract

  While decreased ATP production and redox imbalance are central to mitochondrial disease pathogenesis, efforts to develop effective treatments have been hampered by the lack of imaging markers of oxidative stress. In this study we wished to determine if Tc99m-HMPAO, a SPECT imaging marker of cerebral blood flow and glutathione/protein thiol content, could be used to monitor the effect(s) of EPI-743, an oral redox modulating, para-benzoquinone based therapeutic for mitochondrial disease. We hypothesized that treatment changes in HMPAO uptake would be inversely proportional to changes in oxidative stress within the brain and directly correlate to clinical response to EPI-743 therapy. Twenty-two patients with mitochondrial disease were treated with EPI-743. Each underwent baseline and 3-month Tc99m-HMPAO SPECT scanning along with clinical/neurologic evaluations. Diseases treated were: Leigh syndrome (n=7), polymerase γ deficiency (n=5), MELAS (n=5), Friedreich ataxia (n=2), Kearns-Sayre syndrome, Pearson syndrome, and mtDNA depletion syndrome. Neuro-anatomic uptake analyses of HMPAO were performed with NeuroGam™ (Segami Corp.) statistical software and clinical response was assessed by the Newcastle Paediatric Mitochondrial Disease Scale or Newcastle Mitochondrial Disease Adult Scale depending on patient age. For all 22 patients there was a significant linear correlation between the change in cerebellar uptake of HMPAO and the improvement in Newcastle score (r=0.623, **p=0.00161). The MELAS subgroup showed a significant relationship of whole brain uptake (n=5, r=0.917, *p=0.028) to improvement in Newcastle score. We conclude that Tc99m-HMPAO SPECT scanning has promise as a general marker of the oxidative state of the brain and its response to redox modulating therapies. Further studies will be needed to confirm these findings in a more homogenous study population.

  View details for DOI 10.1016/j.ymgme.2012.09.023

  View details for Web of Science ID 000311816200010

  View details for PubMedID 23084792

• Leigh syndrome caused by a novel m.4296G > A mutation in mitochondrial tRNA isoleucine MITOCHONDRION Cox, R., Platt, J., Chen, L. C., Tang, S., Wong, L., Enns, G. M. 2012; 12 (2): 258-261

  Abstract

  Leigh syndrome is a severe neurodegenerative disease with heterogeneous genetic etiology. We report a novel m.4296G>A variant in the mitochondrial tRNA isoleucine gene in a child with Leigh syndrome, mitochondrial proliferation, lactic acidosis, and abnormal respiratory chain enzymology. The variant is present at >75% heteroplasmy in blood and cultured fibroblasts from the proband, <5% in asymptomatic maternal relatives, and is absent in 3000 controls. It is located in the highly conserved anticodon region of tRNA(Ile) where three other pathogenic changes have been described. We conclude that there is strong evidence to classify m.4296G>A as a pathogenic mutation causing Leigh syndrome.

  View details for DOI 10.1016/j.mito.2011.09.006

  View details for Web of Science ID 000301906600011

  View details for PubMedID 21982779

• Initial experience in the treatment of inherited mitochondrial disease with EPI-743 MOLECULAR GENETICS AND METABOLISM Enns, G. M., Kinsman, S. L., Perlman, S. L., Spicer, K. M., Abdenur, J. E., Cohen, B. H., Amagata, A., Barnes, A., Kheifets, V., Shrader, W. D., Thoolen, M., Blankenberg, F., Miller, G. 2012; 105 (1): 91-102

  Abstract

  Inherited mitochondrial respiratory chain disorders are progressive, life-threatening conditions for which there are limited supportive treatment options and no approved drugs. Because of this unmet medical need, as well as the implication of mitochondrial dysfunction as a contributor to more common age-related and neurodegenerative disorders, mitochondrial diseases represent an important therapeutic target. Thirteen children and one adult with genetically-confirmed mitochondrial disease (polymerase γ deficiency, n=4; Leigh syndrome, n=4; MELAS, n=3; mtDNA deletion syndrome, n=2; Friedreich ataxia, n=1) at risk for progressing to end-of-life care within 90 days were treated with EPI-743, a novel para-benzoquinone therapeutic, in a subject controlled, open-label study. Serial measures of safety and efficacy were obtained that included biochemical, neurological, quality-of-life, and brain redox assessments using technetium-99m-hexamethylpropyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) radionuclide imaging. Twelve patients treated with EPI-743 have survived; one polymerase γ deficiency patient died after developing pneumonia and one patient with Surf-1 deficiency died after completion of the protocol. Of the 12 survivors, 11 demonstrated clinical improvement, with 3 showing partial relapse, and 10 of the survivors also had an improvement in quality-of-life scores at the end of the 13-week emergency treatment protocol. HMPAO SPECT scans correlated with clinical response; increased regional and whole brain HMPAO uptake was noted in the clinical responders and the one subject who did not respond clinically had decreased regional and whole brain HMPAO uptake. EPI-743 has modified disease progression in >90% of patients in this open-label study as assessed by clinical, quality-of-life, and non-invasive brain imaging parameters. Data obtained herein suggest that EPI-743 may represent a new drug for the treatment of inherited mitochondrial respiratory chain disorders. Prospective controlled trials will be undertaken to substantiate these initial promising observations. Furthermore, HMPAO SPECT imaging may be a valuable tool for the detection of central nervous system redox defects and for monitoring response to treatments directed at modulating abnormal redox.

  View details for DOI 10.1016/j.ymgme.2011.10.009

  View details for PubMedID 22115768

• High-quality DNA sequence capture of 524 disease candidate genes PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Shen, P., Wang, W., Krishnakumar, S., Palm, C., Chi, A., Enns, G. M., Davis, R. W., Speed, T. P., Mindrinos, M. N., Scharfe, C. 2011; 108 (16): 6549-6554

  Abstract

  The accurate and complete selection of candidate genomic regions from a DNA sample before sequencing is critical in molecular diagnostics. Several recently developed technologies await substantial improvements in performance, cost, and multiplex sample processing. Here we present the utility of long padlock probes (LPPs) for targeted exon capture followed by array-based sequencing. We found that on average 92% of 5,471 exons from 524 nuclear-encoded mitochondrial genes were successfully amplified from genomic DNA from 63 individuals. Only 144 exons did not amplify in any sample due to high GC content. One LPP was sufficient to capture sequences from <100-500 bp in length and only a single-tube capture reaction and one microarray was required per sample. Our approach was highly reproducible and quick (<8 h) and detected DNA variants at high accuracy (false discovery rate 1%, false negative rate 3%) on the basis of known sample SNPs and Sanger sequence verification. In a patient with clinical and biochemical presentation of ornithine transcarbamylase (OTC) deficiency, we identified copy-number differences in the OTC gene at exon-level resolution. This shows the ability of LPPs to accurately preserve a sample's genome information and provides a cost-effective strategy to identify both single nucleotide changes and structural variants in targeted resequencing.

  View details for DOI 10.1073/pnas.1018981108

  View details for PubMedID 21467225

• Novel Deoxyguanosine Kinase Gene Mutations and Viral Infection Predispose Apparently Healthy Children to Fulminant Liver Failure JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Shieh, J. T., Berquist, W. E., Zhang, Q., Chou, P., Wong, L. C., Enns, G. M. 2009; 49 (1): 130-132

  View details for PubMedID 19502998

• Mapping Gene Associations in Human Mitochondria using Clinical Disease Phenotypes PLOS COMPUTATIONAL BIOLOGY Scharfe, C., Lu, H. H., Neuenburg, J. K., Allen, E. A., Li, G., Klopstock, T., Cowan, T. M., Enns, G. M., Davis, R. W. 2009; 5 (4)

  Abstract

  Nuclear genes encode most mitochondrial proteins, and their mutations cause diverse and debilitating clinical disorders. To date, 1,200 of these mitochondrial genes have been recorded, while no standardized catalog exists of the associated clinical phenotypes. Such a catalog would be useful to develop methods to analyze human phenotypic data, to determine genotype-phenotype relations among many genes and diseases, and to support the clinical diagnosis of mitochondrial disorders. Here we establish a clinical phenotype catalog of 174 mitochondrial disease genes and study associations of diseases and genes. Phenotypic features such as clinical signs and symptoms were manually annotated from full-text medical articles and classified based on the hierarchical MeSH ontology. This classification of phenotypic features of each gene allowed for the comparison of diseases between different genes. In turn, we were then able to measure the phenotypic associations of disease genes for which we calculated a quantitative value that is based on their shared phenotypic features. The results showed that genes sharing more similar phenotypes have a stronger tendency for functional interactions, proving the usefulness of phenotype similarity values in disease gene network analysis. We then constructed a functional network of mitochondrial genes and discovered a higher connectivity for non-disease than for disease genes, and a tendency of disease genes to interact with each other. Utilizing these differences, we propose 168 candidate genes that resemble the characteristic interaction patterns of mitochondrial disease genes. Through their network associations, the candidates are further prioritized for the study of specific disorders such as optic neuropathies and Parkinson disease. Most mitochondrial disease phenotypes involve several clinical categories including neurologic, metabolic, and gastrointestinal disorders, which might indicate the effects of gene defects within the mitochondrial system. The accompanying knowledgebase (http://www.mitophenome.org/) supports the study of clinical diseases and associated genes.

  View details for DOI 10.1371/journal.pcbi.1000374

  View details for PubMedID 19390613

• Inherited disorders affecting mitochondrial function are associated with glutathione deficiency and hypocitrullinemia PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Atkuri, K. R., Cowan, T. M., Kwan, T., Ng, A., Herzenberg, L. A., Herzenberg, L. A., Enns, G. M. 2009; 106 (10): 3941-3945

  Abstract

  Disorders affecting mitochondria, including those that directly affect the respiratory chain function or result from abnormalities in branched amino acid metabolism (organic acidemias), have been shown to be associated with impaired redox balance. Almost all of the evidence underlying this conclusion has been obtained from studies on patient biopsies or animal models. Since the glutathione (iGSH) system provides the main protection against oxidative damage, we hypothesized that untreated oxidative stress in individuals with mitochondrial dysfunction would result in chronic iGSH deficiency. We confirm this hypothesis here in studies using high-dimensional flow cytometry (Hi-D FACS) and biochemical analysis of freshly obtained blood samples from patients with mitochondrial disorders or organic acidemias. T lymphocyte subsets, monocytes and neutrophils from organic acidemia and mitochondrial patients who were not on antioxidant supplements showed low iGSH levels, whereas similar subjects on antioxidant supplements showed normal iGSH. Measures of iROS levels in blood were insufficient to reveal the chronic oxidative stress in untreated patients. Patients with organic acidemias showed elevated plasma protein carbonyls, while plasma samples from all patients tested showed hypocitrullinemia. These findings indicate that measurements of iGSH in leukocytes may be a particularly useful biomarker to detect redox imbalance in mitochondrial disorders and organic acidemias, thus providing a relatively non-invasive means to monitor disease status and response to therapies. Furthermore, studies here suggest that antioxidant therapy may be useful for relieving the chronic oxidative stress that otherwise occurs in patients with mitochondrial dysfunction.

  View details for DOI 10.1073/pnas.0813409106

  View details for PubMedID 19223582

• Survival after treatment with phenylacetate and benzoate for urea-cycle disorders NEW ENGLAND JOURNAL OF MEDICINE Enns, G. M., Berry, S. A., Berry, G. T., Rhead, W. J., Brusilow, S. W., Hamosh, A. 2007; 356 (22): 2282-2292

  Abstract

  The combination of intravenous sodium phenylacetate and sodium benzoate has been shown to lower plasma ammonium levels and improve survival in small cohorts of patients with historically lethal urea-cycle enzyme defects.We report the results of a 25-year, open-label, uncontrolled study of sodium phenylacetate and sodium benzoate therapy (Ammonul, Ucyclyd Pharma) in 299 patients with urea-cycle disorders in whom there were 1181 episodes of acute hyperammonemia.Overall survival was 84% (250 of 299 patients). Ninety-six percent of the patients survived episodes of hyperammonemia (1132 of 1181 episodes). Patients over 30 days of age were more likely than neonates to survive an episode (98% vs. 73%, P<0.001). Patients 12 or more years of age (93 patients), who had 437 episodes, were more likely than all younger patients to survive (99%, P<0.001). Eighty-one percent of patients who were comatose at admission survived. Patients less than 30 days of age with a peak ammonium level above 1000 micromol per liter (1804 microg per deciliter) were least likely to survive a hyperammonemic episode (38%, P<0.001). Dialysis was also used in 56 neonates during 60% of episodes and in 80 patients 30 days of age or older during 7% of episodes.Prompt recognition of a urea-cycle disorder and treatment with both sodium phenylacetate and sodium benzoate, in conjunction with other therapies, such as intravenous arginine hydrochloride and the provision of adequate calories to prevent catabolism, effectively lower plasma ammonium levels and result in survival in the majority of patients. Hemodialysis may also be needed to control hyperammonemia, especially in neonates and older patients who do not have a response to intravenous sodium phenylacetate and sodium benzoate.

  View details for PubMedID 17538087

• Molecular-clinical correlations in a family with variable tissue mitochondrial DNA T8993G mutant load MOLECULAR GENETICS AND METABOLISM Enns, G. M., Bai, R., Beck, A. E., Wong, L. 2006; 88 (4): 364-371

  Abstract

  Unlike many pathogenic mitochondrial DNA mutations, the T8993G mutation associated with Leigh syndrome (LS) and neurogenic muscle weakness, ataxia, retinitis pigmentosa (NARP) typically shows little variation in mutant load between different tissue types. We describe the molecular and clinical findings in a family with variable disease severity and tissue T8993G mutant loads. Real-time ARMS qPCR testing showed that two brothers with features of NARP and LS had high mutant loads (>90%) in all tissues tested, similar to previously reported cases. Their sister, who has mild speech delay but attends normal school, was found to have a relatively high mutant load (mean 93%) in tissues derived from endoderm (buccal mucosa) and mesoderm (blood and skin fibroblasts). However, in tissue derived from ectoderm (hair bulbs), she carried a considerably lower proportion of mutant mtDNA. Because both surface ectoderm, which gives rise to outer epithelia and hair, and neuroectoderm, which gives rise to the central nervous system, are derived from ectoderm, it is tempting to speculate that the mutant load detected in the oligosymptomatic sister's hair bulbs is a reflection of the brain mutant load. We conclude that significant variation in tissue mutant load may occur in at least some individuals that harbor the T8993G mutation. This adds additional complexity to genetic counseling and prenatal diagnosis in such instances. Given the shared embryonic origin of hair bulbs and brain, we recommend performing hair bulb mtDNA analysis in asymptomatic or oligosymptomatic individuals that have high blood mutant loads in order to understand better the genotype-phenotype correlations related to the T8993G mutation.

  View details for DOI 10.1016/j.ymgme.2006.02.001

  View details for PubMedID 16546428

• Relationship of primary mitochondrial respiratory chain dysfunction to fiber type abnormalities in skeletal muscle CLINICAL GENETICS Enns, G. M., Hoppel, C. L., DeArmond, S. J., Schelley, S., Bass, N., Weisiger, K., Horoupian, D., Packman, S. 2005; 68 (4): 337-348

  Abstract

  Variation in the size and relative proportion of type 1 and type 2 muscle fibers can occur in a number of conditions, including structural myopathies, neuropathies, and various syndromes. In most cases, the pathogenesis of such fiber type changes is unknown and the etiology is heterogeneous. Skeletal muscle mitochondrial respiratory chain analysis was performed in 10 children aged 3 weeks to 5 years with abnormalities in muscle fiber type, size, and proportion. Five children were classified as having definite, four as probable, and one as possible mitochondrial disease. Type 1 fiber predominance was the most common histological finding (six of 10). On light microscopy, four cases had subtle concomitants of a mitochondriopathy, including mildly increased glycogen, lipid, and/or succinate dehydrogenase staining, and one case had more prominent evidence of underlying mitochondrial disease with marked subsarcolemmal staining. Most cases (nine of 10) had abnormal mitochondrial morphology on electron microscopy. All were found to have mitochondrial electron transport chain (ETC) abnormalities and met diagnostic criteria for mitochondrial disease. We did not ascertain any patients who had isolated fiber type abnormalities and normal respiratory chain analysis during the period of study. We conclude that mitochondrial ETC disorders may represent an etiology of at least a subset of muscle fiber type abnormalities. To establish an etiologic diagnosis and to determine the frequency of such changes in mitochondrial disease, we suggest analysis of ETC function in individuals with fiber type changes in skeletal muscle, even in the absence of light histological features suggestive of mitochondrial disorders.

  View details for DOI 10.1111/j.1399-0004.2005.00499.x

  View details for Web of Science ID 000231621900008

  View details for PubMedID 16143021

• The contribution of mitochondria to common disorders MOLECULAR GENETICS AND METABOLISM Enns, G. M. 2003; 80 (1-2): 11-26

  Abstract

  Mitochondrial dysfunction secondary to mitochondrial and nuclear DNA mutations has been associated with energy deficiency in multiple organ systems and a variety of severe, often fatal, clinical syndromes. Although the production of energy is indeed the primary function of mitochondria, attention has also been directed toward their role producing reactive oxygen and nitrogen species and the subsequent widespread deleterious effects of these intermediates. The generation of toxic reactive intermediates has been implicated in a number of relatively common disorders, including neurodegenerative diseases, diabetes, and cancer. Understanding the role mitochondrial dysfunction plays in the pathogenesis of common disorders has provided unique insights into a number of diseases and offers hope for potential new therapies.

  View details for DOI 10.1016/j.ymgme.2003.08.009

  View details for PubMedID 14567954

• Mitochondrial respiratory chain complex I deficiency with clinical and biochemical features of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency JOURNAL OF PEDIATRICS Enns, G. M., Bennett, M. J., Hoppel, C. L., Goodman, S. I., Weisiger, K., Ohnstad, C., Golabi, M., Packman, S. 2000; 136 (2): 251-254

  Abstract

  The mitochondrial respiratory chain and the fatty acid oxidation cycle are theoretically interdependent on each other for normal function. We describe a patient with complex I deficiency who had clinical and biochemical features of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency including liver failure, cardiomyopathy, and consistent urine organic acid pattern. Patients with features of either a respiratory chain or fatty acid oxidation disorder should have the defect characterized biochemically because of the implications with respect to potential therapy and genetic counseling.

  View details for Web of Science ID 000085289400026

  View details for PubMedID 10657835

• Newborn Screening for X-Linked Adrenoleukodystrophy (X-ALD): Biochemical, Molecular, and Clinical Characteristics of Other Genetic Conditions. Genes Mares Beltran, C. F., Tise, C. G., Barrick, R., Niehaus, A. D., Sponberg, R., Chang, R., Enns, G. M., Abdenur, J. E. 2024; 15 (7)

  Abstract

  The state of California (CA) added X-linked adrenoleukodystrophy (X-ALD) to newborn screening (NBS) in 2016 via the measurement of C26:0-lysophosphatidylcholine (C26:0-LPC) in a two-tier fashion, followed by sequencing of the ABCD1 gene. This has resulted in the identification of individuals with genetic conditions beyond X-ALD that can also result in elevated C26:0-LPC by NBS. We describe the biochemical, molecular, and clinical characteristics of nine patients from two metabolic centers in California who screened positive by NBS for elevated C26:0-LPC between 2016 and 2022 and were ultimately diagnosed with a genetic condition other than X-ALD. Seven individuals were diagnosed with Zellweger spectrum disorder (ZSD) due to biallelic variants in PEX genes. One male was diagnosed with Klinefelter syndrome and one female was found to have an X chromosome contiguous gene deletion syndrome after the identification of a heterozygous VUS and hemizygous VUS variant in ABCD1, respectively. Patients with ZSD had significantly higher first- and second-tier C26:0-LPC levels compared to the two non-ZSD cases. Identification of children with ZSD and atypical patterns of ABCD1 variants is a secondary benefit of NBS for X-ALD, leading to earlier diagnosis, prompt therapeutic initiation, and more accurate genetic counseling. As screening for X-ALD continues via the measurement of C26:0-LPC, our knowledge of additional genetic conditions associated with elevated C26:0-LPC will continue to advance, allowing for increased recognition of other genetic disorders for which early intervention is warranted.

  View details for DOI 10.3390/genes15070838

  View details for PubMedID 39062617

  View details for PubMedCentralID PMC11275617

• Cardiac transplantation in pediatric patients with inborn errors of metabolism: Outcomes from a single center Null, E., Tolani, D., Rosenthal, D. N., Enns, G. M. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2024

  View details for DOI 10.1016/j.ymgme.2024.108237

  View details for Web of Science ID 001300271800084

• High prevalence of hepatic fibrosis in liver tissue from individuals with argininosuccinate lyase deficiency Burrage, L., Ali, S., Nisar, A., Quan, T., Aceves, N., Shneider, B., Leung, D., Nagamani, S., Enns, G., Jain, S., Goss, J., Hazard, F., Schady, D. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2024

  View details for DOI 10.1016/j.ymgme.2024.108172

  View details for Web of Science ID 001300271800020

• Characteristics and management of US pediatric patients with Gaucher disease from the Gaucher Outcome Survey Goker-Alpan, O., Burrow, A., Enns, G. M., Ficicioglu, C., Kishnani, P. S., Ortiz, D., Prada, C. E., Vats, D., Weinreb, N. J., Robinson, I., Pathak, R. R., Wright, E., Botha, J., Wilcox, W. R. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2024

  View details for DOI 10.1016/j.ymgme.2023.107854

  View details for Web of Science ID 001192169300116

• Specifications of the ACMG/AMP guidelines for ACADVL variant interpretation. Molecular genetics and metabolism Flowers, M., Dickson, A., Miller, M. J., Spector, E., Enns, G. M., Baudet, H., Pasquali, M., Racacho, L., Sadre-Bazzaz, K., Wen, T., Fogarty, M., Fernandez, R., Weaver, M. A., Feigenbaum, A., Graham, B. H., Mao, R. 2023; 140 (3): 107668

  Abstract

  Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is a relatively common inborn error of metabolism, but due to difficulty in accurately predicting affected status through newborn screening, molecular confirmation of the causative variants by sequencing of the ACADVL gene is necessary. Although the ACMG/AMP guidelines have helped standardize variant classification, ACADVL variant classification remains disparate due to a phenotype that can be nonspecific, the possibility of variants that produce late-onset disease, and relatively high carrier frequency, amongst other challenges. Therefore, an ACADVL-specific variant curation expert panel (VCEP) was created to facilitate the specification of the ACMG/AMP guidelines for VLCADD. We expect these guidelines to help streamline, increase concordance, and expedite the classification of ACADVL variants.

  View details for DOI 10.1016/j.ymgme.2023.107668

  View details for PubMedID 37549443

• Contributions from medical geneticists in clinical trials of genetic therapies: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG). Genetics in medicine : official journal of the American College of Medical Genetics Peña, L. D., Burrage, L. C., Enns, G. M., Esplin, E. D., Harding, C., Mendell, J. R., Niu, Z. N., Scharfe, C., Yu, T., Koeberl, D. D. 2023: 100831

  View details for DOI 10.1016/j.gim.2023.100831

  View details for PubMedID 37031408

• A Phase 1 Study of Oral Vitamin D3 in Boys and Young Men With X-Linked Adrenoleukodystrophy. Neurology. Genetics Van Haren, K. P., Cunanan, K., Awani, A., Gu, M., Peña, D., Chromik, L. C., Považan, M., Rossi, N. C., Goodman, J., Sundaram, V., Winterbottom, J., Raymond, G. V., Cowan, T., Enns, G. M., Waubant, E., Steinman, L., Barker, P. B., Spielman, D., Fatemi, A. 2023; 9 (2): e200061

  Abstract

  There are no therapies for preventing cerebral demyelination in X-linked adrenoleukodystrophy (ALD). Higher plasma vitamin D levels have been linked to lower risk of inflammatory brain lesions. We assessed the safety and pharmacokinetics of oral vitamin D dosing regimens in boys and young men with ALD.In this open-label, multicenter, phase 1 study, we recruited boys and young men with ALD without brain lesions to a 12-month study of daily oral vitamin D3 supplementation. Our primary outcome was attainment of plasma 25-hydroxyvitamin D levels in target range (40-80 ng/mL) at 6 and 12 months. Secondary outcomes included safety and glutathione levels in the brain, measured with magnetic resonance spectroscopy, and blood, measured via mass spectrometry. Participants were initially assigned to a fixed dosing regimen starting at 2,000 IU daily, regardless of weight. After a midstudy safety assessment, we modified the dosing regimen, so all subsequent participants were assigned to a weight-stratified dosing regimen starting as low as 1,000 IU daily.Between October 2016 and June 2019, we enrolled 21 participants (n = 12, fixed-dose regimen; n = 9, weight-stratified regimen) with a median age of 6.7 years (range: 1.9-22 years) and median weight of 20 kg (range: 11.7-85.5 kg). The number of participants achieving target vitamin D levels was similar in both groups at 6 months (fixed dose: 92%; weight stratified: 78%) and 12 months (fixed dose: 67%; weight stratified: 67%). Among the 12 participants in the fixed-dose regimen, half had asymptomatic elevations in either urine calcium:creatinine or plasma 25-hydroxyvitamin D; no laboratory deviations occurred with the weight-stratified regimen. Glutathione levels in the brain, but not the blood, increased significantly between baseline and 12 months.Our vitamin D dosing regimens were well tolerated and achieved target 25-hydroxyvitamin D levels in most participants. Brain glutathione levels warrant further study as a biomarker for vitamin D and ALD.This study provides Class IV evidence that fixed or weight-stratified vitamin D supplementation achieved target levels of 25-hydroxyvitamin D in boys and young men with X-ALD without brain lesions.

  View details for DOI 10.1212/NXG.0000000000200061

  View details for PubMedID 37090939

  View details for PubMedCentralID PMC10117697

• MT-ATP6 mitochondrial disease identified by newborn screening reveals a distinct biochemical phenotype. American journal of medical genetics. Part A Tise, C. G., Verscaj, C. P., Mendelsohn, B. A., Woods, J., Lee, C. U., Enns, G. M., Stander, Z., Hall, P. L., Cowan, T. M., Cusmano-Ozog, K. P. 2023

  Abstract

  Although decreased citrulline is used as a newborn screening (NBS) marker to identify proximal urea cycle disorders (UCDs), it is also a feature of some mitochondrial diseases, including MT-ATP6 mitochondrial disease. Here we describe biochemical and clinical features of 11 children born to eight mothers from seven separate families who were identified with low citrulline by NBS (range 3-5muM; screening cutoff >5) and ultimately diagnosed with MT-ATP6 mitochondrial disease. Follow-up testing revealed a pattern of hypocitrullinemia together with elevated propionyl-(C3) and 3-hydroxyisovaleryl-(C5-OH) acylcarnitines, and a homoplasmic pathogenic variant in MT-ATP6 in all cases. Single and multivariate analysis of NBS data from the 11 cases using Collaborative Laboratory Integrated Reports (CLIR; https://clir.mayo.edu) demonstrated citrulline <1st percentile, C3>50th percentile, and C5-OH >90th percentile when compared with reference data, as well as unequivocal separation from proximal UCD cases and false-positive low citrulline cases using dual scatter plots. Five of the eight mothers were symptomatic at the time of their child(ren)'s diagnosis, and all mothers and maternal grandmothers evaluated molecularly and biochemically had a homoplasmic pathogenic variant in MT-ATP6, low citrulline, elevated C3, and/or elevated C5-OH. All molecularly confirmed individuals (n=17) with either no symptoms (n=12), migraines (n=1), or a neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) phenotype (n=3) were found to have an A or U mitochondrial haplogroup, while one child with infantile-lethal Leigh syndrome had a B haplogroup.

  View details for DOI 10.1002/ajmg.a.63159

  View details for PubMedID 36883293

• Outcomes after liver transplantation in MPV17 deficiency: A rebuttal. Pediatric transplantation Huang, A. C., Ebel, N. H., Romero, D., Enns, G. M., Esquivel, C. O., Bonham, C. 2023: e14472

  View details for DOI 10.1111/petr.14472

  View details for PubMedID 36872458

• BIOCHEMICAL, MOLECULAR, AND CLINICAL CHARACTERISTICS OF PEROXISOMAL DISORDERS DETECTED BY CALIFORNIA NEWBORN SCREENING (NBS) PROGRAM Beltran, C., Abdenur, J., Chang, R., Barrick, R., Spongberg, R., Tise, C. G., Niehaus, A. D., Enns, G. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2023: 72

  View details for DOI 10.1016/j.ymgme.2023.107455

  View details for Web of Science ID 001175367500082

• Validation of a targeted metabolomics panel for improved second-tier newborn screening. Journal of inherited metabolic disease Mak, J., Peng, G., Le, A., Gandotra, N., Enns, G. M., Scharfe, C., Cowan, T. M. 2023

  Abstract

  Improved second-tier assays are needed to reduce the number of false positives in newborn screening (NBS) for inherited metabolic disorders including those on the Recommended Uniform Screening Panel (RUSP). We developed an expanded metabolite panel for second-tier testing of dried blood spot (DBS) samples from screen-positive cases reported by the California NBS program, consisting of true- and false-positives from four disorders: glutaric acidemia type 1 (GA1), methylmalonic acidemia (MMA), ornithine transcarbamylase deficiency (OTCD), and very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). This panel was assembled from known disease markers and new features discovered by untargeted metabolomics and applied to second-tier analysis of single DBS punches using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in a 3-min run. Additionally, we trained a Random Forest (RF) machine learning classifier to improve separation of true- and false positive cases. Targeted metabolomic analysis of 121 analytes from DBS extracts in combination with RF classification at a sensitivity of 100% reduced false positives for GA1 by 83%, MMA by 84%, OTCD by 100%, and VLCADD by 51%. This performance was driven by a combination of known disease markers (3-hydroxyglutaric acid, methylmalonic acid, citrulline, C14:1), other amino acids and acylcarnitines, and novel metabolites identified to be isobaric to several long-chain acylcarnitine and hydroxy-acylcarnitine species. These findings establish the effectiveness of this second-tier test to improve screening for these four conditions and demonstrate the utility of supervised machine learning in reducing false-positives for conditions lacking clearly discriminating markers, with future studies aimed at optimizing and expanding the panel to additional disease targets. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jimd.12591

  View details for PubMedID 36680545

• Fractionated plasma N-glycan profiling of novel cohort of ATP6AP1-CDG subjects identifies phenotypic association. Journal of inherited metabolic disease Alharbi, H., Daniel, E. J., Thies, J., Chang, I., Goldner, D. L., Ng, B. G., Witters, P., Aqul, A., Velez-Bartolomei, F., Enns, G. M., Hsu, E., Kichula, E., Lee, E., Lourenco, C., Poskanzer, S. A., Rasmussen, S., Saarela, K., Wang, Y. M., Raymond, K. M., Schultz, M. J., Freeze, H. H., Lam, C., Edmondson, A. C., He, M. 2023

  Abstract

  ATP6AP1-CDG is an X-linked disorder typically characterized by hepatopathy, immunodeficiency and an abnormal type II transferrin glycosylation pattern. Here, we present eleven new patients and clinical updates with biochemical characterization on one previously reported patient. We also document intrafamilial phenotypic variability and atypical presentations, expanding the symptomatology of ATP6AP1-CDG to include dystonia, hepatocellular carcinoma and lysosomal abnormalities on hepatic histology. Three of our subjects received successful liver transplantation. We performed N-glycan profiling of total and fractionated plasma proteins for six patients and show associations with varying phenotypes, demonstrating potential diagnostic and prognostic value of fractionated N-glycan profiles. The aberrant N-linked glycosylation in purified transferrin and remaining plasma glycoprotein fractions normalized in one patient post hepatic transplant, while the increases of Man4GlcNAc2 and Man5GlcNAc2 in purified immunoglobulins persisted. Interestingly, in the single patient with isolated immune deficiency phenotype, elevated high-mannose glycans were detected on purified immunoglobulins without glycosylation abnormalities on transferrin or the remaining plasma glycoprotein fractions. Given the diverse and often tissue specific clinical presentations and the need of clinical management post hepatic transplant in ATP6AP1-CDG patients, these results demonstrate that fractionated plasma N-glycan profiling could be a valuable tool in diagnosis and disease monitoring. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jimd.12589

  View details for PubMedID 36651831

• Outcomes after liver transplantation in MPV17 deficiency (Navajo neurohepatopathy): A single-center case series. Pediatric transplantation Huang, A. C., Ebel, N. H., Romero, D., Martin, B., Jhun, I., Brown, M., Enns, G. M., Esquivel, C., Bonham, C. 2022: e14274

  Abstract

  BACKGROUND: MPV17-related mitochondrial DNA maintenance defect (MPV17 deficiency) is a rare, autosomal recessive mitochondrial DNA depletion syndrome with a high mortality rate in infancy and early childhood due to progression to liver failure. Liver transplantation for children with MPV17 deficiency has been considered controversial due to uncertainty about the potential progression of extrahepatic manifestations following liver transplantation.METHODS: We describe our institution's experience for two infants diagnosed with infantile MPV17 deficiency who presented in acute on chronic liver failure, but with normal development and normal neurological status who successfully underwent liver transplantation.RESULTS: Both patients underwent successful liver transplantation with normal development and neurological status at 3years and 16months post-transplant, respectively.CONCLUSIONS: In this rare disease population, we describe two infants with MPV17 deficiency who underwent liver transplantation for acute on chronic liver failure who continue to have normal development, without progression of neurological disease. MPV17 deficiency should not be considered a contraindication to liver transplantation.

  View details for DOI 10.1111/petr.14274

  View details for PubMedID 35466509

• Response to triheptanoin therapy in critically ill patients with LC-FAOD: Report of patients treated through an expanded access program. Molecular genetics and metabolism Vockley, J., Enns, G. M., Ramirez, A. N., Bedrosian, C. L., Reineking, B., Lu, X., Ray, K., Rahman, S., Marsden, D. 2022

  Abstract

  Long-chain fatty acid oxidation disorders (LC-FAOD) are a group of inborn errors of metabolism wherein patients are unable to process long-chain fatty acids into useable energy in the mitochondria. LC-FAOD commonly affects organ systems with high energy demand, manifesting as hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy, rhabdomyolysis, and skeletal myopathy, as well as peripheral neuropathy and retinopathy in some subtypes. Collectively, LC-FAOD have a high mortality rate, especially in cases of early onset disease, and in the presence of cardiomyopathy. Triheptanoin is a synthetic medium-odd chain triglyceride, produced using a GMP-compliant process, which was designed to replenish mitochondrial metabolic deficits and restore energy homeostasis. Prior to its approval, triheptanoin was only available through clinical trials or to seriously ill patients as part of an expanded access program (EAP) following physician request. This retrospective study examined the impact of triheptanoin on cardiovascular parameters, in critically ill patients who participated in the EAP from February 2013 to January 2018. These patients persisted in critical condition despite receiving standard treatment in highly qualified centers by expert metabolic physicians and dietitians. Physician-completed questionnaires and narrative summaries were used to evaluate the disease presentation and management prior to the trigger event leading to triheptanoin request and use, and the response to triheptanoin treatment. Following triheptanoin initiation, most patients survived the initial trigger event (e.g., severe urinary tract infection, pneumonia) and demonstrated improvements in both short-term and long-term LC-FAOD manifestations. In patients with cardiomyopathy, stabilization or improvement from pretreatment levels was reported in left ventricular ejection fraction and left ventricular mass, in particular, all infants with cardiomyopathy showed improvement in cardiac function during triheptanoin therapy. Triheptanoin therapy was generally well tolerated. The study results are consistent with the existing positive benefit/risk profile of triheptanoin and reflect the effect of triheptanoin improving cardiac function in patients experiencing severe episodes of metabolic decompensation despite standard therapy.

  View details for DOI 10.1016/j.ymgme.2022.04.001

  View details for PubMedID 35459555

• SUCCESSFUL CARDIAC TRANSPLANTATION AND LONG-TERM FOLLOW-UP IN DNAJC19-ASSOCIATED DILATED CARDIOMYOPATHY WITH ATAXIA Tahata, S., Tise, C., Floyd, B., Cusmano-Ozog, K., Ruzhnikov, M., Enns, G. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2022: 302

  View details for Web of Science ID 000772339900104

• PEGZILARGINASE IN ARGINASE 1 DEFICIENCY: RESULTS OF THE PEACE PIVOTAL PHASE 3 CLINICAL TRIAL Enns, G. M., Russo, R., Bradford, E., Bubb, G., Sloan, L. S., Gasperini, S., Diaz, G. A. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2022: 269

  View details for Web of Science ID 000772339900048

• NEUROIMAGING FINDINGS IN INBORN ERRORS OF METABOLISM: ATYPICAL FINDINGS FROM FIVE CASES AFFECTED BY SMALL MOLECULE DISORDERS Morales, J., Dahmoush, H., Enns, G. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2022: 251-252

  View details for Web of Science ID 000772339900017

• Biochem for the Win! The added value of biochemical genetic testing for diagnosis and variant interpretation in the genomic era Tise, C., Grand, K., Corado, J., Gates, R., Graham, J., Enns, G., Gomez-Ospina, N., Mak, J., Cowan, T., Cusmano-Ozog, K. ELSEVIER SCIENCE INC. 2022: S24

  View details for DOI 10.1016/j.gim.2022.01.075

  View details for Web of Science ID 000788465500037

• Clinical characterization of a new individual with mild SC4MOL deficiency: diagnostic and therapeutic implications JOURNAL OF TRANSLATIONAL GENETICS AND GENOMICS Morales, J., Curry, C. J., Tise, C. G., Kratz, L., Enns, G. M. 2022; 6 (2): 257-265

  View details for DOI 10.20517/jtgg.2022.01

  View details for Web of Science ID 001208119200008

• Variable clinical severity in TANGO2 deficiency: Case series and literature review. American journal of medical genetics. Part A Schymick, J., Leahy, P., Cowan, T., Ruzhnikov, M. R., Gates, R., Fernandez, L., Pramanik, G., Undiagnosed Diseases Network, Yarlagadda, V., Wheeler, M., Bernstein, J. A., Enns, G. M., Lee, C. 2021

  Abstract

  Biallelic pathogenic variants in the TANGO2 (transport and Golgi organization 2 homolog) gene have been identified as causing a rare metabolic disorder characterized by susceptibility to recurrent rhabdomyolysis, lactic acidosis, encephalopathy, and life-threatening tachyarrhythmias. Recently published reports suggest variable clinical severity and phenotypes. This study details five new patients from two families with biallelic pathogenic variants in the TANGO2 gene identified by whole exome sequencing and includes the largest number of affected individuals from a single family reported to date. We document significant intrafamilial variability and highlight that milder phenotypes may be underrecognized. We present biochemical and clinical data to help highlight the features that aid in consideration of this condition in the differential with disorders of fatty acid oxidation. We also present a comprehensive literature review summarizing the molecular, clinical, and biochemical findings for 92 individuals across 13 publications. Of the 27 pathogenic variants reported to date, the recurrent exons 3-9 deletion represents the most common variant seen in 42% of individuals with TANGO2 deficiency. Common clinical features seen in >70% of all individuals include acute metabolic crisis, rhabdomyolysis, neurologic abnormalities, developmental delay, and intellectual disability. Findings such as elevated creatine kinase, hypothyroidism, ketotic hypoglycemia, QT prolongation, or abnormalities of long-chain acylcarnitines and urine dicarboxylic acids should raise clinical suspicion for this life-threatening condition.

  View details for DOI 10.1002/ajmg.a.62543

  View details for PubMedID 34668327

• Diagnostic challenges and disease management in patients with a mild Zellweger spectrum disorder phenotype. Molecular genetics and metabolism Enns, G. M., Ammous, Z., Himes, R. W., Nogueira, J., Palle, S., Sullivan, M., Ramirez, C. 2021

  Abstract

  Peroxisome Biogenesis Disorders-Zellweger spectrum disorder (PBD-ZSD) is a rare, autosomal recessive peroxisome biogenesis disorder that presents with variable symptoms. In patients with PBD-ZSD, pathogenic variants in the PEX family of genes disrupt normal peroxisomal function, impairing alpha- and beta-oxidation of very-long-chain fatty acids and synthesis of bile acids, resulting in increased levels of toxic bile acid intermediates and multisystem organ damage. The spectrum of severity in PBD-ZSD is variable, with some patients dying in the first year of life, while others live into adulthood. Symptoms of mild PBD-ZSD include various combinations of developmental delay, craniofacial dysmorphic features, visual impairment, sensorineural hearing loss, liver disease, and adrenal insufficiency. Disease progression in mild PBD-ZSD is generally slow, and may include extended periods of stability in some cases. The presence and extent to which symptoms occur in mild PBD-ZSD represents a diagnostic challenge that can cause delays in diagnosis with potential significant implications related to disease monitoring and treatment. There is some support for the pharmacologic therapies of Lorenzo's oil, docosohexanoic acid, and batyl alcohol in altering symptoms; however, systematic long-term studies are lacking. Cholic acid (CA) therapy has demonstrated treatment efficacy in patients with PBD-ZSD, including decreased toxic bile acid intermediates, transaminase levels, and liver inflammation, with improvement in growth parameters. However, these responses are most apparent in patients diagnosed and treated at a young age. Advanced liver disease may limit the efficacy of CA, underscoring the need to diagnose and treat these patients before significant liver damage and other related complications occur. Here we discuss the signs and symptoms of PBD-ZSD in patients with mild disease, standard diagnostic tools, factors affecting disease management, and available pharmacological interventions.

  View details for DOI 10.1016/j.ymgme.2021.09.007

  View details for PubMedID 34625341

• Profound neonatal lactic acidosis and renal tubulopathy in a patient with glycogen storage disease type IXa2 secondary to a de novo pathogenic variant in PHKA2 MOLECULAR GENETICS AND METABOLISM REPORTS Morales, J., Tise, C. G., Narang, A., Grimm, P. C., Enns, G. M., Lee, C. U. 2021; 27

  View details for DOI 10.1016/j.ymgmr.2021.100765

  View details for Web of Science ID 000656785700011

• Profound neonatal lactic acidosis and renal tubulopathy in a patient with glycogen storage disease type IXɑ2 secondary to a de novo pathogenic variant in PHKA2. Molecular genetics and metabolism reports Morales, J. A., Tise, C. G., Narang, A., Grimm, P. C., Enns, G. M., Lee, C. U. 2021; 27: 100765

  Abstract

  The phenotype of individuals with glycogen storage disease (GSD) IX appears to be highly variable, even within subtypes. Features include short stature, fasting hypoglycemia with ketosis, hepatomegaly, and transaminitis. GSD IXɑ2 is caused by hemizygous pathogenic variants in PHKA2, and results in deficiency of the phosphorylase kinase enzyme, particularly in the liver. Like other GSDs, GSD IXɑ2 can present with hypoglycemia and post-prandial lactic acidosis, but has never been reported in a newborn, nor with lactic acidosis as the presenting feature. Here we describe the clinical presentation and course of a newborn boy with profound neonatal lactic and metabolic acidosis, renal tubulopathy, and sensorineural hearing loss (SNHL) diagnosed with GSD IXɑ2 through exome sequencing. Review of the literature suggests this case represents an atypical and severe presentation of GSD IXɑ2 and proposes expansion of the phenotype to include neonatal lactic acidosis and renal tubulopathy.

  View details for DOI 10.1016/j.ymgmr.2021.100765

  View details for PubMedID 34277355

  View details for PubMedCentralID PMC8261893

• Compound heterozygous KCTD7 variants in progressive myoclonus epilepsy. Journal of neurogenetics Burke, E. A., Sturgeon, M., Zastrow, D. B., Fernandez, L., Prybol, C., Marwaha, S., Frothingham, E. P., Ward, P. A., Eng, C. M., Fresard, L., Montgomery, S. B., Enns, G. M., Fisher, P. G., Wolfe, L. A., Harding, B., Carrington, B., Bishop, K., Sood, R., Huang, Y., Elkahloun, A., Toro, C., Bassuk, A. G., Wheeler, M. T., Markello, T. C., Gahl, W. A., Malicdan, M. C. 2021: 1–10

  Abstract

  KCTD7 is a member of the potassium channel tetramerization domain-containing protein family and has been associated with progressive myoclonic epilepsy (PME), characterized by myoclonus, epilepsy, and neurological deterioration. Here we report four affected individuals from two unrelated families in which we identified KCTD7 compound heterozygous single nucleotide variants through exome sequencing. RNAseq was used to detect a non-annotated splicing junction created by a synonymous variant in the second family. Whole-cell patch-clamp analysis of neuroblastoma cells overexpressing the patients' variant alleles demonstrated aberrant potassium regulation. While all four patients experienced many of the common clinical features of PME, they also showed variable phenotypes not previously reported, including dysautonomia, brain pathology findings including a significantly reduced thalamus, and the lack of myoclonic seizures. To gain further insight into the pathogenesis of the disorder, zinc finger nucleases were used to generate kctd7 knockout zebrafish. Kctd7 homozygous mutants showed global dysregulation of gene expression and increased transcription of c-fos, which has previously been correlated with seizure activity in animal models. Together these findings expand the known phenotypic spectrum of KCTD7-associated PME, report a new animal model for future studies, and contribute valuable insights into the disease.

  View details for DOI 10.1080/01677063.2021.1892095

  View details for PubMedID 33970744

• A resource of lipidomics and metabolomics data from individuals with undiagnosed diseases SCIENTIFIC DATA Kyle, J. E., Stratton, K. G., Zink, E. M., Kim, Y., Bloodsworth, K. J., Monroe, M. E., Bacino, C. A., Bacino, C. A., Hanchard, N. A., Lewis, R. A., Rosenfeld, J. A., Scott, D. A., Tran, A. A., Ward, P. A., Burrage, L. C., Clark, G. D., Alejandro, M. E., Posey, J. E., Wangler, M. F., Lee, B. H., Craigen, W. J., Bellen, H. J., Nicholas, S. K., Bostwick, B. L., Samson, S. L., Goldman, A. M., Moretti, P. M., Eng, C. M., Muzny, D. M., Orengo, J. P., Vogel, T. P., Lalani, S. R., Murdock, D. R., Azamian, M. S., Orange, J. S., Emrick, L. T., Dhar, S. U., Balasubramanyam, A., Potocki, L., Yamamoto, S., Yang, Y., Chen, S., Jamal, F., Karaviti, L., Marom, R., Lincoln, S. A., Walsh, C. A., Beggs, A. H., Rodan, L. H., Stoler, J. M., Berry, G. T., Cobban, L. A., MacRae, C. A., Krier, J. B., Silverman, E. K., Fieg, E. L., Maas, R. L., Loscalzo, J., Aday, A., Korrick, S., Goldstein, D. B., Stong, N., Sullivan, J. A., Spillmann, R. C., Pena, L. M., Tan, Q., Walley, N. M., Jiang, Y., McConkie-Rosell, A., Schoch, K., Shashi, V., Cope, H., Holm, I. A., Kohane, I. S., McCray, A. T., Esteves, C., LeBlanc, K., Might, M., Kelley, E., Worthey, E. A., Dorset, D. C., Boone, B. E., Levy, S. E., Birch, C. L., Jones, A. L., Brown, D. M., Bick, D. P., Newberry, J., Lazar, J., May, T., Sweetser, D. A., Briere, L. C., Pallais, J., Cooper, C. M., High, F., Walker, M., Colley, H. A., Mamounas, L. A., Manolio, T. A., Burke, E. A., Godfrey, R. A., Groden, C. A., Gahl, W. A., Wolfe, L. A., Markello, T. C., Lau, C., Draper, D. D., Gould, S. E., Nehrebecky, M. E., Wahl, C. E., Batzli, G. F., Macnamara, E. F., Dayal, J. G., Eckstein, D. J., Mulvihill, J. J., Tifft, C. J., Urv, T. K., Wise, A. L., Murphy, J. L., Gropman, A. L., Howerton, E. M., Krasnewich, D. M., Johnston, J. M., Pusey, B. N., Adams, D. R., Maduro, V. V., Malicdan, M. V., Davids, M., Estwick, T., Novacic, D., Sharma, P., Toro, C., Yu, G., Behnam, B., D'Souza, P., Ferreira, C., Morimoto, M., Baker, E. H., Yang, J., Gourdine, J. F., Brush, M., Haendel, M., Ashley, E. A., Bernstein, J. A., Sampson, J. B., Zastrow, D. B., Friedman, N. D., Merker, J. D., McCormack, C. E., Fisher, P. G., Davidson, J. M., Dries, A. M., Enns, G. M., Majcherska, M. M., Reuter, C. M., Waggott, D. M., Kohler, J. N., Coakley, T. R., Smith, K. S., Wheeler, M. T., Bonner, D., Fernandez, L., Hom, J., Huang, Y., Marwaha, S., Zhao, C., Martinez-Agosto, J. A., Dell'Angelica, E. C., Papp, J. C., Douine, E. D., Nelson, S. F., Martin, M. G., Palmer, C., Parker, N. H., Butte, M. J., Yoon, A. J., Loo, S. K., Fogel, B. L., Dipple, K. M., Sinsheimer, J. S., Allard, P., Barseghyan, H., Dorrani, N., Lee, H., Vilain, E., Eskin, A., Renteria, G., Signer, R., Wan, J., Zheng, A., Westerfield, M., Phillips, J. A., Cogan, J. D., Newman, J. H., Robertson, A. K., Hamid, R., Bican, A., Brokamp, E., Duncan, L., Kozuira, M., Rives, L., Shakachite, L., Waters, K. M., Webb-Robertson, B. M., Koeller, D. M., Metz, T. O., Undiagnosed Dis Network 2021; 8 (1): 114

  Abstract

  Every year individuals experience symptoms that remain undiagnosed by healthcare providers. In the United States, these rare diseases are defined as a condition that affects fewer than 200,000 individuals. However, there are an estimated 7000 rare diseases, and there are an estimated 25-30 million Americans in total (7.6-9.2% of the population as of 2018) affected by such disorders. The NIH Common Fund Undiagnosed Diseases Network (UDN) seeks to provide diagnoses for individuals with undiagnosed disease. Mass spectrometry-based metabolomics and lipidomics analyses could advance the collective understanding of individual symptoms and advance diagnoses for individuals with heretofore undiagnosed disease. Here, we report the mass spectrometry-based metabolomics and lipidomics analyses of blood plasma, urine, and cerebrospinal fluid from 148 patients within the UDN and their families, as well as from a reference population of over 100 individuals with no known metabolic diseases. The raw and processed data are available to the research community so that they might be useful in the diagnoses of current or future patients suffering from undiagnosed disorders.

  View details for DOI 10.1038/s41597-021-00894-y

  View details for Web of Science ID 000642148100001

  View details for PubMedID 33883556

  View details for PubMedCentralID PMC8060404

• Unexpected diagnoses in patients with abnormal newborn screening Tise, C., Velez-Bartolomei, F., Morales, J., Lee, C., Bernstein, J., Enns, G. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2021: S354

  View details for Web of Science ID 000639219800534

• Clinical outcomes of major clinical events and emergency triheptanoin use in critically ill patients with long-chain fatty acid oxidation disorders Enns, G., Marsden, D., Ramirez, A., Bedrosian, C., Reineking, B., Lu, X., Rahman, S., Vockley, J. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2021: S86-S87

  View details for Web of Science ID 000639219800129

• Tailoring the ACMG/AMP sequence variant interpretation guidelines to the unique aspects of germline ACADVL variants Flowers, M., Weaver, M., Baudet, H., Pasquali, M., Enns, G., Feigenbaum, A., Lyon, E., Miller, M., Graham, B., Spector, E., Racacho, L., McLachlan, M., Sadre-Bazzaz, K., Harris, H., Wang, Y., Dickson, A., Mao, R. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2021: S254

  View details for Web of Science ID 000639219800384

• Retrospective study of the disease course in pediatric patients with severe MMA caused by MMUT mutations: design and baseline characteristics Enns, G., Baker, P., Li, H., Morgan, T., Vockley, J. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2021: S23-S25

  View details for Web of Science ID 000639219800035

• Refining ClinGen loss of function variant recommendations for the phenylalanine hydroxylase (PAH) gene: the PAH variant curation expert panel's experience Groopman, E., Weaver, M., Zastrow, D., Enns, G., Feigenbaum, A., Lichter-Konecki, U., Lyon, E., Pasquali, M., Caldovic, L., Ross, J., Craigen, W. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2021: S231

  View details for Web of Science ID 000639219800351

• Aicardi-Goutières syndrome may present with positive newborn screen for X-linked adrenoleukodystrophy. American journal of medical genetics. Part A Tise, C. G., Morales, J. A., Lee, A. S., Velez-Bartolomei, F. n., Floyd, B. J., Levy, R. J., Cusmano-Ozog, K. P., Feigenbaum, A. S., Ruzhnikov, M. R., Lee, C. U., Enns, G. M. 2021

  Abstract

  We report three unrelated probands, two male and one female, diagnosed with Aicardi-Goutières syndrome (AGS) after screening positive on California newborn screening (CA NBS) for X-linked adrenoleukodystrophy (X-ALD) due to elevated C26:0 lysophosphatidylcholine (C26:0-LPC). Follow-up evaluation was notable for elevated C26:0, C26:1, and C26:0/C22:0 ratio, and normal red blood cell plasmalogens levels in all three probands. Diagnoses were confirmed by molecular sequencing prior to 12 months of age after clinical evaluation was inconsistent with X-ALD or suggestive of AGS. For at least one proband, the early diagnosis of AGS enabled candidacy for enrollment into a therapeutic clinical trial. This report demonstrates the importance of including AGS on the differential diagnosis for individuals who screen positive for X-ALD, particularly infants with abnormal neurological features, as this age of onset would be highly unusual for X-ALD. While AGS is not included on the Recommended Universal Screening Panel, affected individuals can be identified early through state NBS programs so long as providers are aware of a broader differential that includes AGS. This report is timely, as state NBS algorithms for X-ALD are actively being established, implemented, and refined.

  View details for DOI 10.1002/ajmg.a.62160

  View details for PubMedID 33683010

• PERIOPERATIVE MANAGEMENT AND POST-LIVER TRANSPLANTATION OUTCOMES IN UREA CYCLE DISORDERS, MAPLE SYRUP URINE DISEASE AND ORGANIC ACIDEMIAS: 20 YEARS' EXPERIENCE Ebel, N., Vuong, P., Baker, C., Brubaker, A., Than, P., Enns, G., Esquivel, C. O. WILEY. 2020: 881A–882A

  View details for Web of Science ID 000574027003241

• PERIOPERATIVE MANAGEMENT AND POST-LIVER TRANSPLANTATION OUTCOMES IN METHYLMALONIC ACIDEMIA, PROPIONIC ACIDEMIA AND UREA CYCLE DISORDERS: OUR 20 YEAR EXPERIENCE Vuong, P., Ebel, N., Baker, C. V., Brubaker, A., Than, P., Enns, G., Esquivel, C. O. LIPPINCOTT WILLIAMS & WILKINS. 2020: S547

  View details for Web of Science ID 000618872101227

• Reducing False-Positive Results in Newborn Screening Using Machine Learning. International journal of neonatal screening Peng, G., Tang, Y., Cowan, T. M., Enns, G. M., Zhao, H., Scharfe, C. 2020; 6 (1)

  Abstract

  Newborn screening (NBS) for inborn metabolic disorders is a highly successful public health program that by design is accompanied by false-positive results. Here we trained a Random Forest machine learning classifier on screening data to improve prediction of true and false positives. Data included 39 metabolic analytes detected by tandem mass spectrometry and clinical variables such as gestational age and birth weight. Analytical performance was evaluated for a cohort of 2777 screen positives reported by the California NBS program, which consisted of 235 confirmed cases and 2542 false positives for one of four disorders: glutaric acidemia type 1 (GA-1), methylmalonic acidemia (MMA), ornithine transcarbamylase deficiency (OTCD), and very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). Without changing the sensitivity to detect these disorders in screening, Random Forest-based analysis of all metabolites reduced the number of false positives for GA-1 by 89%, for MMA by 45%, for OTCD by 98%, and for VLCADD by 2%. All primary disease markers and previously reported analytes such as methionine for MMA and OTCD were among the top-ranked analytes. Random Forest's ability to classify GA-1 false positives was found similar to results obtained using Clinical Laboratory Integrated Reports (CLIR). We developed an online Random Forest tool for interpretive analysis of increasingly complex data from newborn screening.

  View details for DOI 10.3390/ijns6010016

  View details for PubMedID 32190768

• Hypoglycemia in CDG patients due to PMM2 mutations: Follow up on hyperinsulinemic patients. JIMD reports Moravej, H., Altassan, R., Jaeken, J., Enns, G. M., Ellaway, C., Balasubramaniam, S., De Lonlay, P., Coman, D., Mercimek-Andrews, S., Witters, P., Morava, E. 2020; 51 (1): 76–81

  Abstract

  Background: Phosphomannomutase 2 deficiency (PMM2-CDG) is the most common congenital disorder of glycosylation (CDG). Hypoglycemia has been reported in various CDG including PMM2-CDG. The frequency and etiology of hypoglycemia in PMM2-CDG are not well studied.Methods: We conducted a systematic review of the literature on genetically and/or biochemically confirmed PMM2-CDG patients who developed hypoglycemia. Prospective follow-up information on the patients who received diazoxide therapy was collected and evaluated.Results: A total of 165 peer-reviewed articles reporting on 933 PMM2-CDG patients were assessed. Hypoglycemia was specifically mentioned only in 23 of these patients (2.5%). Hyperinsulinism was identified in 10 patients (43% of all hypoglycemic patients). Among these 10 patients, seven were successfully treated with diazoxide. However, most patients remained on therapy longer than a year to stay free of hypoglycemia.Conclusion: Hypoglycemia is a rarely reported finding in patients with PMM2-CDG. Diazoxide-responsive hyperinsulinism was found to have a good prognosis on medication in our PMM2-CDG patients with hypoglycemia. No genotype-phenotype correlation was observed with respect to hyperinsulinism. A prospective study should be undertaken to explore the hypothesis that hypoglycemia is underdiagnosed in PMM2-CDG and to evaluate whether hyperinsulinism is always associated with hypoglycemia.

  View details for DOI 10.1002/jmd2.12085

  View details for PubMedID 32071842

• Clinical effect and safety profile of pegzilarginase in patients with arginase 1 deficiency. Journal of inherited metabolic disease Diaz, G. A., Schulze, A. n., McNutt, M. C., Leão-Teles, E. n., Merritt, J. L., Enns, G. M., Batzios, S. n., Bannick, A. n., Zori, R. T., Sloan, L. S., Potts, S. L., Bubb, G. n., Quinn, A. G. 2020

  Abstract

  Hyperargininemia in patients with arginase 1 deficiency (ARG1-D) is considered a key driver of disease manifestations, including spasticity, developmental delay, and seizures. Pegzilarginase (AEB1102) is an investigational enzyme therapy which is being developed as a novel arginine lowering approach. We report the safety and efficacy of intravenously (IV) administered pegzilarginase in pediatric and adult ARG1-D patients (n = 16) from a Phase 1/2 study (101A) and the first 12 weeks of an open-label extension study (102A). Substantial disease burden at baseline included lower-limb spasticity, developmental delay, and previous hyperammonemic episodes in 75%, 56%, and 44% of patients, respectively. Baseline plasma arginine (pArg) was elevated (median 389 μM, range 238-566) on standard disease management. Once weekly repeat dosing resulted in a median decrease of pArg of 277 μM after 20 cumulative doses (n = 14) with pArg in the normal range (40 to 115 μM) in 50% of patients at 168 hours post dose (mean pegzilarginase dose 0.10 mg/kg). Lowering pArg was accompanied by improvements in one or more key mobility assessments (6MWT, GMFM-D & E) in 79% of patients. In 101A, seven hypersensitivity reactions occurred in four patients (out of 162 infusions administered). Other common treatment-related adverse events (AEs) included vomiting, hyperammonemia, pruritus, and abdominal pain. Treatment-related serious AEs that occurred in five patients were all observed in 101A. Pegzilarginase was effective in lowering pArg levels with an accompanying clinical response in patients with ARG1-D. The improvements with pegzilarginase occurred in patients receiving standard treatment approaches, which suggests that pegzilarginase could offer benefit over existing disease management.

  View details for DOI 10.1002/jimd.12343

  View details for PubMedID 33325055

• Ethnic Variability in Newborn Metabolic Screening Markers Associated with False-Positive Outcomes. Journal of inherited metabolic disease Peng, G. n., Tang, Y. n., Gandotra, N. n., Enns, G. M., Cowan, T. M., Zhao, H. n., Scharfe, C. n. 2020

  Abstract

  Newborn screening (NBS) programs utilize information on a variety of clinical variables such as gestational age, sex and birth weight to reduce false-positive screens for inborn metabolic disorders. Here we study the influence of ethnicity on metabolic marker levels in a diverse newborn population. NBS data from screen-negative singleton babies (n = 100 000) were analyzed, which included blood metabolic markers measured by tandem mass spectrometry and ethnicity status reported by the parents. Metabolic marker levels were compared between major ethnic groups (Asian, Black, Hispanic, White) using effect size analysis, which controlled for group size differences and influence from clinical variables. Marker level differences found between ethnic groups were correlated to NBS data from 2532 false-positive cases for four metabolic diseases: glutaric acidemia type 1 (GA-1), methylmalonic acidemia (MMA), ornithine transcarbamylase deficiency (OTCD), and very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). In result, 79% of the metabolic markers (34 of 43) had ethnicity-related differences. Compared to the other groups, Black infants had elevated GA-1 markers (C5DC, Cohen's d = 0.37, P < .001), Hispanics had elevated MMA markers (C3, Cohen's d = 0.13, P < .001, and C3/C2, Cohen's d = 0.27, P < .001); and Whites had elevated VLCADD markers (C14, Cohen's d = 0.28, P < .001, and C14:1, Cohen's d = 0.22, P < .001) and decreased OTCD markers (citrulline, Cohen's d = -0.26, P < .001). These findings correlated with the higher false-positive rates in Black infants for GA-1, in Hispanics for MMA, and in Whites for OTCD and for VLCADD. Web-based tools are available to analyze ethnicity-related changes in newborn metabolism and to support developing methods to identify false-positives in metabolic screening. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jimd.12236

  View details for PubMedID 32216101

• Clinical Spectrum and Functional Consequences Associated with Bi-Allelic Pathogenic PNPT1 Variants. Journal of clinical medicine Rius, R., Van Bergen, N. J., Compton, A. G., Riley, L. G., Kava, M. P., Balasubramaniam, S., Amor, D. J., Fanjul-Fernandez, M., Cowley, M. J., Fahey, M. C., Koenig, M. K., Enns, G. M., Sadedin, S., Wilson, M. J., Tan, T. Y., Thorburn, D. R., Christodoulou, J. 2019; 8 (11)

  Abstract

  PNPT1 (PNPase-polynucleotide phosphorylase) is involved in multiple RNA processing functions in the mitochondria. Bi-allelic pathogenic PNPT1 variants cause heterogeneous clinical phenotypes affecting multiple organs without any established genotype-phenotype correlations. Defects in PNPase can cause variable combined respiratory chain complex defects. Recently, it has been suggested that PNPase can lead to activation of an innate immune response. To better understand the clinical and molecular spectrum of patients with bi-allelic PNPT1 variants, we captured detailed clinical and molecular phenotypes of all 17 patients reported in the literature, plus seven new patients, including a 78-year-old male with the longest reported survival. A functional follow-up of genomic sequencing by cDNA studies confirmed a splicing defect in a novel, apparently synonymous, variant. Patient fibroblasts showed an accumulation of mitochondrial unprocessed PNPT1 transcripts, while blood showed an increased interferon response. Our findings suggest that functional analyses of the RNA processing function of PNPase are more sensitive than testing downstream defects in oxidative phosphorylation (OXPHPOS) enzyme activities. This research extends our knowledge of the clinical and functional consequences of bi-allelic pathogenic PNPT1 variants that may guide management and further efforts into understanding the pathophysiological mechanisms for therapeutic development.

  View details for DOI 10.3390/jcm8112020

  View details for PubMedID 31752325

• De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder. Genetics in medicine : official journal of the American College of Medical Genetics Mirzaa, G. M., Chong, J. X., Piton, A., Popp, B., Foss, K., Guo, H., Harripaul, R., Xia, K., Scheck, J., Aldinger, K. A., Sajan, S. A., Tang, S., Bonneau, D., Beck, A., White, J., Mahida, S., Harris, J., Smith-Hicks, C., Hoyer, J., Zweier, C., Reis, A., Thiel, C. T., Jamra, R. A., Zeid, N., Yang, A., Farach, L. S., Walsh, L., Payne, K., Rohena, L., Velinov, M., Ziegler, A., Schaefer, E., Gatinois, V., Genevieve, D., Simon, M. E., Kohler, J., Rotenberg, J., Wheeler, P., Larson, A., Ernst, M. E., Akman, C. I., Westman, R., Blanchet, P., Schillaci, L., Vincent-Delorme, C., Gripp, K. W., Mattioli, F., Guyader, G. L., Gerard, B., Mathieu-Dramard, M., Morin, G., Sasanfar, R., Ayub, M., Vasli, N., Yang, S., Person, R., Monaghan, K. G., Nickerson, D. A., van Binsbergen, E., Enns, G. M., Dries, A. M., Rowe, L. J., Tsai, A. C., Svihovec, S., Friedman, J., Agha, Z., Qamar, R., Rodan, L. H., Martinez-Agosto, J., Ockeloen, C. W., Vincent, M., Sunderland, W. J., Bernstein, J. A., Undiagnosed Diseases Network, Eichler, E. E., Vincent, J. B., University of Washington Center for Mendelian Genomics (UW-CMG), Bamshad, M. J. 2019

  Abstract

  PURPOSE: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292).METHODS: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships.RESULTS: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment.CONCLUSION: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.

  View details for DOI 10.1038/s41436-019-0693-9

  View details for PubMedID 31723249

• Case series of sebelipase alfa hypersensitivity reactions and successful sebelipase alfa rapid desensitization. JIMD reports Huffaker, M. F., Liu, A. Y., Enns, G. M., Vijay, S., Amor, A. J., Adkinson, N. F. 2019; 49 (1): 30–36

  Abstract

  Allergic immune-mediated hypersensitivity reactions are known potential complications of enzyme replacement therapy. Sebelipase alfa, recombinant lysosomal acid lipase (LAL), is a potentially life-altering treatment for patients with LAL deficiency. There is very little information on the diagnosis and management of immediate hypersensitivity reactions to this drug. Here we present three unique cases of hypersensitivity reactions to sebelipase alfa, spanning a broad age spectrum from infancy to adulthood, each managed with successful rapid desensitization.

  View details for DOI 10.1002/jmd2.12066

  View details for PubMedID 31497479

• Assessing the strength of evidence for genes implicated in fatty acid oxidation disorders using the ClinGen clinical validity framework. Molecular genetics and metabolism McGlaughon, J. L., Pasquali, M., Wallace, K., Ross, J., Senol-Cosar, O., Shen, W., Weaver, M. A., Feigenbaum, A., Lyon, E., Enns, G. M., Mao, R., Baudet, H. G. 2019

  Abstract

  Newborn screening is an incredibly useful tool for the early identification of many metabolic disorders, including fatty acid oxidation (FAO) disorders. In many cases, molecular tests are necessary to reach a final diagnosis, highlighting the need for a thorough evaluation of genes implicated in FAO disorders. Using the ClinGen (Clinical Genome Resource) clinical validity framework, thirty genes were analyzed for the strength of evidence supporting their association with FAO disorders. Evidence was gathered from the literature by biocurators and presented to disease experts for review in order to assign a clinical validity classification of Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Reported Evidence. Of the gene-disease relationships evaluated, 22/30 were classified as Definitive, three as Moderate, one as Limited, three as No Reported Evidence and one as Disputed. Gene-disease relationships with a Limited, Disputed, and No Reported Evidence were found on two, six, and up to four panels out of 30 FAO disorder-specific panels, respectively, in the National Institute of Health Genetic Testing Registry, while over 70% of the genes on panels are definitively associated with an FAO disorder. These results highlight the need to systematically assess the clinical relevance of genes implicated in fatty acid oxidation disorders in order to improve the interpretation of genetic testing results and diagnosis of patients with these disorders.

  View details for DOI 10.1016/j.ymgme.2019.07.008

  View details for PubMedID 31399326

• STANDARDIZING METABOLIC DISEASE GENE AND VARIANT CURATION: THE CLINGEN INBORN ERRORS OF METABOLISM WORKING GROUP Zastrow, D., Baudet, H., Thomas, A., Shen, W., Si, C., Weaver, M., Liu, J., Goldstein, J., Thaxton, C., Ross, J., Crowley, S., Kurtz, C., McGlaughon, J., Seifert, B., Udani, R., Wallace, K., Enns, G., Feigenbaum, A., Lichter-Konecki, U., Lyon, E., Pasquali, M., Blau, N., Bali, D., Caganna, M., Hegde, M., Mooney, S., Senol, O., Watson, M., Rehder, C., Steiner, R., Craigen, W., Mao, R. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2019: 313

  View details for Web of Science ID 000483451500168

• Extracutaneous manifestations in phacomatosis cesioflammea and cesiomarmorata: Case series and literature review AMERICAN JOURNAL OF MEDICAL GENETICS PART A Kumar, A., Zastrow, D. B., Kravets, E. J., Beleford, D., Ruzhnikov, M. Z., Grove, M. E., Dries, A. M., Kohler, J. N., Waggott, D. M., Yang, Y., Huang, Y., Mackenzie, K. M., Eng, C. M., Fisher, P. G., Ashley, E. A., Teng, J. M., Stevenson, D. A., Shieh, J. T., Wheeler, M. T., Bernstein, J. A., Adams, D. R., Aday, A., Alejandro, M. E., Allard, P., Azamian, M. S., Bacino, C. A., Baker, E., Balasubramanyam, A., Barseghyan, H., Batzli, G. F., Beggs, A. H., Behnam, B., Bellen, H. J., Bican, A., Bick, D. P., Birch, C. L., Bonner, D., Boone, B. E., Bostwick, B. L., Briere, L. C., Brokamp, E., Brown, D. M., Brush, M., Burke, E. A., Burrage, L. C., Butte, M. J., Chen, S., Clark, G. D., Coakley, T. R., Cogan, J. D., Colley, H. A., Cooper, C. M., Cope, H., Craigen, W. J., D'Souza, P., Davids, M., Davidson, J. M., Dayal, J. G., Dell'Angelica, E. C., Dhar, S. U., Dipple, K. M., Donnell-Fink, L. A., Dorrani, N., Dorset, D. C., Douine, E. D., Draper, D. D., Eckstein, D. J., Emrick, L. T., Enns, G. M., Eskin, A., Esteves, C., Estwick, T., Fairbrother, L., Fernandez, L., Ferreira, C., Fieg, E. L., Fogel, B. L., Friedman, N. D., Gahl, W. A., Glanton, E., Godfrey, R. A., Goldman, A. M., Goldstein, D. B., Gould, S. E., Gourdine, J. F., Groden, C. A., Gropman, A. L., Haendel, M., Hamid, R., Hanchard, N. A., High, F., Holm, I. A., Hom, J., Howerton, E. M., Jamal, F., Jiang, Y., Johnston, J. M., Jones, A. L., Karaviti, L., Koeller, D. M., Kohane, I. S., Krasnewich, D. M., Korrick, S., Koziura, M., Krier, J. B., Kyle, J. E., Lalani, S. R., Lau, C., Lazar, J., LeBlanc, K., Lee, B. H., Lee, H., Levy, S. E., Lewis, R. A., Lincoln, S. A., Loo, S. K., Loscalzo, J., Maas, R. L., Macnamara, E. F., MacRae, C. A., Maduro, V. V., Majcherska, M. M., Malicdan, M., Mamounas, L. A., Manolio, T. A., Markello, T. C., Marom, R., Martin, M. G., Martinez-Agosto, J. A., Marwaha, S., May, T., McConkie-Rosell, A., McCormack, C. E., McCray, A. T., Merker, J. D., Metz, T. O., Might, M., Moretti, P. M., Morimoto, M., Mulvihill, J. J., Murdock, D. R., Murphy, J. L., Muzny, D. M., Nehrebecky, M. E., Nelson, S. F., Newberry, J., Newman, J. H., Nicholas, S. K., Novacic, D., Orange, J. S., Orengo, J. P., Pallais, J., Palmer, C. S., Papp, J. C., Parker, N. H., Pena, L. M., Phillips, J. A., Posey, J. E., Postlethwait, J. H., Potocki, L., Pusey, B. N., Reuter, C. M., Rives, L., Robertson, A. K., Rodan, L. H., Rosenfeld, J. A., Sampson, J. B., Samson, S. L., Schoch, K., Scott, D. A., Shakachite, L., Sharma, P., Shashi, V., Signer, R., Silverman, E. K., Sinsheimer, J. S., Smith, K. S., Spillmann, R. C., Staler, J. M., Stong, N., Sullivan, J. A., Sweetser, D. A., Tan, Q., Tifft, C. J., Toro, C., Tran, A. A., Urv, T. K., Vilain, E., Vogel, T. P., Wahl, C. E., Walley, N. M., Walsh, C. A., Walker, M., Wan, J., Wangler, M. F., Ward, P. A., Waters, K. M., Webb-Robertson, B. M., Westerfield, M., Wise, A. L., Wolfe, L. A., Worthey, E. A., Yamamoto, S., Yang, J., Yoon, A. J., Yu, G., Zhao, C., Zheng, A., Undiagnosed Dis Network 2019; 179 (6): 966–77

  View details for DOI 10.1002/ajmg.a.61134

  View details for Web of Science ID 000468322800015

• A toolkit for genetics providers in follow-up of patients with non-diagnostic exome sequencing JOURNAL OF GENETIC COUNSELING Zastrow, D. B., Kohler, J. N., Bonner, D., Reuter, C. M., Fernandez, L., Grove, M. E., Fisk, D. G., Yang, Y., Eng, C. M., Ward, P. A., Bick, D., Worthey, E. A., Fisher, P. G., Ashley, E. A., Bernstein, J. A., Wheeler, M. T., Adams, D. R., Aday, A., Alejandro, M. E., Allard, P., Ashley, E. A., Azamian, M. S., Bacino, C. A., Baker, E., Balasubramanyam, A., Barseghyan, H., Batzli, G. F., Beggs, A. H., Behnam, B., Bellen, H. J., Bernstein, J. A., Bican, A., Bick, D. P., Birch, C. L., Boone, B. E., Bostwick, B. L., Briere, L. C., Brokamp, E., Brown, D. M., Brush, M., Burke, E. A., Burrage, L. C., Butte, M. J., Chen, S., Clark, G. D., Coakley, T. R., Cogan, J. D., Colley, H. A., Cooper, C. M., Cope, H., Craigen, W. J., D'Souza, P., Davids, M., Dayal, J. G., Dell'Angelica, E. C., Dhar, S. U., Dipple, K. M., Donnell-Fink, L. A., Dorrani, N., Dorset, D. C., Douine, E. D., Draper, D. D., Dries, A. M., Eckstein, D. J., Emrick, L. T., Eng, C. M., Enns, G. M., Eskin, A., Esteves, C., Estwick, T., Fairbrother, L., Ferreira, C., Fieg, E. L., Fisher, P. G., Fogel, B. L., Gahl, W. A., Glanton, E., Godfrey, R. A., Goldman, A. M., Goldstein, D. B., Gould, S. E., Gourdine, J. F., Groden, C. A., Gropman, A. L., Haendel, M., Hamid, R., Hanchard, N. A., High, F., Holm, I. A., Hom, J., Howerton, E. M., Huang, Y., Jamal, F., Jiang, Y., Johnston, J. M., Jones, A. L., Karaviti, L., Koeller, D. M., Kohane, I. S., Krasnewich, D. M., Korrick, S., Koziura, M., Krier, J. B., Kyle, J. E., Lalani, S. R., Lau, C., Lazar, J., LeBlanc, K., Lee, B. H., Lee, H., Levy, S. E., Lewis, R. A., Lincoln, S. A., Loo, S. K., Loscalzo, J., Maas, R. L., Macnamara, E. F., MacRae, C. A., Maduro, V. V., Majcherska, M. M., Malicdan, M. V., Mamounas, L. A., Manolio, T. A., Markello, T. C., Marom, R., Martin, G., Martinez-Agosto, J. A., Marwaha, S., May, T., McConkie-Rosell, A., McCormack, C. E., McCray, A. T., Merker, J. D., Metz, T. O., Might, M., Moretti, P. M., Morimoto, M., Nehrebecky, M. E., Nelson, S. F., Newberry, J., Newman, J. H., Nicholas, S. K., Novacic, D., Orange, J. S., Orengo, J. P., Pallais, J., Palmer, C. S., Papp, J. C., Postlethwait, J. H., Potocki, L., Pusey, B. N., Rives, L., Robertson, A. K., Rodan, L. H., Rosenfeld, J. A., Sampson, J. B., Samson, S. L., Schoch, K., Scott, D. A., Shakachite, L., Sharma, P., Shashi, V., Signer, R., Silverman, E. K., Sinsheimer, J. S., Smith, K. S., Spillmann, R. C., Stoler, J. M., Stong, N., Sullivan, J. A., Sweetser, D. A., Tan, Q., Tifft, C. J., Toro, C., Tran, A. A., Urv, T. K., Vilain, E., Vogel, T. P., Waggott, D. M., Wahl, C. E., Walley, N. M., Walsh, C. A., Walker, M., Wan, J., Wangler, M. F., Ward, P. A., Waters, K. M., Webb-Robertson, B. M., Westerfield, M., Wheeler, M. T., Wise, A. L., Wolfe, L. A., Worthey, E. A., Yamamoto, S., Yang, J., Yang, Y., Yoon, A. J., Yu, G., Zhao, C., Zheng, A., Undiagnosed Dis Network 2019; 28 (2): 213–28

  View details for DOI 10.1002/jgc4.1119

  View details for Web of Science ID 000463993600005

• Combining newborn metabolic and DNA analysis for second-tier testing of methylmalonic acidemia GENETICS IN MEDICINE Peng, G., Shen, P., Gandotra, N., Le, A., Fung, E., Jelliffe-Pawlowski, L., Davis, R. W., Enns, G. M., Zhao, H., Cowan, T. M., Scharfe, C. 2019; 21 (4): 896–903

  View details for DOI 10.1038/s41436-018-0272-5

  View details for Web of Science ID 000463167300016

• Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy. PloS one Kahn-Kirby, A. H., Amagata, A., Maeder, C. I., Mei, J. J., Sideris, S., Kosaka, Y., Hinman, A., Malone, S. A., Bruegger, J. J., Wang, L., Kim, V., Shrader, W. D., Hoff, K. G., Latham, J. C., Ashley, E. A., Wheeler, M. T., Bertini, E., Carrozzo, R., Martinelli, D., Dionisi-Vici, C., Chapman, K. A., Enns, G. M., Gahl, W., Wolfe, L., Saneto, R. P., Johnson, S. C., Trimmer, J. K., Klein, M. B., Holst, C. R. 2019; 14 (3): e0214250

  Abstract

  Mitochondrial disease is a family of genetic disorders characterized by defects in the generation and regulation of energy. Epilepsy is a common symptom of mitochondrial disease, and in the vast majority of cases, refractory to commonly used antiepileptic drugs. Ferroptosis is a recently-described form of iron- and lipid-dependent regulated cell death associated with glutathione depletion and production of lipid peroxides by lipoxygenase enzymes. Activation of the ferroptosis pathway has been implicated in a growing number of disorders, including epilepsy. Given that ferroptosis is regulated by balancing the activities of glutathione peroxidase-4 (GPX4) and 15-lipoxygenase (15-LO), targeting these enzymes may provide a rational therapeutic strategy to modulate seizure. The clinical-stage therapeutic vatiquinone (EPI-743, α-tocotrienol quinone) was reported to reduce seizure frequency and associated morbidity in children with the mitochondrial disorder pontocerebellar hypoplasia type 6. We sought to elucidate the molecular mechanism of EPI-743 and explore the potential of targeting 15-LO to treat additional mitochondrial disease-associated epilepsies.Primary fibroblasts and B-lymphocytes derived from patients with mitochondrial disease-associated epilepsy were cultured under standardized conditions. Ferroptosis was induced by treatment with the irreversible GPX4 inhibitor RSL3 or a combination of pharmacological glutathione depletion and excess iron. EPI-743 was co-administered and endpoints, including cell viability and 15-LO-dependent lipid oxidation, were measured.EPI-743 potently prevented ferroptosis in patient cells representing five distinct pediatric disease syndromes with associated epilepsy. Cytoprotection was preceded by a dose-dependent decrease in general lipid oxidation and the specific 15-LO product 15-hydroxyeicosatetraenoic acid (15-HETE).These findings support the continued clinical evaluation of EPI-743 as a therapeutic agent for PCH6 and other mitochondrial diseases with associated epilepsy.

  View details for DOI 10.1371/journal.pone.0214250

  View details for PubMedID 30921410

  View details for PubMedCentralID PMC6438538

• STANDARDIZING METABOLIC DISEASE GENE AND VARIANT CURATION: THE CLINGEN INBORN ERRORS OF METABOLISM WORKING GROUP Zastrow, D., Baudet, H., Thomas, A., Shen, W., Si, C., Weaver, M., Liu, J., Goldstein, J., Thaxton, C., Ross, J., Crowley, S., Kurtz, C., McGlaughon, J., Seifert, B., Udani, R., Wallace, K., Enns, G., Feigenbaum, A., Lichter-Konecki, U., Lyon, E., Pasquali, M., Blau, N., Bali, D., Caganna, M., Hegde, M., Mooney, S., Senol, O., Watson, M., Rehder, C., Steiner, R., Craigen, W., Mao, R. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2019: 336–40

  View details for Web of Science ID 000463310000181

• Elevated methylmalonic acidemia (MMA) screening markers in Hispanic and preterm newborns MOLECULAR GENETICS AND METABOLISM Peng, G., de Fontnouvelle, C. A., Enns, G. M., Cowan, T. M., Zhao, H., Scharfe, C. 2019; 126 (1): 39–42

  View details for DOI 10.1016/j.ymgme.2018.11.006

  View details for Web of Science ID 000456356400006

• Perspectives on urea cycle disorder management: Results of a clinician survey. Molecular genetics and metabolism Enns, G. M., Porter, M. H., Francis-Sedlak, M. n., Burdett, A. n., Vockley, J. n. 2019

  Abstract

  Urea cycle disorders (UCDs) are rare inborn errors of urea synthesis. US and European consensus statements on the diagnosis and treatment of UCDs were last published in 2001 and 2019, respectively. Recommendations are based primarily on case reports and expert opinion and there is limited agreement or consistency related to long-term management approaches. A clinician survey was conducted to assess current real-world practices and perspectives on challenges and unmet needs.A 14-item multiple-choice survey was administered to physicians in 2017. Clinicians who reported actively managing at least 1 patient with UCD were eligible to participate. Descriptive statistics were calculated for each survey item (frequencies for categorical variables; means, standard deviations, medians, and ranges for continuous variables).Sixty-six US clinicians completed the survey (65 geneticists; 1 pediatric neurologist). Over 90% of responders agreed or strongly agreed that even modest elevations in ammonia could cause physiological and functional brain damage; >80% of respondents agreed that asymptomatic UCD patients are at risk of brain damage over time due to mild/subclinical elevations in ammonia. Eighty-six percent of clinicians agreed or strongly agreed with recommending genetic testing for female relatives when a patient is diagnosed with ornithine transcarbamylase deficiency. Ninety-four percent of respondents agreed that patients have better disease control when they are more adherent to their UCD therapy. Nearly 90% indicated that clinicians and patients would benefit from updated UCD management guidance. More than half (53%) of respondents rated the symptoms of UCDs as extremely or very burdensome to the everyday lives of patients and their families; only 8% rated UCD symptoms as slightly or not at all burdensome. The majority of clinicians agreed (48%) or strongly agreed (32%) that caring for a child or family member with a UCD has a negative impact on the quality of life and/or health of family members/guardians (e.g. stress, relationships, ability to work).This self-reported survey suggests a need for updated and expanded clinical guidance on the long-term treatment and management of UCD patients.

  View details for DOI 10.1016/j.ymgme.2019.07.009

  View details for PubMedID 31377149

• Conducting an investigator-initiated randomized double-blinded intervention trial in acute decompensation of inborn errors of metabolism: Lessons from the N-Carbamylglutamate Consortium. Translational science of rare diseases Ah Mew, N., Cnaan, A., McCarter, R., Choi, H., Glass, P., Rice, K., Scavo, L., Gillespie, C. W., Diaz, G. A., Berry, G. T., Wong, D., Konczal, L., McCandless, S. E., Coughlin Ii, C. R., Weisfeld-Adams, J. D., Ficicioglu, C., Yudkoff, M., Enns, G. M., Lichter-Konecki, U., Gallagher, R., Tuchman, M. 2018; 3 (3-4): 157–70

  Abstract

  Organic acidemias and urea cycle disorders are ultra-rare inborn errors of metabolism characterized by episodic acute decompensation, often associated with hyperammonemia, resulting in brain edema and encephalopathy. Retrospective reports and translational studies suggest that N-carbamylglutamate (NCG) may be effective in reducing ammonia levels during acute decompensation in two organic acidemias, propionic and methylmalonic acidemia (PA and MMA), and in two urea cycle disorders, carbamylphosphate synthetase 1 and ornithine transcarbamylase deficiency (CPSD and OTCD). We established the 9-site N-carbamylglutamate Consortium (NCGC) in order to conduct two randomized double-blind, placebo-controlled trials of NCG in acute hyperammonemia of PA, MMA, CPSD and OTCD. Conducting clinical trials is challenging in any disease, but poses unique barriers and risks in the ultra-rare disorders. As the number of clinical trials in orphan diseases increases, evaluating the successes and opportunities for improvement in such trials is essential. We summarize herein the design, methods, experiences, challenges and lessons from the NCGC-conducted trials.

  View details for DOI 10.3233/TRD-180031

  View details for PubMedID 30613471

• FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia. JCI insight Manoli, I., Sysol, J. R., Epping, M. W., Li, L., Wang, C., Sloan, J. L., Pass, A., Gagne, J., Ktena, Y. P., Li, L., Trivedi, N. S., Ouattara, B., Zerfas, P. M., Hoffmann, V., Abu-Asab, M., Tsokos, M. G., Kleiner, D. E., Garone, C., Cusmano-Ozog, K., Enns, G. M., Vernon, H. J., Andersson, H. C., Grunewald, S., Elkahloun, A. G., Girard, C. L., Schnermann, J., DiMauro, S., Andres-Mateos, E., Vandenberghe, L. H., Chandler, R. J., Venditti, C. P. 2018; 3 (23)

  Abstract

  Methylmalonic acidemia (MMA), an organic acidemia characterized by metabolic instability and multiorgan complications, is most frequently caused by mutations in methylmalonyl-CoA mutase (MUT). To define the metabolic adaptations in MMA in acute and chronic settings, we studied a mouse model generated by transgenic expression of Mut in the muscle. Mut-/-;TgINS-MCK-Mut mice accurately replicate the hepatorenal mitochondriopathy and growth failure seen in severely affected patients and were used to characterize the response to fasting. The hepatic transcriptome in MMA mice was characterized by the chronic activation of stress-related pathways and an aberrant fasting response when compared with controls. A key metabolic regulator, Fgf21, emerged as a significantly dysregulated transcript in mice and was subsequently studied in a large patient cohort. The concentration of plasma FGF21 in MMA patients correlated with disease subtype, growth indices, and markers of mitochondrial dysfunction but was not affected by renal disease. Restoration of liver Mut activity, by transgenesis and liver-directed gene therapy in mice or liver transplantation in patients, drastically reduced plasma FGF21 and was associated with improved outcomes. Our studies identify mitocellular hormesis as a hepatic adaptation to metabolic stress in MMA and define FGF21 as a highly predictive disease biomarker.

  View details for PubMedID 30518688

• FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia JCI INSIGHT Manoli, I., Sysol, J. R., Epping, M. W., Li, L., Wang, C., Sloan, J. L., Pass, A., Gagne, J., Ktena, Y. P., Li, L., Trivedi, N. S., Ouattara, B., Zerfas, P. M., Hoffmann, V., Abu-Asab, M., Tsokos, M. G., Kleiner, D. E., Garone, C., Cusmano-Ozog, K., Enns, G. M., Vernon, H. J., Andersson, H. C., Grunewald, S., Elkahloun, A. G., Girard, H. L., Schnermann, J., Dimauro, S., Andres-Mateos, E., Vandenberghe, L. H., Chandler, R. J., Venditti, C. P. 2018; 3 (23)

  View details for DOI 10.1172/jci.insight.124351

  View details for Web of Science ID 000452436000010

• Elevated methylmalonic acidemia (MMA) screening markers in Hispanic and preterm newborns. Molecular genetics and metabolism Peng, G., de Fontnouvelle, C. A., Enns, G. M., Cowan, T. M., Zhao, H., Scharfe, C. 2018

  Abstract

  Analysis of California newborn screening (NBS) data revealed a high prevalence of Hispanic infants testing positive for methylmalonic acidemia (MMA), a trend seen for both true- and false-positive cases. Here we show that Hispanic infants have significantly higher levels of MMA screening markers than non-Hispanics. Preterm birth and increased birth weight were found to be associated with elevated MMA marker levels but could not entirely explain these differences. While the preterm birth rate was higher in Blacks than Hispanics, Black infants had on average the lowest MMA marker levels. Preterm birth was associated with lower birth weight and increased MMA marker levels suggesting that gestational age is the stronger predictive covariate compared to birth weight. These findings could help explain why MMA false-positive results are more likely in Hispanic than in Black infants, which could inform screening and diagnostic procedures for MMA and potentially other disorders in newborns.

  View details for PubMedID 30448007

• Unique aspects of sequence variant interpretation for inborn errors of metabolism (IEM): The ClinGen IEM Working Group and the Phenylalanine Hydroxylase Gene. Human mutation Zastrow, D. B., Baudet, H., Shen, W., Thomas, A., Si, Y., Weaver, M. A., Lager, A. M., Liu, J., Mangels, R., Dwight, S. S., Wright, M. W., Dobrowolski, S. F., Eilbeck, K., Enns, G. M., Feigenbaum, A., Lichter-Konecki, U., Lyon, E., Pasquali, M., Watson, M., Blau, N., Steiner, R. D., Craigen, W. J., Mao, R., ClinGen Inborn Errors of Metabolism Working Group 2018; 39 (11): 1569–80

  Abstract

  The ClinGen Inborn Errors of Metabolism Working Group was tasked with creating a comprehensive, standardized knowledge base of genes and variants for metabolic diseases. Phenylalanine hydroxylase (PAH) deficiency was chosen to pilot development of the Working Group's standards and guidelines. A PAH variant curation expert panel (VCEP) was created to facilitate this process. Following ACMG-AMP variant interpretation guidelines, we present the development of these standards in the context of PAH variant curation and interpretation. Existing ACMG-AMP rules were adjusted based on disease (6) or strength (5) or both (2). Disease adjustments include allele frequency thresholds, functional assay thresholds, and phenotype-specific guidelines. Our validation of PAH-specific variant interpretation guidelines is presented using 85 variants. The PAH VCEP interpretations were concordant with existing interpretations in ClinVar for 69 variants (81%). Development of biocurator tools and standards are also described. Using the PAH-specific ACMG-AMP guidelines, 714 PAH variants have been curated and will be submitted to ClinVar. We also discuss strategies and challenges in applying ACMG-AMP guidelines to autosomal recessive metabolic disease, and the curation of variants in these genes.

  View details for PubMedID 30311390

• Unique aspects of sequence variant interpretation for inborn errors of metabolism (IEM): The ClinGen IEM Working Group and the Phenylalanine Hydroxylase Gene HUMAN MUTATION Zastrow, D. B., Baudet, H., Shen, W., Thomas, A., Si, Y., Weaver, M. A., Lager, A. M., Liu, J., Mangels, R., Dwight, S. S., Wright, M. W., Dobrowolski, S. F., Eilbeck, K., Enns, G. M., Feigenbaum, A., Lichter-Konecki, U., Lyon, E., Pasquali, M., Watson, M., Blau, N., Steiner, R. D., Craigen, W. J., Mao, R., ClinGen Inborn Errors Metab 2018; 39 (11): 1569–80

  View details for DOI 10.1002/humu.23649

  View details for Web of Science ID 000447138900011

• Combining newborn metabolic and DNA analysis for second-tier testing of methylmalonic acidemia. Genetics in medicine : official journal of the American College of Medical Genetics Peng, G., Shen, P., Gandotra, N., Le, A., Fung, E., Jelliffe-Pawlowski, L., Davis, R. W., Enns, G. M., Zhao, H., Cowan, T. M., Scharfe, C. 2018

  Abstract

  PURPOSE: Improved second-tier tools are needed to reduce false-positive outcomes in newborn screening (NBS) for inborn metabolic disorders on the Recommended Universal Screening Panel (RUSP).METHODS: We designed an assay for multiplex sequencing of 72 metabolic genes (RUSPseq) from newborn dried blood spots. Analytical and clinical performance was evaluated in 60 screen-positive newborns for methylmalonic acidemia (MMA) reported by the California Department of Public Health NBS program. Additionally, we trained a Random Forest machine learning classifier on NBS data to improve prediction of true and false-positive MMA cases.RESULTS: Of 28 MMA patients sequenced, we found two pathogenic or likely pathogenic (P/LP) variants in a MMA-related gene in 24 patients, and one pathogenic variant and a variant of unknown significance (VUS) in 1 patient. No such variant combinations were detected in MMA false positives and healthy controls. Random Forest-based analysis of the entire NBS metabolic profile correctly identified the MMA patients and reduced MMA false-positive cases by 51%. MMA screen-positive newborns were more likely of Hispanic ethnicity.CONCLUSION: Our two-pronged approach reduced false positives by half and provided a reportable molecular finding for 89% of MMA patients. Challenges remain in newborn metabolic screening and DNA variant interpretation in diverse multiethnic populations.

  View details for PubMedID 30209273

• Current clinical evidence does not support a link between TBL1XR1 and Rett syndrome: Description of one patient with Rett features and a novel mutation in TBL1XR1, and a review of TBL1XR1 phenotypes AMERICAN JOURNAL OF MEDICAL GENETICS PART A Zaghlula, M., Glaze, D. G., Enns, G. M., Potocki, L., Schwabe, A. L., Suter, B. 2018; 176 (7): 1683–87

  View details for PubMedID 29777588

• Mitochondrial disease phenotypes of 999 patients in the North American Mitochondrial Disease Consortium (NAMDC) Barca, E., Cooley, V., Schoenaker, R., Emmanuele, V., DiMauro, S., Cohen, B., Karaa, A., Vladutiu, G., Haas, R., Haas, R., Van Hove, J., Scaglia, F., Parikh, S., Bedoyan, J., DeBrosse, S., Gavrilova, R., Saneto, R., Enns, G., Stacpoole, P., Ganesh, J., Larson, A., Zolkipli-Cunningham, Z., Falk, M., Goldstein, A., Tarnopolsky, M., Camp, K., Krotoski, D., Engelstad, K., Rosales, X., Kriger, J., Buchsbaum, R., Thompson, J., Hirano, M. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090800152

• PERSPECTIVES ON UREA CYCLE DISORDER MANAGEMENT: RESULTS OF A CLINICIAN SURVEY Burdett, A., Francis-Sedlak, M., Vockley, J., Enns, G. M. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2018: 221–22

  View details for Web of Science ID 000428001200054

• A New Approach to Rare Diseases of Children: The Undiagnosed Diseases Network. The Journal of pediatrics Reuter, C. M., Brimble, E. n., DeFilippo, C. n., Dries, A. M., Enns, G. M., Ashley, E. A., Bernstein, J. A., Fisher, P. G., Wheeler, M. T. 2018

  View details for PubMedID 29331327

• Triheptanoin: A Rescue Therapy for Cardiogenic Shock in Carnitine-acylcarnitine Translocase Deficiency. JIMD reports Mahapatra, S., Ananth, A., Baugh, N., Damian, M., Enns, G. M. 2018; 39: 19–23

  Abstract

  Carnitine-acylcarnitine translocase (CACT) deficiency is a rare long-chain fatty acid oxidation disorder (LC-FAOD) with high mortality due to cardiomyopathy or lethal arrhythmia. Triheptanoin (UX007), an investigational drug composed of synthetic medium odd-chain triglycerides, is a novel therapy in development for LC-FAOD patients. However, cases of its safe and efficacious use to reverse severe heart failure in CACT deficiency are limited. Here, we present a detailed report of an infant with CACT deficiency admitted in metabolic crisis that progressed into severe cardiogenic shock who was successfully treated by triheptanoin. The child was managed, thereafter, on triheptanoin until her death at 3 years of age from a cardiopulmonary arrest in the setting of acute respiratory illness superimposed on chronic hypercarbic respiratory failure.

  View details for PubMedID 28689308

• Triheptanoin: A Rescue Therapy for Cardiogenic Shock in Carnitine-acylcarnitine Translocase Deficiency JIMD REPORTS, VOL 39 Mahapatra, S., Ananth, A., Baugh, N., Damian, M., Enns, G. M., Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters 2018; 39: 19–23

  View details for DOI 10.1007/8904_2017_36

  View details for Web of Science ID 000460678800004

• Prenatal treatment of ornithine transcarbamylase deficiency. Molecular genetics and metabolism Wilnai, Y. n., Blumenfeld, Y. J., Cusmano, K. n., Hintz, S. R., Alcorn, D. n., Benitz, W. E., Berquist, W. E., Bernstein, J. A., Castillo, R. O., Concepcion, W. n., Cowan, T. M., Cox, K. L., Lyell, D. J., Esquivel, C. O., Homeyer, M. n., Hudgins, L. n., Hurwitz, M. n., Palma, J. P., Schelley, S. n., Akula, V. P., Summar, M. L., Enns, G. M. 2018

  Abstract

  Patients with neonatal urea cycle defects (UCDs) typically experience severe hyperammonemia during the first days of life, which results in serious neurological injury or death. Long-term prognosis despite optimal pharmacological and dietary therapy is still poor. The combination of intravenous sodium phenylacetate and sodium benzoate (Ammonul®) can eliminate nitrogen waste independent of the urea cycle. We report attempts to improve outcomes for males with severe ornithine transcarbamylase deficiency (OTCD), a severe X-linked condition, via prenatal intravenous administration of Ammonul and arginine to heterozygous carrier females of OTCD during labor.Two heterozygote OTCD mothers carrying male fetuses with a prenatal diagnosis of OTCD received intravenous Ammonul, arginine and dextrose-containing fluids shortly before birth. Maintenance Ammonul and arginine infusions and high-caloric enteral nutrition were started immediately after birth. Ammonul metabolites were measured in umbilical cord blood and the blood of the newborn immediately after delivery. Serial ammonia and biochemical analyses were performed following delivery.Therapeutic concentrations of Ammonul metabolites were detected in umbilical cord and neonatal blood samples. Plasma ammonia and glutamine levels in the postnatal period were within the normal range. Peak ammonia levels in the first 24-48h were 53mcmol/l and 62mcmol/l respectively. The boys did not experience neurological sequelae secondary to hyperammonemia and received liver transplantation at ages 3months and 5months. The patients show normal development at ages 7 and 3years.Prenatal treatment of mothers who harbor severe OTCD mutations and carry affected male fetuses with intravenous Ammonul and arginine, followed by immediate institution of maintenance infusions after delivery, results in therapeutic levels of benzoate and phenylacetate in the newborn at delivery and, in conjunction with high-caloric enteral nutrition, prevents acute hyperammonemia and neurological decompensation. Following initial medical management, early liver transplantation may improve developmental outcome.

  View details for PubMedID 29396029

• Management of ophthalmologic manifestations of mitochondrial diseases Response GENETICS IN MEDICINE Parikh, S., Goldstein, A., Karaa, A., Koenig, M., Anselm, I., Brunel-Guitton, C., Christodoulou, J., Cohen, B. H., Dimmock, D., Enns, G. M., Falk, M. J., Feigenbaum, A., Frye, R. E., Ganesh, J., Griesemer, D., Haas, R., Horvath, R., Korson, M., Kruer, M. C., Mancuso, M., McCormack, S., Raboisson, M., Reimschisel, T., Salvarinova, R., Saneto, R. P., Scaglia, F., Shoffner, J., Stacpoole, P. W., Sue, C. M., Tarnopolsky, M., Van Karnebeek, C., Wolfe, L. A., Cunningham, Z., Rahman, S., Chinnery, P. F. 2017; 19 (12)

  View details for PubMedID 29215644

• Correction of hyperleucinemia in MSUD patients on leucine-free dietary therapy MOLECULAR GENETICS AND METABOLISM Scott, A. I., Cusmano-Ozog, K., Enns, G. M., Cowan, T. M. 2017; 122 (4): 156–59

  View details for DOI 10.1016/j.ymgme.2017.09.012

  View details for Web of Science ID 000418879000003

• Correction of hyperleucinemia in MSUD patients on leucine-free dietary therapy. Molecular genetics and metabolism Scott, A. I., Cusmano-Ozog, K., Enns, G. M., Cowan, T. M. 2017

  Abstract

  PURPOSE: Maple Syrup Urine Disease (MSUD) is a rare disorder of branched-chain amino acid catabolism associated with encephalopathy from accumulation of leucine. Leucine is closely monitored during normal growth and particularly during acute illness. As most hospitals do not have access to rapid plasma amino acid quantification, the initial management is often empirical. A model describing the reduction of plasma leucine in hyperleucinemic patients on leucine-free formula would help to guide management and optimize testing frequency.METHODS: We retrospectively reviewed charts from 15 MSUD patients comprising 29 episodes of hyperleucinemia that were managed with leucine-free formula. Episodes were categorized by clinical presentation.RESULTS: Upon leucine restriction, plasma leucine concentrations fell exponentially at a rate proportional to approximately 50% of the starting value over each 24-hour period. Recovery appears to be sensitive to clinical status and triggering event of the hyperleucinemic episode. Patients with upper respiratory infections generally recovered slowly, while cases of dietary non-adherence resolved more quickly.CONCLUSION: This general model may help anticipate leucine levels during clinical management of MSUD patients when using nutritional support and leucine-free formula. The response of individual patients may vary depending on clinical status and triggering factors.

  View details for PubMedID 29032949

• Pediatric mitochondrial diseases and the heart CURRENT OPINION IN PEDIATRICS Enns, G. M. 2017; 29 (5): 541–51

  Abstract

  Mitochondrial disorders are an increasingly recognized cause of heart dysfunction, with the primary manifestations being cardiomyopathy and conduction defects. This review focuses on the complex genetics of mitochondrial disease and recently discovered conditions that affect mitochondrial function.Next-generation sequencing techniques, especially whole-exome sequencing, have led to the discovery of a number of conditions that cause mitochondrial dysfunction and subsequent cardiac abnormalities. Nuclear DNA defects are the main cause of mitochondrial disease in children, with disease pathogenesis being related to either abnormalities in specific mitochondrial electron transport chain subunits or in proteins related to subunit or mitochondrial DNA maintenance, mitochondrial protein translation, lipid bilayer structure, or other aspects of mitochondrial function.Currently, symptomatic therapy using standard medications targeting relief of complications is the primary approach to treatment. There are no US Food and Drug Administration-approved therapies for the specific treatment of mitochondrial disease. However, on the basis of recent advances in understanding of the pathophysiology of these complex disorders, various novel approaches are either in clinical trials or in development.

  View details for PubMedID 28719387

• Acylcarnitine Profiles Reflect Metabolic Vulnerability for Necrotizing Enterocolitis in Newborns Born Premature. journal of pediatrics Sylvester, K. G., Kastenberg, Z. J., Moss, R. L., Enns, G. M., Cowan, T. M., Shaw, G. M., Stevenson, D. K., Sinclair, T. J., Scharfe, C., Ryckman, K. K., Jelliffe-Pawlowski, L. L. 2017; 181: 80-85 e1

  Abstract

  To evaluate the association between newborn acylcarnitine profiles and the subsequent development of necrotizing enterocolitis (NEC) with the use of routinely collected newborn screening data in infants born preterm.A retrospective cohort study was conducted with the use of discharge records for infants born preterm admitted to neonatal intensive care units in California from 2005 to 2009 who had linked state newborn screening results. A model-development cohort of 94 110 preterm births from 2005 to 2008 was used to develop a risk-stratification model that was then applied to a validation cohort of 22 992 births from 2009.Fourteen acylcarnitine levels and acylcarnitine ratios were associated with increased risk of developing NEC. Each log unit increase in C5 and free carnitine /(C16 + 18:1) was associated with a 78% and a 76% increased risk for developing NEC, respectively (OR 1.78, 95% CI 1.53-2.02, and OR 1.76, 95% CI 1.51-2.06). Six acylcarnitine levels, along with birth weight and total parenteral nutrition, identified 89.8% of newborns with NEC in the model-development cohort (area under the curve 0.898, 95% CI 0.889-0.907) and 90.8% of the newborns with NEC in the validation cohort (area under the curve 0.908, 95% CI 0.901-0.930).Abnormal fatty acid metabolism was associated with prematurity and the development of NEC. Metabolic profiling through newborn screening may serve as an objective biologic surrogate of risk for the development of disease and thus facilitate disease-prevention strategies.

  View details for DOI 10.1016/j.jpeds.2016.10.019

  View details for PubMedID 27836286

• Pathogenic variants in HTRA2 cause an early-onset mitochondrial syndrome associated with 3-methylglutaconic aciduria JOURNAL OF INHERITED METABOLIC DISEASE Olahova, M., Thompson, K., Hardy, S. A., Barbosa, I. A., Besse, A., Anagnostou, M., White, K., Davey, T., Simpson, M. A., Champion, M., Enns, G., Schelley, S., Lightowlers, R. N., Chrzanowska-Lightowlers, Z. M., McFarland, R., Deshpande, C., Bonnen, P. E., Taylor, R. W. 2017; 40 (1): 121-130

  Abstract

  Mitochondrial diseases collectively represent one of the most heterogeneous group of metabolic disorders. Symptoms can manifest at any age, presenting with isolated or multiple-organ involvement. Advances in next-generation sequencing strategies have greatly enhanced the diagnosis of patients with mitochondrial disease, particularly where a mitochondrial aetiology is strongly suspected yet OXPHOS activities in biopsied tissue samples appear normal. We used whole exome sequencing (WES) to identify the molecular basis of an early-onset mitochondrial syndrome-pathogenic biallelic variants in the HTRA2 gene, encoding a mitochondria-localised serine protease-in five subjects from two unrelated families characterised by seizures, neutropenia, hypotonia and cardio-respiratory problems. A unifying feature in all affected children was 3-methylglutaconic aciduria (3-MGA-uria), a common biochemical marker observed in some patients with mitochondrial dysfunction. Although functional studies of HTRA2 subjects' fibroblasts and skeletal muscle homogenates showed severely decreased levels of mutant HTRA2 protein, the structural subunits and complexes of the mitochondrial respiratory chain appeared normal. We did detect a profound defect in OPA1 processing in HTRA2-deficient fibroblasts, suggesting a role for HTRA2 in the regulation of mitochondrial dynamics and OPA1 proteolysis. In addition, investigated subject fibroblasts were more susceptible to apoptotic insults. Our data support recent studies that described important functions for HTRA2 in programmed cell death and confirm that patients with genetically-unresolved 3-MGA-uria should be screened by WES with pathogenic variants in the HTRA2 gene prioritised for further analysis.

  View details for DOI 10.1007/s10545-016-9977-2

  View details for Web of Science ID 000391132500009

  View details for PubMedCentralID PMC5203855

• Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Parikh, S., Goldstein, A., Karaa, A., Koenig, M. K., Anselm, I., Brunel-Guitton, C., Christodoulou, J., Cohen, B. H., Dimmock, D., Enns, G. M., Falk, M. J., Feigenbaum, A., Frye, R. E., Ganesh, J., Griesemer, D., Haas, R., Horvath, R., Korson, M., Kruer, M. C., Mancuso, M., McCormack, S., Raboisson, M. J., Reimschisel, T., Salvarinova, R., Saneto, R. P., Scaglia, F., Shoffner, J., Stacpoole, P. W., Sue, C. M., Tarnopolsky, M., Van Karnebeek, C., Wolfe, L. A., Cunningham, Z. Z., Rahman, S., Chinnery, P. F. 2017

  Abstract

  The purpose of this statement is to provide consensus-based recommendations for optimal management and care for patients with primary mitochondrial disease. This statement is intended for physicians who are engaged in the diagnosis and management of these patients. Working group members were appointed by the Mitochondrial Medicine Society. The panel included members with several different areas of expertise. The panel members utilized surveys and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve. Consensus-based recommendations are provided for the routine care and management of patients with primary genetic mitochondrial disease.

  View details for PubMedID 28749475

• De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability. American journal of human genetics Küry, S. n., van Woerden, G. M., Besnard, T. n., Proietti Onori, M. n., Latypova, X. n., Towne, M. C., Cho, M. T., Prescott, T. E., Ploeg, M. A., Sanders, S. n., Stessman, H. A., Pujol, A. n., Distel, B. n., Robak, L. A., Bernstein, J. A., Denommé-Pichon, A. S., Lesca, G. n., Sellars, E. A., Berg, J. n., Carré, W. n., Busk, Ø. L., van Bon, B. W., Waugh, J. L., Deardorff, M. n., Hoganson, G. E., Bosanko, K. B., Johnson, D. S., Dabir, T. n., Holla, Ø. L., Sarkar, A. n., Tveten, K. n., de Bellescize, J. n., Braathen, G. J., Terhal, P. A., Grange, D. K., van Haeringen, A. n., Lam, C. n., Mirzaa, G. n., Burton, J. n., Bhoj, E. J., Douglas, J. n., Santani, A. B., Nesbitt, A. I., Helbig, K. L., Andrews, M. V., Begtrup, A. n., Tang, S. n., van Gassen, K. L., Juusola, J. n., Foss, K. n., Enns, G. M., Moog, U. n., Hinderhofer, K. n., Paramasivam, N. n., Lincoln, S. n., Kusako, B. H., Lindenbaum, P. n., Charpentier, E. n., Nowak, C. B., Cherot, E. n., Simonet, T. n., Ruivenkamp, C. A., Hahn, S. n., Brownstein, C. A., Xia, F. n., Schmitt, S. n., Deb, W. n., Bonneau, D. n., Nizon, M. n., Quinquis, D. n., Chelly, J. n., Rudolf, G. n., Sanlaville, D. n., Parent, P. n., Gilbert-Dussardier, B. n., Toutain, A. n., Sutton, V. R., Thies, J. n., Peart-Vissers, L. E., Boisseau, P. n., Vincent, M. n., Grabrucker, A. M., Dubourg, C. n., Tan, W. H., Verbeek, N. E., Granzow, M. n., Santen, G. W., Shendure, J. n., Isidor, B. n., Pasquier, L. n., Redon, R. n., Yang, Y. n., State, M. W., Kleefstra, T. n., Cogné, B. n., Petrovski, S. n., Retterer, K. n., Eichler, E. E., Rosenfeld, J. A., Agrawal, P. B., Bézieau, S. n., Odent, S. n., Elgersma, Y. n., Mercier, S. n. 2017; 101 (5): 768–88

  Abstract

  Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.

  View details for PubMedID 29100089

• Expanding the phenotype of hawkinsinuria: new insights from response to N-acetyl-L-cysteine. Journal of inherited metabolic disease Gomez-Ospina, N., Scott, A. I., Oh, G. J., Potter, D., Goel, V. V., Destino, L., Baugh, N., Enns, G. M., Niemi, A., Cowan, T. M. 2016; 39 (6): 821-829

  Abstract

  Hawkinsinuria is a rare disorder of tyrosine metabolism that can manifest with metabolic acidosis and growth arrest around the time of weaning off breast milk, typically followed by spontaneous resolution of symptoms around 1 year of age. The urinary metabolites hawkinsin, quinolacetic acid, and pyroglutamic acid can aid in identifying this condition, although their relationship to the clinical manifestations is not known. Herein we describe clinical and laboratory findings in two fraternal twins with hawkinsinuria who presented with failure to thrive and metabolic acidosis. Close clinical follow-up and laboratory testing revealed previously unrecognized hypoglycemia, hypophosphatemia, combined hyperlipidemia, and anemia, along with the characteristic urinary metabolites, including massive pyroglutamic aciduria. Treatment with N-acetyl-L-cysteine (NAC) restored normal growth and normalized or improved most biochemical parameters. The dramatic response to NAC therapy supports the idea that glutathione depletion plays a key role in the pathogenesis of hawkinsinuria.

  View details for PubMedID 27488560

• An Open-Label, Dose-Escalation Study to Assess the Safety, Tolerability, Efficacy, Pharmacokinetics and Pharmacodynamics of Cysteamine Bitartrate Delayed-release Capsules (RP103) for Treatment of Children with Inherited Mitochondrial Disease (RP103-MITO-001) Cohen, B. H., Enns, G. M., Haas, R., Longo, N., Scaglia, F., Lang, W., Sile, S. ELSEVIER SCI LTD. 2016: 117

  View details for Web of Science ID 000388431500086

• Triheptanoin treatment in patients with pediatric cardiomyopathy associated with long chain-fatty acid oxidation disorders. Molecular genetics and metabolism Vockley, J., Charrow, J., Ganesh, J., Eswara, M., DIAZ, G. A., McCracken, E., Conway, R., Enns, G. M., Starr, J., Wang, R., Abdenur, J. E., Sanchez-de-Toledo, J., Marsden, D. L. 2016; 119 (3): 223-231

  Abstract

  Long-chain fatty acid oxidation disorders (LC-FAOD) can cause cardiac hypertrophy and cardiomyopathy, often presenting in infancy, typically leading to death or heart transplant despite ongoing treatment. Previous data on triheptanoin treatment of cardiomyopathy in LC-FAOD suggested a clinical benefit on heart function during acute failure. An additional series of LC-FAOD patients with critical emergencies associated with cardiomyopathy was treated with triheptanoin under emergency treatment or compassionate use protocols. Case reports from 10 patients (8 infants) with moderate or severe cardiomyopathy associated with LC-FAOD are summarized. The majority of these patients were detected by newborn screening, with follow up confirmatory testing, including mutation analysis; all patients were managed with standard treatment, including medium chain triglyceride (MCT) oil. While on this regimen, they presented with acute heart failure requiring hospitalization and cardiac support (ventilation, ECMO, vasopressors) and, in some cases, resuscitation. The patients discontinued MCT oil and began treatment with triheptanoin, an investigational drug. Triheptanoin is expected to provide anaplerotic metabolites, to replace deficient TCA cycle intermediates and improve effective energy metabolism. Cardiac function was measured by echocardiography and ejection fraction (EF) was assessed. EF was moderately to severely impaired prior to triheptanoin treatment, ranging from 12-45%. Improvements in EF began between 2 and 21days following initiation of triheptanoin, and peaked at 33-71%, with 9 of 10 patients achieving EF in the normal range. Continued treatment was associated with longer-term stabilization of clinical signs of cardiomyopathy. The most common adverse event observed was gastrointestinal distress. Of the 10 patients, 7 have continued on treatment, 1 elected to discontinue due to tolerability issues, and 2 patients died from other causes. Two of the case histories illustrate that cardiomyopathy may also develop later in childhood and/or persist into adulthood. Overall, the presented cases suggest a therapeutic effect of triheptanoin in the management of acute cardiomyopathy associated with LC-FAOD.

  View details for DOI 10.1016/j.ymgme.2016.08.008

  View details for PubMedID 27590926

• Nutritional interventions in primary mitochondrial disorders: Developing an evidence base. Molecular genetics and metabolism Camp, K. M., Krotoski, D., Parisi, M. A., Gwinn, K. A., Cohen, B. H., Cox, C. S., Enns, G. M., Falk, M. J., Goldstein, A. C., Gopal-Srivastava, R., Gorman, G. S., Hersh, S. P., Hirano, M., Hoffman, F. A., Karaa, A., MacLeod, E. L., McFarland, R., Mohan, C., Mulberg, A. E., Odenkirchen, J. C., Parikh, S., Rutherford, P. J., Suggs-Anderson, S. K., Tang, W. H., Vockley, J., Wolfe, L. A., Yannicelli, S., Yeske, P. E., Coates, P. M. 2016; 119 (3): 187-206

  Abstract

  In December 2014, a workshop entitled "Nutritional Interventions in Primary Mitochondrial Disorders: Developing an Evidence Base" was convened at the NIH with the goals of exploring the use of nutritional interventions in primary mitochondrial disorders (PMD) and identifying knowledge gaps regarding their safety and efficacy; identifying research opportunities; and forging collaborations among researchers, clinicians, patient advocacy groups, and federal partners. Sponsors included the NIH, the Wellcome Trust, and the United Mitochondrial Diseases Foundation. Dietary supplements have historically been used in the management of PMD due to their potential benefits and perceived low risk, even though little evidence exists regarding their effectiveness. PMD are rare and clinically, phenotypically, and genetically heterogeneous. Thus patient recruitment for randomized controlled trials (RCTs) has proven to be challenging. Only a few RCTs examining dietary supplements, singly or in combination with other vitamins and cofactors, are reported in the literature. Regulatory issues pertaining to the use of dietary supplements as treatment modalities further complicate the research and patient access landscape. As a preface to exploring a research agenda, the workshop included presentations and discussions on what PMD are; how nutritional interventions are used in PMD; challenges and barriers to their use; new technologies and approaches to diagnosis and treatment; research opportunities and resources; and perspectives from patient advocacy, industry, and professional organizations. Seven key areas were identified during the workshop. These areas were: 1) defining the disease, 2) clinical trial design, 3) biomarker selection, 4) mechanistic approaches, 5) challenges in using dietary supplements, 6) standards of clinical care, and 7) collaboration issues. Short- and long-term goals within each of these areas were identified. An example of an overarching goal is the enrollment of all individuals with PMD in a natural history study and a patient registry to enhance research capability. The workshop demonstrates an effective model for fostering and enhancing collaborations among NIH and basic research, clinical, patient, pharmaceutical industry, and regulatory stakeholders in the mitochondrial disease community to address research challenges on the use of dietary supplements in PMD.

  View details for DOI 10.1016/j.ymgme.2016.09.002

  View details for PubMedID 27665271

• De Novo Mutations in CHD4, an ATP-Dependent Chromatin Remodeler Gene, Cause an Intellectual Disability Syndrome with Distinctive Dysmorphisms AMERICAN JOURNAL OF HUMAN GENETICS Weiss, K., Terhal, P. A., Cohen, L., Bruccoleri, M., Irving, M., Martinez, A. F., Rosenfeld, J. A., Machol, K., Yang, Y., Liu, P., Walkiewicz, M., Beuten, J., Gomez-Ospina, N., Haude, K., Fong, C., Enns, G. M., Bernstein, J. A., Fan, J., Gotway, G., Ghorbani, M., van Gassen, K., Monroe, G. R., van Haaften, G., Basel-Vanagaite, L., Yang, X., Campeau, P. M., Muenke, M. 2016; 99 (4): 934-941

  Abstract

  Chromodomain helicase DNA-binding protein 4 (CHD4) is an ATP-dependent chromatin remodeler involved in epigenetic regulation of gene transcription, DNA repair, and cell cycle progression. Also known as Mi2β, CHD4 is an integral subunit of a well-characterized histone deacetylase complex. Here we report five individuals with de novo missense substitutions in CHD4 identified through whole-exome sequencing and web-based gene matching. These individuals have overlapping phenotypes including developmental delay, intellectual disability, hearing loss, macrocephaly, distinct facial dysmorphisms, palatal abnormalities, ventriculomegaly, and hypogonadism as well as additional findings such as bone fusions. The variants, c.3380G>A (p.Arg1127Gln), c.3443G>T (p.Trp1148Leu), c.3518G>T (p.Arg1173Leu), and c.3008G>A, (p.Gly1003Asp) (GenBank: NM_001273.3), affect evolutionarily highly conserved residues and are predicted to be deleterious. Previous studies in yeast showed the equivalent Arg1127 and Trp1148 residues to be crucial for SNF2 function. Furthermore, mutations in the same positions were reported in malignant tumors, and a de novo missense substitution in an equivalent arginine residue in the C-terminal helicase domain of SMARCA4 is associated with Coffin Siris syndrome. Cell-based studies of the p.Arg1127Gln and p.Arg1173Leu mutants demonstrate normal localization to the nucleus and HDAC1 interaction. Based on these findings, the mutations potentially alter the complex activity but not its formation. This report provides evidence for the role of CHD4 in human development and expands an increasingly recognized group of Mendelian disorders involving chromatin remodeling and modification.

  View details for DOI 10.1016/j.ajhg.2016.08.001

  View details for PubMedID 27616479

• Impaired Health-Related Quality of Life in Children and Families Affected by Methylmalonic Acidemia. Journal of genetic counseling Splinter, K., Niemi, A., Cox, R., Platt, J., Shah, M., Enns, G. M., Kasahara, M., Bernstein, J. A. 2016; 25 (5): 936-944

  Abstract

  An understanding of health related quality of life (HRQoL) in children and families affected by methylmalonic acidemia (MMA) is important in planning counseling and therapeutic intervention. Liver transplantation (LT) is used as a treatment for MMA; however, its risks and benefits continue to be investigated. The purpose of this study was twofold: (1) to measure HRQoL in children and families affected by MMA using the Pediatric Quality of Life Inventory (PedsQL™) parent version, and (2) to assess the impact of LT on HRQoL by comparing LT and non-LT patient scores and free responses. Parents/caregivers reported lower scores on the majority of the PedsQL™ scales as compared to samples of healthy children, children with solid organ transplants for indications other than MMA, and families affected by chronic conditions. Scores for children with MMA were lowest in school and social functioning and scores for families were lowest in worry and activity impairment. There were no significant differences in LT and non-LT patient scores on the PedsQL™ scales. Our results document the negative impact of MMA on HRQoL.

  View details for DOI 10.1007/s10897-015-9921-x

  View details for PubMedID 26667650

• The M405V allele of the glutaryl-CoA dehydrogenase gene is an important marker for glutaric aciduria type I (GA-I) low excretors. Molecular genetics and metabolism Schillaci, L. P., Greene, C. L., Strovel, E., Rispoli-Joines, J., Spector, E., Woontner, M., Scharer, G., Enns, G. M., Gallagher, R., Zinn, A. B., McCandless, S. E., Hoppel, C. L., Goodman, S. I., Bedoyan, J. K. 2016; 119 (1-2): 50-56

  Abstract

  Glutaric aciduria type I (GA-I) is an autosomal recessive organic aciduria resulting from a functional deficiency of glutaryl-CoA dehydrogenase, encoded by GCDH. Two clinically indistinguishable diagnostic subgroups of GA-I are known; low and high excretors (LEs and HEs, respectively). Early medical and dietary interventions can result in significantly better outcomes and improved quality of life for patients with GA-I. We report on nine cases of GA-I LE patients all sharing the M405V allele with two cases missed by newborn screening (NBS) using tandem mass spectrometry (MS/MS). We describe a novel case with the known pathogenic M405V variant and a novel V133L variant, and present updated and previously unreported clinical, biochemical, functional and molecular data on eight other patients all sharing the M405V allele. Three of the nine patients are of African American ancestry, with two as siblings. GCDH activity was assayed in six of the nine patients and varied from 4 to 25% of the control mean. We support the use of urine glutarylcarnitine as a biochemical marker of GA-I by demonstrating that glutarylcarnitine is efficiently cleared by the kidney (50-90%) and that plasma and urine glutarylcarnitine follow a linear relationship. We report the allele frequencies for three known GA-I LE GCDH variants (M405V, V400M and R227P) and note that both the M405V and V400M variants are significantly more common in the population of African ancestry compared to the general population. This report highlights the M405V allele as another important molecular marker in patients with the GA-I LE phenotype. Therefore, the incorporation into newborn screening of molecular screening for the M405V and V400M variants in conjunction with MS/MS could help identify asymptomatic at-risk GA-I LE patients that could potentially be missed by current NBS programs.

  View details for DOI 10.1016/j.ymgme.2016.06.012

  View details for PubMedID 27397597

• Living donor liver transplantation for inborn errors of metabolism - An underutilized resource in the United States. Pediatric transplantation Pham, T. A., Enns, G. M., Esquivel, C. O. 2016; 20 (6): 770-773

  Abstract

  Inborn metabolic diseases of the liver can be life-threatening disorders that cause debilitating and permanent neurological damage. Symptoms may manifest as early as the neonatal period. Liver transplant replaces the enzymatically deficient liver, allowing for metabolism of toxic metabolites. LDLT for metabolic disorders is rarely performed in the United States as compared to countries such as Japan, where they report >2000 cases performed within the past two decades. Patient and graft survival is comparable to that of the United States, where most of the studies are based on deceased donors. No living donor complications were observed, suggesting that LDLT is as safe and effective as deceased donor transplants performed in the USA. Increased utilization of living donors in the USA will allow for early transplantation to prevent permanent neurological damage in those with severe disease. Pediatric transplant centers should consider utilizing living donors when feasible for children with metabolic disorders of the liver.

  View details for DOI 10.1111/petr.12746

  View details for PubMedID 27392539

• Clinical Course of Six Children With GNAO1 Mutations Causing a Severe and Distinctive Movement Disorder PEDIATRIC NEUROLOGY Ananth, A. L., Robichaux-Viehoever, A., Kim, Y., Hanson-Kahn, A., Cox, R., Enns, G. M., Strober, J., Willing, M., Schlaggar, B. L., Wu, Y. W., Bernstein, J. A. 2016; 59: 81-84

  Abstract

  Mutations in GNAO1 have been described in 11 patients to date. Although most of these individuals had epileptic encephalopathy, four patients had a severe movement disorder as the prominent feature. We describe the largest series of patients with de novoGNAO1 mutations who have severe chorea, developmental delay, and hypotonia in the absence of epilepsy.Six patients with recurrent missense mutations in GNAO1 as detected by whole exome sequencing were identified at three institutions. We describe the presentation, clinical course, and response to treatment of these patients.All six patients exhibited global developmental delay and hypotonia from infancy. Chorea developed by age four years in all but one patient, who developed chorea at 14 years. Treatments with neuroleptics and tetrabenazine were most effective in the baseline management of chorea. The chorea became gradually progressive and marked by episodes of severe, refractory ballismus requiring intensive care unit admissions in four of six patients. Exacerbations indirectly led to the death of two patients.Patients with GNAO1 mutations can present with a severe, progressive movement disorder in the absence of epilepsy. Exacerbations may be refractory to treatment and can result in life-threatening secondary complications. Early and aggressive treatment of these exacerbations with direct admission to intensive care units for treatment with anesthetic drips may prevent some secondary complications. However the chorea and ballismus can be refractory to maximum medical therapy.

  View details for DOI 10.1016/j.pediatrneurol.2016.02.018

  View details for PubMedID 27068059

• Prenatally Diagnosed Cases of Binder Phenotype Complicated by Respiratory Distress in the Immediate Postnatal Period. Journal of ultrasound in medicine Blumenfeld, Y. J., Davis, A. S., Hintz, S. R., Milan, K., Messner, A. H., Barth, R. A., Hudgins, L., Chueh, J., Homeyer, M., Bernstein, J. A., Enns, G., Atwal, P., Manning, M. 2016; 35 (6): 1353-1358

  Abstract

  Binder phenotype, or maxillonasal dysostosis, is a distinctive pattern of facial development characterized by a short nose with a flat nasal bridge, an acute nasolabial angle, a short columella, a convex upper lip, and class III malocclusion. We report 3 cases of prenatally diagnosed Binder phenotype associated with perinatal respiratory impairment.

  View details for DOI 10.7863/ultra.15.02050

  View details for PubMedID 27162279

• Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures AMERICAN JOURNAL OF HUMAN GENETICS Petrovski, S., Kury, S., Myers, C. T., Anyane-Yeboa, K., Cogne, B., Bialer, M., Xia, F., Hemati, P., Riviello, J., Mehaffey, M., Besnard, T., Becraft, E., Wadley, A., Politi, A. R., Colombo, S., Zhu, X., Ren, Z., Andrews, I., Dudding-Byth, T., Schneider, A. L., Wallace, G., Rosen, A. B., Schelley, S., Enns, G. M., Corre, P., Dalton, J., Mercier, S., Latypova, X., Schmitt, S., Guzman, E., Moore, C., Bier, L., Heinzen, E. L., Karachunski, P., Shur, N., Grebe, T., Basinger, A., Nguyen, J. M., Bezieau, S., Wierenga, K., Bernstein, J. A., Scheffer, I. E., Rosenfeld, J. A., Mefford, H. C., Isidor, B., Goldstein, D. B. 2016; 98 (5): 1001-1010

  Abstract

  Whole-exome sequencing of 13 individuals with developmental delay commonly accompanied by abnormal muscle tone and seizures identified de novo missense mutations enriched within a sub-region of GNB1, a gene encoding the guanine nucleotide-binding protein subunit beta-1, Gβ. These 13 individuals were identified among a base of 5,855 individuals recruited for various undiagnosed genetic disorders. The probability of observing 13 or more de novo mutations by chance among 5,855 individuals is very low (p = 7.1 × 10(-21)), implicating GNB1 as a genome-wide-significant disease-associated gene. The majority of these 13 mutations affect known Gβ binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for Gα-Gβγ interaction (resulting in a constitutively active Gβγ) or through the disruption of residues relevant for interaction between Gβγ and certain downstream effectors (resulting in reduced interaction with the effectors). Strikingly, 8 of the 13 individuals recruited here for a neurodevelopmental disorder have a germline de novo GNB1 mutation that overlaps a set of five recurrent somatic tumor mutations for which recent functional studies demonstrated a gain-of-function effect due to constitutive activation of G protein downstream signaling cascades for some of the affected residues.

  View details for DOI 10.1016/j.ajhg.2016.03.011

  View details for PubMedID 27108799

• Line intensities and temperature-dependent line broadening coefficients of Q-branch transitions in the v(2) band of ammonia near 10.4 mu m JOURNAL OF QUANTITATIVE SPECTROSCOPY & RADIATIVE TRANSFER Sur, R., Spearrin, R. M., Peng, W. Y., Strand, C. L., Jeffries, J. B., Enns, G. M., Hanson, R. K. 2016; 175: 90-99

  View details for DOI 10.1016/j.jqsrt.2016.02.002

  View details for Web of Science ID 000373542700009

• Line intensities and temperature-dependent line broadening coefficients of Q-branch transitions in the v2 band of ammonia near 10.4 μm. Journal of quantitative spectroscopy & radiative transfer Sur, R., Spearrin, R. M., Peng, W. Y., Strand, C. L., Jeffries, J. B., Enns, G. M., Hanson, R. K. 2016; 175: 90-99

  Abstract

  We report measured line intensities and temperature-dependent broadening coefficients of NH3 with Ar, N2, O2, CO2, H2O, and NH3 for nine sQ(J,K) transitions in the ν2 fundamental band in the frequency range 961.5-967.5 cm-1. This spectral region was chosen due to the strong NH3 absorption strength and lack of spectral interference from H2O and CO2 for laser-based sensing applications. Spectroscopic parameters were determined by multi-line fitting using Voigt lineshapes of absorption spectra measured with two quantum cascade lasers in thermodynamically-controlled optical cells. The temperature dependence of broadening was measured over a range of temperatures between 300 and 600 K. These measurements aid the development of mid-infrared NH3 sensors for a broad range of gas mixtures and at elevated temperatures.

  View details for DOI 10.1016/j.jqsrt.2016.02.002

  View details for PubMedID 29225373

  View details for PubMedCentralID PMC5722251

• Rapid progression and mortality of lysosomal acid lipase deficiency presenting in infants GENETICS IN MEDICINE Jones, S. A., Valayannopoulos, V., Schneider, E., Eckert, S., Banikazemi, M., Bialer, M., Cederbaum, S., Chan, A., Dhawan, A., Di Rocco, M., Domm, J., Enns, G. M., Finegold, D., Gargus, J. J., Guardamagna, O., Hendriksz, C., Mahmoud, I. G., Raiman, J., Selim, L. A., Whitley, C. B., Zaki, O., Quinn, A. G. 2016; 18 (5): 452-458

  Abstract

  The purpose of this study was to enhance understanding of lysosomal acid lipase deficiency (LALD) in infancy.Investigators reviewed medical records of infants with LALD and summarized data for the overall population and for patients with and without early growth failure (GF). Kaplan-Meier survival analyses were conducted for the overall population and for treated and untreated patients.Records for 35 patients, 26 with early GF, were analyzed. Prominent symptom manifestations included vomiting, diarrhea, and steatorrhea. Median age at death was 3.7 months; estimated probability of survival past age 12 months was 0.114 (95% confidence interval (CI): 0.009-0.220). Among patients with early GF, median age at death was 3.5 months; estimated probability of survival past age 12 months was 0.038 (95% CI: 0.000-0.112). Treated patients (hematopoietic stem cell transplant (HSCT), n = 9; HSCT and liver transplant, n = 1) in the overall population and the early GF subset survived longer than untreated patients, but survival was still poor (median age at death, 8.6 months).These data confirm and expand earlier insights on the progression and course of LALD presenting in infancy. Despite variations in the nature, onset, and severity of clinical manifestations, and treatment attempts, clinical outcome was poor.Genet Med 18 5, 452-458.

  View details for DOI 10.1038/gim.2015.108

  View details for PubMedID 26312827

• THE M405V ALLELE OF THE GLUTARYL-CoA DEHYDROGENASE GENE IS COMMON AMONG MANY GLUTARIC ACIDURIA TYPE I (GA-I) LOW EXCRETORS Schillaci, L., Greene, C., Strovel, E., Rispoli-Joines, J., Spector, E., Woontner, M., Scharer, G., Enns, G., Gallagher, R., Zinn, A., McCandless, S., Hoppel, C., Goodman, S., Bedoyan, J. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2016: 283

  View details for Web of Science ID 000372683600119

• OPA1-PLUS SYNDROMES MAY INCLUDE CARDIOMYOPATHY - EXPANDING THE PHENOTYPE Myers, A., Goyal, N., Vagelos, R., Zei, P. C., Enns, G. M. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2016: 273–74

  View details for Web of Science ID 000372683600099

• RATE OF LEUCINE CLEARANCE IN MSUD Scott, A. I., Cusmano-Ozog, K., Enns, G. M., Cowan, T. M. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2016: 284

  View details for Web of Science ID 000372683600122

• Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis NATURE COMMUNICATIONS Gomez-Ospina, N., Potter, C. J., Xiao, R., Manickam, K., Kim, M., Kim, K., Shneider, B. L., Picarsic, J. L., Jacobson, T. A., Zhang, J., He, W., Liu, P., Knisely, A. S., Finegold, M. J., Muzny, D. M., Boerwinkle, E., Lupski, J. R., Plon, S. E., Gibbs, R. A., Eng, C. M., Yang, Y., Washington, G. C., Porteus, M. H., Berquist, W. E., Kambham, N., Singh, R. J., Xia, F., Enns, G. M., Moore, D. D. 2016; 7

  View details for DOI 10.1038/ncomms10713

  View details for Web of Science ID 000371035200014

• Clinical Features of Lysosomal Acid Lipase Deficiency. Journal of pediatric gastroenterology and nutrition Burton, B. K., Deegan, P. B., Enns, G. M., Guardamagna, O., Horslen, S., Hovingh, G. K., Lobritto, S. J., Malinova, V., Mclin, V. A., Raiman, J., Di Rocco, M., Santra, S., Sharma, R., Sykut-Cegielska, J., Whitley, C. B., Eckert, S., Valayannopoulos, V., Quinn, A. G. 2015; 61 (6): 619-625

  Abstract

  The aim of this study was to characterize key clinical manifestations of lysosomal acid lipase deficiency (LAL D) in children and adults.Investigators reviewed medical records of LAL D patients ages ≥5 years, extracted historical data, and obtained prospective laboratory and imaging data on living patients to develop a longitudinal dataset.A total of 49 patients were enrolled; 48 had confirmed LAL D. Mean age at first disease-related abnormality was 9.0 years (range 0-42); mean age at diagnosis was 15.2 years (range 1-46). Twenty-nine (60%) were male patients, and 27 (56%) were <20 years of age at the time of consent/assent. Serum transaminases were elevated in most patients with 458 of 499 (92%) of alanine aminotransferase values and 265 of 448 (59%) of aspartate aminotransferase values above the upper limit of normal. Most patients had elevated low-density lipoprotein (64% patients) and total cholesterol (63%) at baseline despite most being on lipid-lowering therapies, and 44% had high-density lipoprotein levels below the lower limit of normal. More than half of the patients with liver biopsies (n = 31, mean age 13 years) had documented evidence of steatosis (87%) and/or fibrosis (52%). Imaging assessments revealed that the median liver volume was ∼1.15 multiples of normal (MN) and median spleen volume was ∼2.2 MN. Six (13%) patients had undergone a liver transplant (ages 9-43.5 years).This study provides the largest longitudinal case review of patients with LAL D and confirms that LAL D is predominantly a pediatric disease causing early and progressive hepatic dysfunction associated with dyslipidemia that often leads to liver failure and transplantation.

  View details for DOI 10.1097/MPG.0000000000000935

  View details for PubMedID 26252914

• Reply. journal of pediatrics Niemi, A., Enns, G. M. 2015; 167 (5): 1173-1174

  View details for DOI 10.1016/j.jpeds.2015.08.031

  View details for PubMedID 26362093

• De novo truncating variants in the AHDC1 gene encoding the AT-hook DNA-binding motif-containing protein 1 are associated with intellectual disability and developmental delay. Cold Spring Harbor molecular case studies Yang, H., Douglas, G., Monaghan, K. G., Retterer, K., Cho, M. T., Escobar, L. F., Tucker, M. E., Stoler, J., Rodan, L. H., Stein, D., Marks, W., Enns, G. M., Platt, J., Cox, R., Wheeler, P. G., Crain, C., Calhoun, A., Tryon, R., Richard, G., Vitazka, P., Chung, W. K. 2015; 1 (1)

  Abstract

  Whole-exome sequencing (WES) represents a significant breakthrough in clinical genetics, and identifies a genetic etiology in up to 30% of cases of intellectual disability (ID). Using WES, we identified seven unrelated patients with a similar clinical phenotype of severe intellectual disability or neurodevelopmental delay who were all heterozygous for de novo truncating variants in the AT-hook DNA-binding motif-containing protein 1 (AHDC1). The patients were all minimally verbal or nonverbal and had variable neurological problems including spastic quadriplegia, ataxia, nystagmus, seizures, autism, and self-injurious behaviors. Additional common clinical features include dysmorphic facial features and feeding difficulties associated with failure to thrive and short stature. The AHDC1 gene has only one coding exon, and the protein contains conserved regions including AT-hook motifs and a PDZ binding domain. We postulate that all seven variants detected in these patients result in a truncated protein missing critical functional domains, disrupting interactions with other proteins important for brain development. Our study demonstrates that truncating variants in AHDC1 are associated with ID and are primarily associated with a neurodevelopmental phenotype.

  View details for DOI 10.1101/mcs.a000562

  View details for PubMedID 27148574

• A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency. The New England journal of medicine Burton, B. K., Balwani, M., Feillet, F., Barić, I., Burrow, T. A., Camarena Grande, C., Coker, M., Consuelo-Sánchez, A., Deegan, P., Di Rocco, M., Enns, G. M., Erbe, R., Ezgu, F., Ficicioglu, C., Furuya, K. N., Kane, J., Laukaitis, C., Mengel, E., Neilan, E. G., Nightingale, S., Peters, H., Scarpa, M., Schwab, K. O., Smolka, V., Valayannopoulos, V., Wood, M., Goodman, Z., Yang, Y., Eckert, S., Rojas-Caro, S., Quinn, A. G. 2015; 373 (11): 1010-20

  Abstract

  Lysosomal acid lipase is an essential lipid-metabolizing enzyme that breaks down endocytosed lipid particles and regulates lipid metabolism. We conducted a phase 3 trial of enzyme-replacement therapy in children and adults with lysosomal acid lipase deficiency, an underappreciated cause of cirrhosis and severe dyslipidemia.In this multicenter, randomized, double-blind, placebo-controlled study involving 66 patients, we evaluated the safety and effectiveness of enzyme-replacement therapy with sebelipase alfa (administered intravenously at a dose of 1 mg per kilogram of body weight every other week); the placebo-controlled phase of the study was 20 weeks long and was followed by open-label treatment for all patients. The primary end point was normalization of the alanine aminotransferase level. Secondary end points included additional disease-related efficacy assessments, safety, and side-effect profile.Substantial disease burden at baseline included a very high level of low-density lipoprotein cholesterol (≥190 mg per deciliter) in 38 of 66 patients (58%) and cirrhosis in 10 of 32 patients (31%) who underwent biopsy. A total of 65 of the 66 patients who underwent randomization completed the double-blind portion of the trial and continued with open-label treatment. At 20 weeks, the alanine aminotransferase level was normal in 11 of 36 patients (31%) in the sebelipase alfa group and in 2 of 30 (7%) in the placebo group (P=0.03), with mean changes from baseline of -58 U per liter versus -7 U per liter (P<0.001). With respect to prespecified key secondary efficacy end points, we observed improvements in lipid levels and reduction in hepatic fat content (P<0.001 for all comparisons, except P=0.04 for triglycerides). The number of patients with adverse events was similar in the two groups; most events were mild and were considered by the investigator to be unrelated to treatment.Sebelipase alfa therapy resulted in a reduction in multiple disease-related hepatic and lipid abnormalities in children and adults with lysosomal acid lipase deficiency. (Funded by Synageva BioPharma and others; ARISE ClinicalTrials.gov number, NCT01757184.).

  View details for DOI 10.1056/NEJMoa1501365

  View details for PubMedID 26352813

• A congenital disorder of deglycosylation: Biochemical characterization of N-glycanase 1 deficiency in patient fibroblasts. Glycobiology He, P., Grotzke, J. E., Ng, B. G., Gunel, M., Jafar-Nejad, H., Cresswell, P., Enns, G. M., Freeze, H. H. 2015; 25 (8): 836-844

  Abstract

  N-Glycanase 1, encoded by NGLY1, catalyzes the deglycosylation of misfolded N-linked glycoproteins retrotranslocated into the cytosol. We identified nine cases with mutations in NGLY1. The patients show developmental delay, seizures, peripheral neuropathy, abnormal liver function and alacrima (absence of tears). The mutations in NGLY1 resulted in the absence of N-glycanase 1 protein in patient-derived fibroblasts. Applying a recently established cellular deglycosylation-dependent Venus fluorescence assay, we found that patient fibroblasts had dramatically reduced fluorescence, indicating a pronounced reduction in N-glycanase enzymatic activity. Using this assay, we could find no evidence of other related activities. Our findings reveal that NGLY1 mutations destroy both N-glycanase 1 protein and enzymatic activity.

  View details for DOI 10.1093/glycob/cwv024

  View details for PubMedID 25900930

• ClinGen - The Clinical Genome Resource NEW ENGLAND JOURNAL OF MEDICINE Rehm, H. L., Berg, J. S., Brooks, L. D., Bustamante, C. D., Evans, J. P., Landrum, M. J., Ledbetter, D. H., Maglott, D. R., Martin, C. L., Nussbaum, R. L., Plon, S. E., Ramos, E. M., Sherry, S. T., Watson, M. S. 2015; 372 (23): 2235-2242

  View details for DOI 10.1056/NEJMsr1406261

  View details for PubMedID 26014595

• Treatment of Methylmalonic Acidemia by Liver or Combined Liver-Kidney Transplantation JOURNAL OF PEDIATRICS Niemi, A., Kim, I. K., Krueger, C. E., Cowan, T. M., Baugh, N., Farrell, R., Bonham, C. A., Concepcion, W., Esquivel, C. O., Enns, G. M. 2015; 166 (6): 1455-?

  Abstract

  To assess biochemical, surgical, and long-term outcomes of liver (LT) or liver-kidney transplantation (LKT) for severe, early-onset methylmalonic acidemia/acid (MMA).A retrospective chart review (December 1997 to May 2012) of patients with MMA who underwent LT or LKT at Lucile Packard Children's Hospital at Stanford.Fourteen patients underwent LT (n = 6) or LKT (n = 8) at mean age 8.2 years (range 0.8-20.7). Eleven (79%) were diagnosed during the neonatal period, including 6 by newborn screening. All underwent deceased donor transplantation; 12 (86%) received a whole liver graft. Postoperative survival was 100%. At a mean follow-up of 3.25 ± 4.2 years, patient survival was 100%, liver allograft survival 93%, and kidney allograft survival 100%. One patient underwent liver re-transplantation because of hepatic artery thrombosis. After transplantation, there were no episodes of hyperammonemia, acidosis, or metabolic decompensation. The mean serum MMA at the time of transplantation was 1648 ± 1492 μmol/L (normal <0.3, range 99-4420). By 3 days, post-transplantation levels fell on average by 87% (mean 210 ± 154 μmol/L), and at 4 months, they were 83% below pre-transplantation levels (mean 305 ± 108 μmol/L). Developmental delay was present in 12 patients (86%) before transplantation. All patients maintained neurodevelopmental abilities or exhibited improvements in motor skills, learning abilities, and social functioning.LT or LKT for MMA eradicates episodes of hyperammonemia, results in excellent long-term survival, and suggests stabilization of neurocognitive development. Long-term follow-up is underway to evaluate whether patients who undergo early LT need kidney transplantation later in life.

  View details for DOI 10.1016/j.jpeds.2015.01.051

  View details for Web of Science ID 000355018200025

  View details for PubMedID 25771389

• Correlation of HMPAO uptake with live single cell synchrotron mid-Infrared spectromicroscopy in inherited mitochondrial disease Holman, E., Chen, L., Holman, H., Enns, G., Blankenberg, F. SOC NUCLEAR MEDICINE INC. 2015

  View details for Web of Science ID 000358738803171

• Long-term safety and efficacy of sapropterin: The PKUDOS registry experience MOLECULAR GENETICS AND METABOLISM Longo, N., Arnold, G. L., Pridjian, G., Enns, G. M., Ficicioglu, C., Parker, S., Cohen-Pfeffer, J. L. 2015; 114 (4): 557-563

  Abstract

  The Phenylketonuria (PKU) Demographics, Outcomes and Safety (PKUDOS) registry is designed to provide longitudinal safety and efficacy data on subjects with PKU who are (or have been) treated with sapropterin dihydrochloride. The PKUDOS population consists of 1189 subjects with PKU: N = 504 who were continuously exposed to sapropterin from date of registry enrollment, N = 211 who had intermittent exposure to the drug, and N = 474 with some other duration of exposure. Subjects continuously exposed to sapropterin showed an average 34% decrease in blood phenylalanine (Phe)--from 591 ± 382 μmol/L at baseline to 392 ± 239 μmol/L (p = 0.0009) after 5 years. This drop in blood Phe was associated with an increase in dietary Phe tolerance [from 1000 ± 959 mg/day (pre-sapropterin baseline) to 1539 ± 840 mg/day after 6 years]. Drug-related adverse events (AEs) were reported in 6% of subjects, were mostly considered non-serious, and were identified in the gastrointestinal, respiratory, and nervous systems. Serious drug-related AEs were reported in ≤ 1% of subjects. Similar safety and efficacy data were observed for children<4 years. Long-term data from the PKUDOS registry suggest that sapropterin has a tolerable safety profile and that continuous use is associated with a significant and persistent decrease in blood Phe and improvements in dietary Phe tolerance.

  View details for DOI 10.1016/j.ymgme.2015.02.003

  View details for PubMedID 25724073

• Identification of HIBCH Gene Mutations Causing Autosomal Recessive Leigh Syndrome: A Gene Involved in Valine Metabolism PEDIATRIC NEUROLOGY Soler-Alfonso, C., Enns, G. M., Koenig, M. K., Saavedra, H., Bonfante-Mejia, E., Northrup, H. 2015; 52 (3): 361-365

  Abstract

  Leigh syndrome is a progressive neurodegenerative disorder with usual onset of symptoms during the first year of life. The disorder has been associated with mutations in over 30 genes. This difficulty with genetic heterogeneity makes whole exome sequencing a more cost-effective approach for investigation of etiology.We describe an individual with typical Leigh syndrome who was found to have compound heterozygous mutations in the gene HIBCH (3-hydroxyisobutyryl coenzyme A hydrolase), an enzyme involved in the catabolism of valine. She exhibited significant clinical improvement after a valine-restricted diet.A subset of patients with uncharacterized Leigh syndrome present with specific biochemical abnormalities. This report highpoints the challenges and restrictions of routine metabolic testing and features the recognition of inborn errors of metabolism as potential treatable causes of Leigh syndrome.

  View details for DOI 10.1016/j.pediatrneurol.2014.10.023

  View details for PubMedID 25591832

• Results of a Global Phase 3, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Efficacy and Safety of Sebelipase Alfa as an Enzyme Replacement Therapy in Children and Adults with Lysosomal Acid Lipase Deficiency Balwani, M., Burton, B., Baric, I., Bialer, M., Burrow, T. A., Camarena Grande, C., Coker, M., Consuelo Sanchez, A., Deegan, P., Di Rocco, M., Enns, G. M., Erbe, R. W., Ezgu, F., Feillet, F., Ficicioglu, C., Furuya, K. N., Bernardo Guelbert, N., Kane, J., Kostyleva, M., Laukaitis, C. M., Malinova, V., Mengel, E., Murphy, E., Neilan, E. G., Nightingale, S., Pastor Rosado, J., Peters, H., Rahman, Y., Scarpa, M., Schwab, K., Smolka, V., Taybert, J., Valayannopoulos, V., Wood, M., Zeniya, M., Yang, Y., Eckert, S., Rojas-Caro, S., Quinn, A. G. WILEY-BLACKWELL. 2014: 1270A

  View details for Web of Science ID 000345517000006

• Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency JOURNAL OF HEPATOLOGY Valayannopoulos, V., Malinova, V., Honzik, T., Balwani, M., Breen, C., Deegan, P. B., Enns, G. M., Jones, S. A., Kane, J. P., Stock, E. O., Tripuraneni, R., Eckert, S., Schneider, E., Hamilton, G., Middleton, M. S., Sirlin, C., Kessler, B., Bourdon, C., Boyadjiev, S. A., Sharma, R., Twelves, C., Whitley, C. B., Quinn, A. G. 2014; 61 (5): 1135-1142

  Abstract

  Lysosomal acid lipase deficiency is an autosomal recessive enzyme deficiency resulting in lysosomal accumulation of cholesteryl esters and triglycerides. LAL-CL04, an ongoing extension study, investigates the long-term effects of sebelipase alfa, a recombinant human lysosomal acid lipase.Sebelipase alfa (1mg/kg or 3mg/kg) was infused every-other-week to eligible subjects. Safety and tolerability assessments, including liver function, lipid profiles and liver volume assessment, were carried out at regular intervals.216 infusions were administered to eight adult subjects through week 52 during LAL-CL04. At week 52, mean alanine aminotransferase and aspartate aminotransferase levels were normal with mean change from baseline of -58% and -40%. Mean changes for low-density lipoprotein, total cholesterol, triglyceride and high-density lipoprotein were -60%, -39%, -36%, and +29%, respectively. Mean liver volume by magnetic resonance imaging and hepatic proton density fat fraction decreased (12% and 55%, respectively). Adverse events were mainly mild and unrelated to sebelipase alfa. Infusion-related reactions were uncommon: three events of moderate severity were reported in two subjects; one patient's event was suggestive of a hypersensitivity-like reaction, but additional testing did not confirm this, and the subject has successfully re-started sebelipase alfa. Of samples tested to date, no anti-drug antibodies have been detected.Long-term dosing with sebelipase alfa in lysosomal acid lipase-deficient patients is well tolerated and produces sustained reductions in transaminases, improvements in serum lipid profile and reduction in the hepatic fat fraction. A randomized, placebo-controlled phase 3 trial in children and adults is underway (ARISE: NCT01757184).

  View details for DOI 10.1016/j.jhep.2014.06.022

  View details for Web of Science ID 000343839900022

  View details for PubMedCentralID PMC4203712

• Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency. Journal of hepatology Valayannopoulos, V., Malinova, V., Honzík, T., Balwani, M., Breen, C., Deegan, P. B., Enns, G. M., Jones, S. A., Kane, J. P., Stock, E. O., Tripuraneni, R., Eckert, S., Schneider, E., Hamilton, G., Middleton, M. S., Sirlin, C., Kessler, B., Bourdon, C., Boyadjiev, S. A., Sharma, R., Twelves, C., Whitley, C. B., Quinn, A. G. 2014; 61 (5): 1135-42

  Abstract

  Lysosomal acid lipase deficiency is an autosomal recessive enzyme deficiency resulting in lysosomal accumulation of cholesteryl esters and triglycerides. LAL-CL04, an ongoing extension study, investigates the long-term effects of sebelipase alfa, a recombinant human lysosomal acid lipase.Sebelipase alfa (1mg/kg or 3mg/kg) was infused every-other-week to eligible subjects. Safety and tolerability assessments, including liver function, lipid profiles and liver volume assessment, were carried out at regular intervals.216 infusions were administered to eight adult subjects through week 52 during LAL-CL04. At week 52, mean alanine aminotransferase and aspartate aminotransferase levels were normal with mean change from baseline of -58% and -40%. Mean changes for low-density lipoprotein, total cholesterol, triglyceride and high-density lipoprotein were -60%, -39%, -36%, and +29%, respectively. Mean liver volume by magnetic resonance imaging and hepatic proton density fat fraction decreased (12% and 55%, respectively). Adverse events were mainly mild and unrelated to sebelipase alfa. Infusion-related reactions were uncommon: three events of moderate severity were reported in two subjects; one patient's event was suggestive of a hypersensitivity-like reaction, but additional testing did not confirm this, and the subject has successfully re-started sebelipase alfa. Of samples tested to date, no anti-drug antibodies have been detected.Long-term dosing with sebelipase alfa in lysosomal acid lipase-deficient patients is well tolerated and produces sustained reductions in transaminases, improvements in serum lipid profile and reduction in the hepatic fat fraction. A randomized, placebo-controlled phase 3 trial in children and adults is underway (ARISE: NCT01757184).

  View details for DOI 10.1016/j.jhep.2014.06.022

  View details for PubMedID 24993530

  View details for PubMedCentralID PMC4203712

• Abnormal Hepatocellular Mitochondria in Methylmalonic Acidemia ULTRASTRUCTURAL PATHOLOGY Wilnai, Y., Enns, G. M., Niemi, A., Higgins, J., Vogel, H. 2014; 38 (5): 309-314

  Abstract

  Methylmalonic acidemia (MMA) is one of the most frequently encountered forms of branched-chain organic acidemias. Biochemical abnormalities seen in some MMA patients, such as lactic acidemia and increased tricarboxylic acid cycle intermediate excretion, suggest mitochondrial dysfunction. In order to investigate the possibility of mitochondrial involvement in MMA, we examined liver tissue for evidence of mitochondrial ultrastructural abnormalities. Five explanted livers obtained from MMA mut(0) patients undergoing liver transplantation were biopsied. All patients had previous episodes of metabolic acidosis, lactic acidemia, ketonuria, and hyperammonemia. All biopsies revealed a striking mitochondriopathy by electron microscopy. Mitochondria were markedly variable in size, shape, and conformation of cristae. The inner matrix appeared to be greatly expanded and the cristae were diminutive and disconnected. No crystalloid inclusions were noted. This series clearly documents extensive mitochondrial ultrastructure abnormalities in liver samples from MMA patients undergoing transplantation, providing pathological evidence for mitochondrial dysfunction in the pathophysiology of MMA mut(0). Considering the trend to abnormally large mitochondria, the metabolic effects of MMA may restrict mitochondrial fission or promote fusion. The correlation between mitochondrial dysfunction and morphological abnormalities in MMA may provide insights for better understanding and monitoring of optimized or novel therapeutic strategies.

  View details for DOI 10.3109/01913123.2014.921657

  View details for Web of Science ID 000345348700003

• Abnormal hepatocellular mitochondria in methylmalonic acidemia. Ultrastructural pathology Wilnai, Y., Enns, G. M., Niemi, A., Higgins, J., Vogel, H. 2014; 38 (5): 309-314

  Abstract

  Methylmalonic acidemia (MMA) is one of the most frequently encountered forms of branched-chain organic acidemias. Biochemical abnormalities seen in some MMA patients, such as lactic acidemia and increased tricarboxylic acid cycle intermediate excretion, suggest mitochondrial dysfunction. In order to investigate the possibility of mitochondrial involvement in MMA, we examined liver tissue for evidence of mitochondrial ultrastructural abnormalities. Five explanted livers obtained from MMA mut(0) patients undergoing liver transplantation were biopsied. All patients had previous episodes of metabolic acidosis, lactic acidemia, ketonuria, and hyperammonemia. All biopsies revealed a striking mitochondriopathy by electron microscopy. Mitochondria were markedly variable in size, shape, and conformation of cristae. The inner matrix appeared to be greatly expanded and the cristae were diminutive and disconnected. No crystalloid inclusions were noted. This series clearly documents extensive mitochondrial ultrastructure abnormalities in liver samples from MMA patients undergoing transplantation, providing pathological evidence for mitochondrial dysfunction in the pathophysiology of MMA mut(0). Considering the trend to abnormally large mitochondria, the metabolic effects of MMA may restrict mitochondrial fission or promote fusion. The correlation between mitochondrial dysfunction and morphological abnormalities in MMA may provide insights for better understanding and monitoring of optimized or novel therapeutic strategies.

  View details for DOI 10.3109/01913123.2014.921657

  View details for PubMedID 24933007

• Clinical whole-exome sequencing: are we there yet? Genetics in medicine Atwal, P. S., Brennan, M., Cox, R., Niaki, M., Platt, J., Homeyer, M., Kwan, A., Parkin, S., Schelley, S., Slattery, L., Wilnai, Y., Bernstein, J. A., Enns, G. M., Hudgins, L. 2014; 16 (9): 717-719

  Abstract

  Background:Clinical laboratories began offering whole-exome sequencing in 2011 at a cost between $4,500 and $9,000. Reported detection rates for deleterious mutations range from 25 to 50%. Based on the experience of our clinical genetics service, actual success rates may be lower than estimated rates. We report results from our own experience along with a survey of clinical geneticists to ascertain (i) current success rates for causal gene detection in a clinical setting; (ii) if there are insurance authorization issues; and (iii) if turnaround times quoted by the clinical laboratories are accurate; we also gauge provider opinions toward clinical whole-exome sequencing.Methods:We reviewed our results and the results of a survey that was electronically distributed to 47 clinical genetics centers.Results:A total of 35 exome reports were available. If all positive results are collated, we observe a success rate of 22.8%. One result incorrectly identified a known benign variant as pathogenic. Some insurers covered all testing, whereas others denied any insurance coverage. Only three (23.1%) of our reports were available within the laboratory's quoted turnaround times. More than 50% of clinicians queried in our survey had not ordered whole-exome sequencing at the current time, many stating concerns regarding interpretation, insurance coverage, and cost.Conclusion:Clinical whole-exome sequencing has proven diagnostic utility; however, currently many clinicians have concerns regarding interpretation of results, insurance coverage, and cost.Genet Med advance online publication 13 February 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.10.

  View details for DOI 10.1038/gim.2014.10

  View details for PubMedID 24525916

• Treatment of Mitochondrial Disorders: Antioxidants and Beyond JOURNAL OF CHILD NEUROLOGY Enns, G. M. 2014; 29 (9): 1235-1240

  Abstract

  Although mitochondrial disorders are among the most common inherited conditions that cause neurologic impairment, there are currently no U.S. Food and Drug Administration (FDA)-approved medications designed to treat primary mitochondrial disease. This is in part related to the lack of biomarkers to monitor disease status or response to treatment and the paucity of randomized, controlled clinical trials focused on mitochondrial disease therapies. Despite this discouraging historical precedent, a number of new approaches to mitochondrial disease therapy are on the horizon. By studying metabolites central to redox chemistry, investigators are gaining new insights into potential noninvasive biomarkers. Controlled clinical trials designed to study the effects of novel redox-modulating therapies, such as EPI-743, in patients with inherited mitochondrial disease are also underway. Furthermore, several new compounds with potential effects on inner mitochondrial membrane function and mitochondrial biogenesis are in development. Such advances are providing the foundation for a new era in mitochondrial disease therapeutics.

  View details for DOI 10.1177/0883073814538509

  View details for PubMedID 24985754

• Clinical whole-exome sequencing: are we there yet? GENETICS IN MEDICINE Atwal, P. S., Brennan, M., Cox, R., Niaki, M., Platt, J., Homeyer, M., Kwan, A., Parkin, S., Schelley, S., Slattery, L., Wilnai, Y., Bernstein, J. A., Enns, G. M., Hudgins, L. 2014; 16 (9): 717-719

  Abstract

  Background:Clinical laboratories began offering whole-exome sequencing in 2011 at a cost between $4,500 and $9,000. Reported detection rates for deleterious mutations range from 25 to 50%. Based on the experience of our clinical genetics service, actual success rates may be lower than estimated rates. We report results from our own experience along with a survey of clinical geneticists to ascertain (i) current success rates for causal gene detection in a clinical setting; (ii) if there are insurance authorization issues; and (iii) if turnaround times quoted by the clinical laboratories are accurate; we also gauge provider opinions toward clinical whole-exome sequencing.Methods:We reviewed our results and the results of a survey that was electronically distributed to 47 clinical genetics centers.Results:A total of 35 exome reports were available. If all positive results are collated, we observe a success rate of 22.8%. One result incorrectly identified a known benign variant as pathogenic. Some insurers covered all testing, whereas others denied any insurance coverage. Only three (23.1%) of our reports were available within the laboratory's quoted turnaround times. More than 50% of clinicians queried in our survey had not ordered whole-exome sequencing at the current time, many stating concerns regarding interpretation, insurance coverage, and cost.Conclusion:Clinical whole-exome sequencing has proven diagnostic utility; however, currently many clinicians have concerns regarding interpretation of results, insurance coverage, and cost.Genet Med advance online publication 13 February 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.10.

  View details for DOI 10.1038/gim.2014.10

  View details for Web of Science ID 000341830800010

• Points to Consider in the Clinical Use of NGS Panels for Mitochondrial Disease: An Analysis of Gene Inclusion and Consent Forms JOURNAL OF GENETIC COUNSELING Platt, J., Cox, R., Enns, G. M. 2014; 23 (4): 594-603

  Abstract

  Mitochondrial next generation sequencing (NGS) panels offer single-step analysis of the numerous nuclear genes involved in the structure, function, and maintenance of mitochondria. However, the complexities of mitochondrial biology and genetics raise points for consideration in clinical use of these tests. To understand the current status of mitochondrial genetic testing, we assessed the gene offerings and consent forms of mitochondrial NGS panels available from seven US-based clinical laboratories. The NGS panels varied markedly in number of genes (101-1204 genes), and the proportion of genes causing "classic" mitochondrial diseases and their phenocopies ranged widely between labs (18 %-94 % of panel contents). All panels included genes not associated with classic mitochondrial diseases (6 %-28 % of panel contents), including genes causing adult-onset neurodegenerative disorders, cancer predisposition, and other genetic syndromes or inborn errors of metabolism. Five of the panels included genes that are not listed in OMIM to be associated with a disease phenotype (5 %-49 % of panel contents). None of the consent documents reviewed had options for patient preference regarding receipt of incidental findings. These findings raise points of discussion applicable to mitochondrial diagnostics, but also to the larger arenas of exome and genome sequencing, including the need to consider the boundaries between clinical and research testing, the necessity of appropriate informed consent, and the responsibilities of clinical laboratories and clinicians. Based on these findings, we recommend careful evaluation by laboratories of the genes offered on NGS panels, clear communication of the predicted phenotypes, and revised consent forms to allow patients to make choices about receiving incidental findings. We hope that our analysis and recommendations will help to maximize the considerable clinical utility of NGS panels for the diagnosis of mitochondrial disease.

  View details for DOI 10.1007/s10897-013-9683-2

  View details for PubMedID 24399097

• Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway (vol 111, pg 236, 2014) GENETICS IN MEDICINE Enns, G. M., Shashi, V., Bainbridge, M., Gambello, M. J., Zahir, F. R., Bast, T., Crimian, R., Schoch, K., Platt, J., Cox, R., Bernstein, J. A., Scavina, M., Walter, R. S., Bibb, A., Jones, M., Hegde, M., Graham, B. H., Need, A. C., Oviedo, A., Schaaf, C. P., Boyle, S., Butte, A. J., Chen, R., Chen, R., Clark, M. J., Haraksingh, R., Cowan, T. M., He, P., Langlois, S., Zoghbi, H. Y., Snyder, M., Gibbs, R. A., Freeze, H. H., Goldstein, D. B., Chen, R., FORGE Canada Consortium 2014; 16 (7): 568

  View details for Web of Science ID 000338601400013

• Monitoring mitochondrial disease related nephropathy and subclinical redox stress of the brain in the kd/kd murine model Blankenberg, F., Enns, G. SOC NUCLEAR MEDICINE INC. 2014

  View details for Web of Science ID 000361438102472

• HMPAO uptake assay with t-BHP or irradiation of primary patient SURF-1 fibroblast cultures Holman, E., Enns, G., Blankenberg, F. SOC NUCLEAR MEDICINE INC. 2014

  View details for Web of Science ID 000361438102471

• Clinical interpretation and implications of whole-genome sequencing. JAMA Dewey, F. E., Grove, M. E., Pan, C., Goldstein, B. A., Bernstein, J. A., Chaib, H., Merker, J. D., Goldfeder, R. L., Enns, G. M., David, S. P., Pakdaman, N., Ormond, K. E., Caleshu, C., Kingham, K., Klein, T. E., Whirl-Carrillo, M., Sakamoto, K., Wheeler, M. T., Butte, A. J., Ford, J. M., Boxer, L., Ioannidis, J. P., Yeung, A. C., Altman, R. B., Assimes, T. L., Snyder, M., Ashley, E. A., Quertermous, T. 2014; 311 (10): 1035-1045

  Abstract

  Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication.To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings.An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings.Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up.Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P < 001).In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.

  View details for DOI 10.1001/jama.2014.1717

  View details for PubMedID 24618965

• Clinical interpretation and implications of whole-genome sequencing. JAMA : the journal of the American Medical Association Dewey, F. E., Grove, M. E., Pan, C., Goldstein, B. A., Bernstein, J. A., Chaib, H., Merker, J. D., Goldfeder, R. L., Enns, G. M., David, S. P., Pakdaman, N., Ormond, K. E., Caleshu, C., Kingham, K., Klein, T. E., Whirl-Carrillo, M., Sakamoto, K., Wheeler, M. T., Butte, A. J., Ford, J. M., Boxer, L., Ioannidis, J. P., Yeung, A. C., Altman, R. B., Assimes, T. L., Snyder, M., Ashley, E. A., Quertermous, T. 2014; 311 (10): 1035-1045

  Abstract

  Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication.To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings.An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings.Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up.Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P < 001).In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.

  View details for DOI 10.1001/jama.2014.1717

  View details for PubMedID 24618965

  View details for PubMedCentralID PMC4119063

• PRENATAL TREATMENT OF ORNITHINE TRANSCARBAMYLASE DEFICIENCY Wilnai, Y., Alcorn, D., Benitz, W., Berquist, W., Bernstein, J., Blumenfeld, Y. J., Castillo, R., Concepcion, W., Cowan, T., Cox, K. L., Cusmano, K., Deirdre, L., Esquival, C., Hintz, S. R., Homeyer, M., Hudgins, L., Palma, J., Summar, M. L., Schelley, S., Vishnu, P., Enns, G. M. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2014: 248

  View details for Web of Science ID 000332500200048

• NEED FOR EVIDENCE-BASED RESEARCH TO ASSESS BENEFITS OF NUTRITION TREATMENTS FOR RARE INBORN ERRORS OF METABOLISM Frazier, D. M., VanCalcar, S., Enns, G. M., McGuire, P. J. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2014: 295–96

  View details for Web of Science ID 000332500200139

• MUTATIONS IN NGLY1 CAUSE AN INHERITED DISORDER OF THE ENDOPLASMIC RETICULUM-ASSOCIATED DEGRADATION (ERAD) PATHWAY Enns, G. M., Shashi, V., Zahir, F., Gambello, M. J., Bainbridge, M. N., Bast, T., Crimian, R., Schoch, K., Zoghbi, H. Y., Platt, J., Cox, R., Bernstein, J., Scavina, M., Walter, R. S., Need, A. C., Oviedo, A., Langlois, S., Bibb, A., Jones, M., Hedge, M., Gibbs, R. A., Schaaf, C. P., Boyle, S., Butte, A. J., Clark, M., Cowan, T., He, P., Snyder, M., Freeze, H. H., Goldstein, D. B., FORGE Canada Consortium ACADEMIC PRESS INC ELSEVIER SCIENCE. 2014: 236–37

  View details for Web of Science ID 000332500200031

• MITOCHONDRIAL COMPLEX CARE CLINIC MODEL - EMPOWERING FAMILIES AS PART OF THE CARE TEAM Niemi, A., Cox, R., Platt, J., Wayman, K., Mark, J., Enns, G. M. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2014: 254

  View details for Web of Science ID 000332500200061

• Severe and rapid disease course in the natural history of infants with lysosomal acid lipase deficiency Jones, S. A., Bernstein, D., Bialer, M., Dhawan, A., Hendriksz, C., Whitley, C. B., Banikazemi, M., Chang, A., Guardamagna, O., Raiman, J., Gamal, I., Selim, L., Cederbaum, S., Di Rocco, M., Domm, J., Enns, G., Finegold, D., Gargus, J., Zaki, O., Eckert, S., Schneider, E., Quinn, A. G., Valayannopouloss, V. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2014: S57–S58

  View details for DOI 10.1016/j.ymgme.2013.12.125

  View details for Web of Science ID 000330746000115

• Practice patterns of mitochondrial disease physicians in North America. Part 1: Diagnostic and clinical challenges. Mitochondrion Parikh, S., Goldstein, A., Koenig, M. K., Scaglia, F., Enns, G. M., Saneto, R. 2014; 14 (1): 26-33

  Abstract

  Mitochondrial medicine is a young subspecialty. Clinicians have a limited evidence base on which to formulate clinical decisions regarding diagnosis, treatment and patient management. Mitochondrial medicine specialists have cobbled together an informal set of rules and paradigms for preventive care and management based in part on anecdotal experience. The Mitochondrial Medicine Society (MMS) assessed the current state of clinical practice from diagnosis, to preventive care and treatment, as provided by various mitochondrial disease specialists in North America. We hope that by obtaining this information we can begin moving towards formulating a set of consensus criteria and establishing standards of care.

  View details for DOI 10.1016/j.mito.2013.07.116

  View details for PubMedID 23891656

• Evidence of redox imbalance in a patient with succinic semialdehyde dehydrogenase deficiency. Molecular genetics and metabolism reports Niemi, A., Brown, C., Moore, T., Enns, G. M., Cowan, T. M. 2014; 1: 129-132

  Abstract

  The pathophysiology of succinic semialdehyde dehydrogenase (SSADH) deficiency is not completely understood. Oxidative stress, mitochondrial pathology, and low reduced glutathione levels have been demonstrated in mice, but no studies have been reported in humans. We report on a patient with SSADH deficiency in whom we found low levels of blood reduced glutathione (GSH), and elevations of dicarboxylic acids in urine, suggestive of possible redox imbalance and/or mitochondrial dysfunction. Thus, targeting the oxidative stress axis may be a potential therapeutic approach if our findings are confirmed in other patients.

  View details for PubMedID 27896081

• Practice patterns of mitochondrial disease physicians in North America. Part 2: treatment, care and management MITOCHONDRION Parikh, S., Goldstein, A., Koenig, M. K., Scaglia, F., Enns, G. M., Saneto, R. 2013; 13 (6): 681-687

  Abstract

  Mitochondrial medicine is a young subspecialty. Clinicians have limited evidence-based guidelines on which to formulate clinical decisions regarding diagnosis, treatment and management for patients with mitochondrial disorders. Mitochondrial medicine specialists have cobbled together an informal set of rules and paradigms for preventive care and management based in part on anecdotal experience. The Mitochondrial Medicine Society (MMS) assessed the current state of clinical practice including diagnosis, preventive care and treatment, as provided by various mitochondrial disease providers in North America. In this second of two reports, we present data related to clinical practice that highlight the challenges clinicians face in the routine care of patients with established mitochondrial disease. Concerning variability in treatment and preventative care approaches were noted. We hope that sharing this information will be a first step toward formulating a set of consensus criteria and establishing standards of care.

  View details for DOI 10.1016/j.mito2013.09.003

  View details for Web of Science ID 000327280500015

  View details for PubMedID 24063850

• Mitochondrial NGS panels: Is more better? Platt, J., Cox, R., Enns, G. M. ELSEVIER SCI LTD. 2013: 919

  View details for DOI 10.1016/j.mito.2013.07.056

  View details for Web of Science ID 000327280500096

• Novel c.316G > C mutation in PDHA1 causes PDH deficiency Khouzam, A., Platt, J., Cox, R., Enns, G. M. ELSEVIER SCI LTD. 2013: 925

  View details for DOI 10.1016/j.mito.2013.07.072

  View details for Web of Science ID 000327280500112

• First-line genetic testing for mitochondrial disorders in the next-generation sequencing era: Comprehensive known disease gene panel or exome sequencing? Bai, R., Haverfield, E., Higgs, J., Suchy, S. F., Arjona, D., Retterer, K., Smaoui, N., Richard, G., Bale, S., Kendall, F. D., Parikh, S., Gropman, A. L., Haas, R., Goldstein, A., Panzer, J. A., Yum, S. W., Falk, M. J., Saneto, R. P., Enns, G. M., Chung, W. K. ELSEVIER SCI LTD. 2013: 934

  View details for DOI 10.1016/j.mito.2013.07.092

  View details for Web of Science ID 000327280500132

• Severe multi-systemic presentation of COX10 deficiency Wilnai, Y., Cox, R., Bai, R., Enns, G. M. ELSEVIER SCI LTD. 2013: 926

  View details for DOI 10.1016/j.mito.2013.07.073

  View details for Web of Science ID 000327280500113

• Molecular and clinical characterization of the myopathic form of mitochondrial DNA depletion syndrome caused by mutations in the thymidine kinase (TK2) gene MOLECULAR GENETICS AND METABOLISM Chanprasert, S., Wang, J., Weng, S., Enns, G. M., Boue, D. R., Wong, B. L., Mendell, J. R., Perry, D. A., Sahenk, Z., Craigen, W. J., Climent Alcala, F. J., Pascual, J. M., Melancon, S., Zhang, V. W., Scaglia, F., Wong, L. C. 2013; 110 (1-2): 153-161

  Abstract

  Mitochondrial DNA (mtDNA) depletion syndromes (MDSs) are a clinically and molecularly heterogeneous group of mitochondrial cytopathies characterized by severe mtDNA copy number reduction in affected tissues. Clinically, MDSs are mainly categorized as myopathic, encephalomyopathic, hepatocerebral, or multi-systemic forms. To date, the myopathic form of MDS is mainly caused by mutations in the TK2 gene, which encodes thymidine kinase 2, the first and rate limiting step enzyme in the phosphorylation of pyrimidine nucleosides. We analyzed 9 unrelated families with 11 affected subjects exhibiting the myopathic form of MDS, by sequencing the TK2 gene. Twelve mutations including 4 novel mutations were detected in 9 families. Skeletal muscle specimens were available from 7 out of 11 subjects. Respiratory chain enzymatic activities in skeletal muscle were measured in 6 subjects, and enzymatic activities were reduced in 3 subjects. Quantitative analysis of mtDNA content in skeletal muscle was performed in 5 subjects, and marked mtDNA content reduction was observed in each. In addition, we outline the molecular and clinical characteristics of this syndrome in a total of 52 patients including those previously reported, and a total of 36 TK2 mutations are summarized. Clinically, hypotonia and proximal muscle weakness are the major phenotypes present in all subjects. In summary, our study expands the molecular and clinical spectrum associated with TK2 deficiency.

  View details for DOI 10.1016/j.ymgme.2013.07.009

  View details for Web of Science ID 000323799400021

• Molecular and clinical characterization of the myopathic form of mitochondrial DNA depletion syndrome caused by mutations in the thymidine kinase (TK2) gene. Molecular genetics and metabolism Chanprasert, S., Wang, J., Weng, S., Enns, G. M., Boué, D. R., Wong, B. L., Mendell, J. R., Perry, D. A., Sahenk, Z., Craigen, W. J., Alcala, F. J., Pascual, J. M., Melancon, S., Zhang, V. W., Scaglia, F., Wong, L. C. 2013; 110 (1-2): 153-161

  Abstract

  Mitochondrial DNA (mtDNA) depletion syndromes (MDSs) are a clinically and molecularly heterogeneous group of mitochondrial cytopathies characterized by severe mtDNA copy number reduction in affected tissues. Clinically, MDSs are mainly categorized as myopathic, encephalomyopathic, hepatocerebral, or multi-systemic forms. To date, the myopathic form of MDS is mainly caused by mutations in the TK2 gene, which encodes thymidine kinase 2, the first and rate limiting step enzyme in the phosphorylation of pyrimidine nucleosides. We analyzed 9 unrelated families with 11 affected subjects exhibiting the myopathic form of MDS, by sequencing the TK2 gene. Twelve mutations including 4 novel mutations were detected in 9 families. Skeletal muscle specimens were available from 7 out of 11 subjects. Respiratory chain enzymatic activities in skeletal muscle were measured in 6 subjects, and enzymatic activities were reduced in 3 subjects. Quantitative analysis of mtDNA content in skeletal muscle was performed in 5 subjects, and marked mtDNA content reduction was observed in each. In addition, we outline the molecular and clinical characteristics of this syndrome in a total of 52 patients including those previously reported, and a total of 36 TK2 mutations are summarized. Clinically, hypotonia and proximal muscle weakness are the major phenotypes present in all subjects. In summary, our study expands the molecular and clinical spectrum associated with TK2 deficiency.

  View details for DOI 10.1016/j.ymgme.2013.07.009

  View details for PubMedID 23932787

• Clinical Effect and Safety Profile of Recombinant Human Lysosomal Acid Lipase in Patients With Cholesteryl Ester Storage Disease HEPATOLOGY Balwani, M., Breen, C., Enns, G. M., Deegan, P. B., Honzik, T., Jones, S., Kane, J. P., Malinova, V., Sharma, R., Stock, E. O., Valayannopoulos, V., Wraith, J. E., Burg, J., Eckert, S., Schneider, E., Quinn, A. G. 2013; 58 (3): 950-957

  Abstract

  Cholesteryl ester storage disease (CESD), an inherited deficiency of lysosomal acid lipase (LAL), is an underappreciated cause of progressive liver disease with no approved therapy. Presenting features include dyslipidemia, elevated transaminases, and hepatomegaly. To assess the clinical effects and safety of the recombinant human LAL, sebelipase alfa, nine patients received four once-weekly infusions (0.35, 1, or 3 mg·kg(-1) ) in LAL-CL01, which is the first human study of this investigational agent. Patients completing LAL-CL01 were eligible to enroll in the extension study (LAL-CL04) in which they again received four once-weekly infusions of sebelipase alfa (0.35, 1, or 3 mg·kg(-1) ) before transitioning to long-term every-other-week infusions (1 or 3 mg·kg(-1) ). Sebelipase alfa was well tolerated, with mostly mild adverse events unrelated to sebelipase alfa. No antidrug antibodies were detected. Transaminases decreased in patients in LAL-CL01 and increased between studies. In seven patients receiving ongoing sebelipase alfa treatment in LAL-CL04, the mean ± standard deviation (SD) decreases for alanine transaminase and aspartate aminotransferase at week 12 compared to the baseline values in LAL-CL01 were 46 ± 21 U/L (-52%) and 21 ± 14 U/L (-36%), respectively (P ≤ 0.05). Through week 12 of LAL-CL04, these seven patients also showed mean decreases from baseline in total cholesterol of 44 ± 41 mg/dL (-22%; P = 0.047), low density lipoprotein-cholesterol of 29 ± 31 mg/dL (-27%; P = 0.078), and triglycerides of 50 ± 38 mg/dL (-28%, P = 0.016) and increases in high density lipoprotein-cholesterol of 5 mg/dL (15%; P = 0.016). Conclusion: These data establish that sebelipase alfa, an investigational enzyme replacement, in patients with CESD is well tolerated, rapidly decreases serum transaminases, and that these improvements are sustained with long-term dosing and are accompanied by improvements in serum lipid profile.

  View details for DOI 10.1002/hep.26289

  View details for Web of Science ID 000329284000016

  View details for PubMedID 23348766

  View details for PubMedCentralID PMC3728169

• Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Manoli, I., Sysol, J. R., Li, L., Houillier, P., Garone, C., Wang, C., Zerfas, P. M., Cusmano-Ozog, K., Young, S., Trivedi, N. S., Cheng, J., Sloan, J. L., Chandler, R. J., Abu-Asab, M., Tsokos, M., Elkahloun, A. G., Rosen, S., Enns, G. M., Berry, G. T., Hoffmann, V., DiMauro, S., Schnermann, J., Venditti, C. P. 2013; 110 (33): 13552-13557

  Abstract

  Isolated methylmalonic acidemia (MMA), caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT), is often complicated by end stage renal disease that is resistant to conventional therapies, including liver transplantation. To establish a viable model of MMA renal disease, Mut was expressed in the liver of Mut(-/-) mice as a stable transgene under the control of an albumin (INS-Alb-Mut) promoter. Mut(-/-);Tg(INS-Alb-Mut) mice, although completely rescued from neonatal lethality that was displayed by Mut(-/-) mice, manifested a decreased glomerular filtration rate (GFR), chronic tubulointerstitial nephritis and ultrastructural changes in the proximal tubule mitochondria associated with aberrant tubular function, as demonstrated by single-nephron GFR studies. Microarray analysis of Mut(-/-);Tg(INS-Alb-Mut) kidneys identified numerous biomarkers, including lipocalin-2, which was then used to monitor the response of the GFR to antioxidant therapy in the mouse model. Renal biopsies and biomarker analysis from a large and diverse patient cohort (ClinicalTrials.gov identifier: NCT00078078) precisely replicated the findings in the animals, establishing Mut(-/-);Tg(INS-Alb-Mut) mice as a unique model of MMA renal disease. Our studies suggest proximal tubular mitochondrial dysfunction is a key pathogenic mechanism of MMA-associated kidney disease, identify lipocalin-2 as a biomarker of increased oxidative stress in the renal tubule, and demonstrate that antioxidants can attenuate the renal disease of MMA.

  View details for DOI 10.1073/pnas.1302764110

  View details for Web of Science ID 000323069200075

  View details for PubMedID 23898205

  View details for PubMedCentralID PMC3746875

• Expanding research to provide an evidence base for nutritional interventions for the management of inborn errors of metabolism MOLECULAR GENETICS AND METABOLISM Camp, K. M., Lloyd-Puryear, M. A., Yao, L., Groft, S. C., Parisi, M. A., Mulberg, A., Gopal-Srivastava, R., Cederbaum, S., Enns, G. M., Ershow, A. G., Frazier, D. M., Gohagan, J., Harding, C., Howell, R. R., Regan, K., Stacpoole, P. W., Venditti, C., Vockley, J., Watson, M., Coates, P. M. 2013; 109 (4): 319-328

  Abstract

  A trans-National Institutes of Health initiative, Nutrition and Dietary Supplement Interventions for Inborn Errors of Metabolism (NDSI-IEM), was launched in 2010 to identify gaps in knowledge regarding the safety and utility of nutritional interventions for the management of inborn errors of metabolism (IEM) that need to be filled with evidence-based research. IEM include inherited biochemical disorders in which specific enzyme defects interfere with the normal metabolism of exogenous (dietary) or endogenous protein, carbohydrate, or fat. For some of these IEM, effective management depends primarily on nutritional interventions. Further research is needed to demonstrate the impact of nutritional interventions on individual health outcomes and on the psychosocial issues identified by patients and their families. A series of meetings and discussions were convened to explore the current United States' funding and regulatory infrastructure and the challenges to the conduct of research for nutritional interventions for the management of IEM. Although the research and regulatory infrastructure are well-established, a collaborative pathway that includes the professional and advocacy rare disease community and federal regulatory and research agencies will be needed to overcome current barriers.

  View details for DOI 10.1016/j.ymgme.2013.05.008

  View details for Web of Science ID 000323084800001

  View details for PubMedID 23806236

  View details for PubMedCentralID PMC4131198

• Glutathione: A redox signature in monitoring EPI-743 therapy in children with mitochondrial encephalomyopathies MOLECULAR GENETICS AND METABOLISM Pastore, A., Petrillo, S., Tozzi, G., Carrozzo, R., Martinelli, D., Dionisi-Vici, C., Di Giovamberardino, G., Ceravolo, F., Klein, M. B., Miller, G., Enns, G. M., Bertini, E., Piemonte, F. 2013; 109 (2): 208-214

  Abstract

  Genetically defined Leigh syndrome (LS) is a rare, fatal inherited neurodegenerative disorder that predominantly affects children. Although mitochondrial dysfunction has clearly been associated with oxidative stress, few studies have specifically examined Leigh syndrome patients' blood glutathione levels. In this study, we analyzed the balance between oxidized and reduced glutathione in lymphocytes of 10 patients with genetically confirmed LS and monitored the effects of glutathione status following 6 months of treatment with EPI-743, a novel redox therapeutic.Lymphocytes were obtained from blood samples of 10 children with a genetically confirmed diagnosis of LS and in 20 healthy subjects. Total, reduced, oxidized and protein-bound glutathione levels were determined by HPLC analysis. Erythrocyte superoxide dismutase and glutathione peroxidase enzyme activities were measured by spectrophotometric assays. Plasma total thiols, carbonyl contents and malondialdehyde were assessed by spectrophotometric and fluorometric assays.A significant impairment of all glutathione forms was detected in patients, including a profound decrease of total and reduced glutathione (GSH) associated with high levels of all oxidized glutathione forms (GSSG+GS-Pro; OX). These findings negatively correlated with the glutathione peroxidase activity, which underwent a significant decrease in patients. After treatment with EPI-743, all patients showed a significant increase in reduced glutathione levels and 96% decrease of OX/GSH ratio.The data presented here strongly support glutathione as a "redox blood signature" in mitochondrial disorders and its use as a clinical trial endpoint in the development of mitochondrial disease therapies.

  View details for DOI 10.1016/j.ymgme.2013.03.011

  View details for Web of Science ID 000320354800014

  View details for PubMedID 23583222

• Comprehensive next-generation sequence analyses of the entire mitochondrial genome reveal new insights into the molecular diagnosis of mitochondrial DNA disorders GENETICS IN MEDICINE Cui, H., Li, F., Chen, D., Wang, G., Truong, C. K., Enns, G. M., Graham, B., Milone, M., Landsverk, M. L., Wang, J., Zhang, W., Wong, L. C. 2013; 15 (5): 388-394

  Abstract

  Purpose:The application of massively parallel sequencing technology to the analysis of the mitochondrial genome has demonstrated great improvement in the molecular diagnosis of mitochondrial DNA-related disorders. The objective of this study was to investigate the performance characteristics and to gain new insights into the analysis of the mitochondrial genome.Methods:The entire mitochondrial genome was analyzed as a single amplicon using a long-range PCR-based enrichment approach coupled with massively parallel sequencing. The interference of the nuclear mitochondrial DNA homologs was distinguished from the actual mitochondrial DNA sequences by comparison with the results obtained from conventional PCR-based Sanger sequencing using multiple pairs of primers.Results:Our results demonstrated the uniform coverage of the entire mitochondrial genome. Massively parallel sequencing of the single amplicon revealed the presence of single-nucleotide polymorphisms and nuclear homologs of mtDNA sequences that cause the erroneous and inaccurate variant calls when PCR/Sanger sequencing approach was used. This single amplicon massively parallel sequencing strategy provides an accurate quantification of mutation heteroplasmy as well as the detection and mapping of mitochondrial DNA deletions.Conclusion:The ability to quantitatively and qualitatively evaluate every single base of the entire mitochondrial genome is indispensible to the accurate molecular diagnosis and genetic counseling of mitochondrial DNA-related disorders. This new approach may be considered as first-line testing for comprehensive analysis of the mitochondrial genome.Genet Med 2013:15(5):388-394.

  View details for DOI 10.1038/gim.2012.144

  View details for Web of Science ID 000318888600011

  View details for PubMedID 23288206

• Mutations in B3GALNT2 Cause Congenital Muscular Dystrophy and Hypoglycosylation of alpha-Dystroglycan AMERICAN JOURNAL OF HUMAN GENETICS Stevens, E., Carss, K. J., Cirak, S., Foley, R., Torelli, S., Willer, T., Tambunan, D. E., Yau, S., Brodd, L., Sewry, C. A., Feng, L., Haliloglu, G., Orhan, D., Dobyns, W. B., Enns, G. M., Manning, M., Krause, A., Salih, M. A., Walsh, C. A., Hurles, M., Campbell, K. P., Manzini, M. C., Stemple, D., Lin, Y., Muntoni, F. 2013; 92 (3): 354-365

  Abstract

  Mutations in several known or putative glycosyltransferases cause glycosylation defects in α-dystroglycan (α-DG), an integral component of the dystrophin glycoprotein complex. The hypoglycosylation reduces the ability of α-DG to bind laminin and other extracellular matrix ligands and is responsible for the pathogenesis of an inherited subset of muscular dystrophies known as the dystroglycanopathies. By exome and Sanger sequencing we identified two individuals affected by a dystroglycanopathy with mutations in β-1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2). B3GALNT2 transfers N-acetyl galactosamine (GalNAc) in a β-1,3 linkage to N-acetyl glucosamine (GlcNAc). A subsequent study of a separate cohort of individuals identified recessive mutations in four additional cases that were all affected by dystroglycanopathy with structural brain involvement. We show that functional dystroglycan glycosylation was reduced in the fibroblasts and muscle (when available) of these individuals via flow cytometry, immunoblotting, and immunocytochemistry. B3GALNT2 localized to the endoplasmic reticulum, and this localization was perturbed by some of the missense mutations identified. Moreover, knockdown of b3galnt2 in zebrafish recapitulated the human congenital muscular dystrophy phenotype with reduced motility, brain abnormalities, and disordered muscle fibers with evidence of damage to both the myosepta and the sarcolemma. Functional dystroglycan glycosylation was also reduced in the b3galnt2 knockdown zebrafish embryos. Together these results demonstrate a role for B3GALNT2 in the glycosylation of α-DG and show that B3GALNT2 mutations can cause dystroglycanopathy with muscle and brain involvement.

  View details for DOI 10.1016/j.ajhg.2013.01.016

  View details for Web of Science ID 000316161700008

  View details for PubMedID 23453667

  View details for PubMedCentralID PMC3591840

• Liver transplantation for urea cycle disorders in pediatric patients: A single-center experience PEDIATRIC TRANSPLANTATION Kim, I. K., Niemi, A., Krueger, C., Bonham, C. A., Concepcion, W., Cowan, T. M., Enns, G. M., Esquivel, C. O. 2013; 17 (2): 158-167

  Abstract

  LT has emerged as a surgical treatment for UCDs. We hypothesize that LT can be safely and broadly utilized in the pediatric population to effectively prevent hyperammonemic crises and potentially improve neurocognitive outcomes. To determine the long-term outcomes of LT for UCDs, charts of children with UCD who underwent LT were retrospectively reviewed at an academic institution between July 2001 and May 2012. A total of 23 patients with UCD underwent LT at a mean age of 3.4 yr. Fifteen (65%) patients received a whole-liver graft, seven patients (30%) received a reduced-size graft, and one patient received a living donor graft. Mean five-yr patient survival was 100%, and allograft survival was 96%. Mean peak blood ammonia (NH(3) ) at presentation was 772 μmol/L (median 500, range 178-2969, normal <30-50). After transplantation, there were no episodes of hyperammonemia. Eleven patients were diagnosed with some degree of developmental delay before transplantation, which remained stable or improved after transplantation. Patients without developmental delay before transplantation maintained their cognitive abilities at long-term follow-up. LT was associated with the eradication of hyperammonemia, removal of dietary restrictions, and potentially improved neurocognitive development. Long-term follow-up is underway to evaluate whether LT at an early age (<1 yr) will attain improved neurodevelopmental outcomes.

  View details for DOI 10.1111/petr.12041

  View details for PubMedID 23347504

• Long term safety and clinical activity of SBC-102, a recombinant human lysosomal acid lipase (rhLAL), in patients with late onset LAL deficiency 9th Annual Research Meeting of the Lysosomal-Disease-Network (LDN) Balwani, M., Malinova, V., Sharma, R., Valayannopoulos, V., Stock, E. O., Boyadjiev, S. A., Kessler, B., Deegan, P., Enns, G. M., Breen, C., Kane, J. P., Schneider, E., Quinn, A. G. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2013: S22–S23

  View details for DOI 10.1016/j.ymgme.2012.11.032

  View details for Web of Science ID 000314670500020

• Pediatric Liver Transplantation as Definitive Therapy for Urea Cycle Disorders 13th Annual State of the Art Winter Symposium of the American-Society-of-Transplant-Surgeons (ASTS) Held in Conjunction with the NATCO Symposium for Advanced Transplant Professionals Kim, I. K., Niemi, A., Krueger, C., Enns, G., Esquivel, C. O. WILEY-BLACKWELL. 2013: 86–86

  View details for Web of Science ID 000312540200100

• ARTHROGRYPOSIS, RENAL DYSFUNCTION AND CHOLESTASIS (ARC) SYNDROME: A NEW PATIENT CASE REPORT Western Regional Meeting of the American-Federation-for-Medical-Research Brennan, M., SLATTERY, L., Esplin, E., Enns, G. M., Hudgins, L., Manning, M. LIPPINCOTT WILLIAMS & WILKINS. 2013: 188–88

  View details for Web of Science ID 000312657900279

• Enzyme Replacement with Recombinant Human Lysosomal Acid Lipase (rhLAL) in Patients with Cholesteryl Ester Storage Disease, the Late Onset Form of LAL Deficiency, Produces Sustained Decreases in Transaminases and Reduction in Liver Fat Content 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) Jones, S., Enns, G. M., Balwani, M., Breen, C., Sharma, R., Deegan, P., Malinova, V., Honzik, T., Valayannopoulos, V., Schneider, E., Burg, J., Quinn, A. G. WILEY-BLACKWELL. 2012: 824A–825A

  View details for Web of Science ID 000310955602712

• Atypical Amyoplasia Congenita in an Infant With Leigh Syndrome: A Mitochondrial Cause of Severe Contractures? AMERICAN JOURNAL OF MEDICAL GENETICS PART A Wilnai, Y., Seaver, L. H., Enns, G. M. 2012; 158A (9): 2353-2357

  Abstract

  Amyoplasia congenita is a distinct form of arthrogryposis with characteristic features including internally rotated and adducted shoulders, extended elbows, flexion, and ulnar deviation of the wrists, and adducted thumbs. Fetal hypokinesia, secondary to a variety of genetic conditions, neuromuscular disorders, and environmental agents, is associated with contractures. In order to increase our understanding of the phenotypic spectrum associated with SURF 1 deficiency, a common cause of mitochondrial respiratory chain complex IV deficiency and Leigh syndrome, we describe a now 6-year-old boy who presented in the neonatal period with amyoplasia congenita. His development was normal until age 10.5 months, at which time he developed severe hypotonia and choreoathetosis following an episode of viral gastroenteritis. Following the onset of neurological symptoms, he gradually developed severe kyphosis and lower limb contractures. Blood and cerebrospinal fluid lactate levels were elevated and head imaging showed characteristic features of Leigh syndrome. He was found to harbor two pathogenic heterozygous mutations in the SURF 1 gene. In this case, mitochondrial dysfunction and the resultant energy deficiency may have played a role in causing abnormal neuronal development during embryogenesis, causing arthrogryposis. A variety of mitochondrial respiratory chain complex deficiencies have been associated with contractures of varying severity. Therefore, mitochondrial disorders should be considered in the differential diagnosis of neonatal arthrogryposis, especially if other characteristic findings such as lactic acidemia or basal ganglia abnormalities are present.

  View details for DOI 10.1002/ajmg.a.35533

  View details for PubMedID 22887355

• Improved redox status after liver transplantation in a patient with MMA mut(0) subtype; functional evidence for EPI-743 therapy Niemi, A., Niemi, A., Moore, T., Cowan, T., Kheifets, V., Enns, G. M. ELSEVIER SCI LTD. 2012: 557–57

  View details for DOI 10.1016/j.mito.2012.07.020

  View details for Web of Science ID 000309023700028

• RECOMBINANT HUMAN LYSOSOMAL ACID LIPASE (LAL) DEMONSTRATES PHARMACODYNAMIC ACTIVITY IN CHOLESTERYL ESTER STORAGE DISEASE (CESD), THE LATE ONSET FORM OF LAL DEFICIENCY Jones, S., Enns, G., Balwani, M., Breen, C., Sharma, R., Deegan, P., Malinova, V., Honzik, T., Valayannopoulos, V., Schneider, E., Burg, J., Quinn, A. G. SPRINGER. 2012: S11–S11

  View details for Web of Science ID 000307513100034

• Outcome of infants diagnosed with 3-methyl-crotonyl-CoA-carboxylase deficiency by newborn screening MOLECULAR GENETICS AND METABOLISM Arnold, G. L., Salazar, D., Neidich, J. A., Suwannarat, P., Graham, B. H., Lichter-Konecki, U., Bosch, A. M., Cusmano-Ozog, K., Enns, G., Wright, E. L., Lanpher, B. C., Owen, N. N., Lipson, M. H., Cerone, R., Levy, P., Wong, L. C., Dezsofi, A. 2012; 106 (4): 439-441

  Abstract

  3-Methyl CoA carboxylase (3-MCC) deficiency is an inborn error of metabolism in the catabolism of the amino acid leucine. Original reports suggested this disorder was associated with significant neurological and biochemical effects. However newborn screening has identified a higher than expected incidence of this disorder with apparent normal outcome in most cases.A retrospective analysis of thirty-five cases of 3-MCC deficiency identified by newborn screening and diagnosed by enzyme or molecular analysis.There was a strong inverse correlation between initial C5OH level and residual enzyme activity. A few reports of hypoglycemia, ketosis, poor feeding/failure to thrive or fasting intolerance were reported, but there was no clear relationship between symptoms and residual enzyme activity. Developmental outcome included several children with mental retardation (including one with Down syndrome and one with schizencephaly) and two with Autism Spectrum disorders but there was no apparent relationship to residual enzyme activity. Free carnitine deficiency was relatively common.Although residual enzyme activity was clearly related to metabolite elevation, there was no apparent relationship with other measures of outcome. The number of reports of neurologic abnormalities or metabolic symptoms (poor feeding, hypoglycemia, fasting intolerance, etc.) is concerning, but the significance is unclear in this retrospective sample.

  View details for DOI 10.1016/j.ymgme.2012.04.006

  View details for Web of Science ID 000307322100007

  View details for PubMedID 22658692

• Propionic acidemia: To liver transplant or not to liver transplant? PEDIATRIC TRANSPLANTATION Chapman, K. A., Summar, M. L., Enns, G. M. 2012; 16 (3): 209-210

  View details for DOI 10.1111/j.1399-3046.2012.01649.x

  View details for Web of Science ID 000302619500008

  View details for PubMedID 22332632

• Pediatric Liver Transplantation as Definitive Therapy for Urea Cycle Disorders 24th Annual Meeting of the European-Association-for-Cardiothoracic-Surgery Kim, I., Niemi, A., Enns, G., Esquivel, C. WILEY-BLACKWELL. 2012: 344–344

  View details for Web of Science ID 000303235502303

• Low glutathione levels in a patient with succinic semialdehyde dehydrogenase (SSADH) deficiency 35th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) Niemi, A., Brown, C., Moore, T., Enns, G. M., Cowan, T. M. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2012: 345–45

  View details for Web of Science ID 000301906400116

• Mutations in KAT6B, Encoding a Histone Acetyltransferase, Cause Genitopatellar Syndrome AMERICAN JOURNAL OF HUMAN GENETICS Campeau, P. M., Kim, J. C., Lu, J. T., Schwartzentruber, J. A., Abdul-Rahman, O. A., Schlaubitz, S., Murdock, D. M., Jiang, M., Lammer, E. J., Enns, G. M., Rhead, W. J., Rowland, J., Robertson, S. P., Cormier-Daire, V., Bainbridge, M. N., Yang, X., Gingras, M., Gibbs, R. A., Rosenblatt, D. S., Majewski, J., Lee, B. H. 2012; 90 (2): 282-289

  Abstract

  Genitopatellar syndrome (GPS) is a skeletal dysplasia with cerebral and genital anomalies for which the molecular basis has not yet been determined. By exome sequencing, we found de novo heterozygous truncating mutations in KAT6B (lysine acetyltransferase 6B, formerly known as MYST4 and MORF) in three subjects; then by Sanger sequencing of KAT6B, we found similar mutations in three additional subjects. The mutant transcripts do not undergo nonsense-mediated decay in cells from subjects with GPS. In addition, human pathological analyses and mouse expression studies point to systemic roles of KAT6B in controlling organismal growth and development. Myst4 (the mouse orthologous gene) is expressed in mouse tissues corresponding to those affected by GPS. Phenotypic differences and similarities between GPS, the Say-Barber-Biesecker variant of Ohdo syndrome (caused by different mutations of KAT6B), and Rubinstein-Taybi syndrome (caused by mutations in other histone acetyltransferases) are discussed. Together, the data support an epigenetic dysregulation of the limb, brain, and genital developmental programs.

  View details for DOI 10.1016/j.ajhg.2011.11.023

  View details for Web of Science ID 000300742200008

  View details for PubMedID 22265014

  View details for PubMedCentralID PMC3276659

• Initial Human Experience with SBC-102, a Recombinant Enzyme Replacement Therapy in Adults with Lysosomal Acid Lipase Deficiency 8th Annual World Symposium of the Lysosomal Disease Network Enns, G., Balwani, M., Deegan, P., Malinova, V. R., Honzik, H., Sharma, R., Valayannopoulos, V., Wraith, E., Schneider, E., Burg, J., Quinn, A. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2012: S29–S29

  View details for DOI 10.1016/j.ymgme.2011.11.055

  View details for Web of Science ID 000299758300066

• Natural history of propionic acidemia MOLECULAR GENETICS AND METABOLISM Pena, L., Franks, J., Chapman, K. A., Gropman, A., Mew, N. A., Chakrapani, A., Island, E., MacLeod, E., Matern, D., Smith, B., Stagni, K., Sutton, V. R., Ueda, K., Urv, T., Venditti, C., Enns, G. M., Summar, M. L. 2012; 105 (1): 5-9

  Abstract

  Propionic acidemia is an organic acidemia that can lead to metabolic acidosis, coma and death, if not treated appropriately in the acute setting. Recent advancements in treatment have allowed patients with propionic acidemia to live beyond the neonatal period and acute presentation. The natural history of the disease is just beginning to be elucidated as individuals reach older ages. Recent studies have identified the genomic mutations in the genes PCCA and PCCB. However, as of yet no clear genotype-phenotype correlations are known. As patients age, the natural progression of propionic acidemia illuminates intellectual difficulties, increased risk for neurological complications, including stroke-like episodes, cardiac complications, and gastrointestinal difficulties, as well as a number of other complications. This article reviews the available literature for the natural history of propionic acidemia.

  View details for DOI 10.1016/j.ymgme.2011.09.022

  View details for Web of Science ID 000299363800003

  View details for PubMedID 21986446

• A Novel Mutation in the HSD17B10 Gene of a 10-Year-Old Boy with Refractory Epilepsy, Choreoathetosis and Learning Disability PLOS ONE Seaver, L. H., He, X., Abe, K., Cowan, T., Enns, G. M., Sweetman, L., Philipp, M., Lee, S., Malik, M., Yang, S. 2011; 6 (11)

  Abstract

  Hydroxysteroid (17beta) dehydrogenase 10 (HSD10) is a mitochondrial multifunctional enzyme encoded by the HSD17B10 gene. Missense mutations in this gene result in HSD10 deficiency, whereas a silent mutation results in mental retardation, X-linked, syndromic 10 (MRXS10). Here we report a novel missense mutation found in the HSD17B10 gene, namely c.194T>C transition (rs104886492), brought about by the loss of two forked methyl groups of valine 65 in the HSD10 active site. The affected boy, who possesses mutant HSD10 (p.V65A), has a neurological syndrome with metabolic derangements, choreoathetosis, refractory epilepsy and learning disability. He has no history of acute decompensation or metabolic acidosis whereas his urine organic acid profile, showing elevated levels of 2-methyl-3-hydroxybutyrate and tiglylglycine, is characteristic of HSD10 deficiency. His HSD10 activity was much lower than the normal control level, with normal β-ketothiolase activity. The c.194T>C mutation in HSD17B10 can be identified by the restriction fragment polymorphism analysis, thereby facilitating the screening of this novel mutation in individuals with intellectual disability of unknown etiology and their family members much easier. The patient's mother is an asymptomatic carrier, and has a mixed ancestry (Hawaiian, Japanese and Chinese). This demonstrates that HSD10 deficiency patients are not confined to a particular ethnicity although previously reported cases were either Spanish or German descendants.

  View details for DOI 10.1371/journal.pone.0027348

  View details for Web of Science ID 000297792400006

  View details for PubMedID 22132097

  View details for PubMedCentralID PMC3222643

• Length of prenatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants: effects on neonatal adaptation and psychomotor development PSYCHOPHARMACOLOGY Casper, R. C., Gilles, A. A., Fleisher, B. E., Baran, J., Enns, G., Lazzeroni, L. C. 2011; 217 (2): 211-219

  Abstract

  This study evaluated the question whether length of in utero exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants might affect neonatal outcome and psychomotor development in infancy.Birth outcome was determined in the offspring of 55 women with major depressive disorder who used SSRI medication for different durations during their pregnancies. At an average age of 14 months, children underwent a pediatric examination and an evaluation with the Bayley Scales of Infant Development (BSID-II).Duration of in utero exposure to SSRIs was negatively associated with total Apgar scores, specifically the activity subscale. Odds ratios for a low score (<2) on this scale were 3.8 and 6.0 at 1 and 5 min, respectively. Newborns with longer exposure were more often admitted to the Neonatal Intensive Care Unit (p < .03). Mental Development Index scores of the infants were not associated with the length of gestational exposure to SSRIs. A longer duration of exposure increased the risk for lower Psychomotor Developmental Index and Behavioral Rating Scale scores in infancy (p = 0.012 and p = 0.007, respectively) on the BSID-II.The findings provide evidence that the length of prenatal SSRI antidepressant use can affect neonatal adjustment and can have an effect on psychomotor test scores in infancy. Importantly, the children's mental development and motor function by neurological examination were within the normal range. Timing of exposure to SSRIs during susceptible periods of fetal development and variations in the severity of maternal depression may have contributed to the associations.

  View details for DOI 10.1007/s00213-011-2270-z

  View details for PubMedID 21499702

• alpha-Tocotrienol quinone modulates oxidative stress response and the biochemistry of aging BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Shrader, W. D., Amagata, A., Barnes, A., Enns, G. M., Hinman, A., Jankowski, O., Kheifets, V., Komatsuzaki, R., Lee, E., Mollard, P., Murase, K., Sadun, A. A., Thoolen, M., Wesson, K., Miller, G. 2011; 21 (12): 3693-3698

  Abstract

  We report that α-tocotrienol quinone (ATQ3) is a metabolite of α-tocotrienol, and that ATQ3 is a potent cellular protectant against oxidative stress and aging. ATQ3 is orally bioavailable, crosses the blood-brain barrier, and has demonstrated clinical response in inherited mitochondrial disease in open label studies. ATQ3 activity is dependent upon reversible 2e-redox-cycling. ATQ3 may represent a broader class of unappreciated dietary-derived phytomolecular redox motifs that digitally encode biochemical data using redox state as a means to sense and transfer information essential for cellular function.

  View details for DOI 10.1016/j.bmcl.2011.04.085

  View details for Web of Science ID 000291145900038

  View details for PubMedID 21600768

• Clinical Report-Health Supervision for Children With Fragile X Syndrome PEDIATRICS Hersh, J. H., Saul, R. A., Saal, H. M., Braddock, S. R., Enns, G. M., Gruen, J. R., Perrin, J. M., Tarini, B. A., Hanson, J. W., Lloyd-Puryear, M. A., Musci, T. J., Rasmussen, S. A., Spire, P. 2011; 127 (5): 994-1006

  View details for DOI 10.1542/peds.2010-3500

  View details for Web of Science ID 000290097800062

• Baseline characteristics of PKU patients enrolled in the PKUDOS registry 34th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2011) Burton, B. K., Longo, N., Arnold, G. L., Enns, G. M., Andersson, H. C., Mofidi, S., Peck, D., Prado, B. C., Pridjian, G., Waisbren, S., White, D. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2011: 273–73

  View details for Web of Science ID 000287773800053

• Long-term follow-up of a patient with early onset CBLG disease 34th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2011) Niemi, A. K., Cusmano-Ozog, K., Rosenblatt, D. S., Enns, G. M. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2011: 306–7

  View details for Web of Science ID 000287773800117

• MITOCHONDRIAL PATHOLOGY IN ANGELMAN SYNDROME Western Regional Meeting of the American-Federation-for-Medical-Research Niemi, A., Cox, R., Scharfe, C., Cherry, A., Enns, G. LIPPINCOTT WILLIAMS & WILKINS. 2011: 165–66

  View details for Web of Science ID 000285542500293

• Suboptimal outcomes in patients with PKU treated early with diet alone: Revisiting the evidence MOLECULAR GENETICS AND METABOLISM Enns, G. M., Koch, R., Brumm, V., Blakely, E., Suter, R., Jurecki, E. 2010; 101 (2-3): 99-109

  Abstract

  The National Institute of Health (NIH) published a Consensus Statement on the screening and management of Phenylketonuria (PKU) in 2000. The panel involved in the development of this consensus statement acknowledged the lack of data regarding the potential for more subtle suboptimal outcomes and the need for further research into treatment options. In subsequent years, the approval of new treatment options for PKU and outcome data for patients treated from the newborn period by dietary therapy alone have become available. We hypothesized that a review of the PKU literature since 2000 would provide further evidence related to neurocognitive, psychosocial, and physical outcomes that could serve as a basis for reassessment of the 2000 NIH Consensus Statement.A systematic review of literature residing in PubMed, Scopus and PsychInfo was performed in order to assess the outcome data over the last decade in diet-alone early-treated PKU patients to assess the need for new recommendations and validity of older recommendations in light of new evidence.The majority of publications (140/150) that contained primary outcome data presented at least one suboptimal outcome compared to control groups or standardized norms/reference values in at least one of the following areas: neurocognitive/psychosocial (N=60; 58 reporting suboptimal outcomes); quality of life (N=6; 4 reporting suboptimal outcomes); brain pathology (N=32; 30 reporting suboptimal outcomes); growth/nutrition (N=34; 29 reporting suboptimal outcomes); bone pathology (N=9; 9 reporting suboptimal outcomes); and/or maternal PKU (N=19; 19 reporting suboptimal outcomes).Despite the remarkable success of public health programs that have instituted newborn screening and early introduction of dietary therapy for PKU, there is a growing body of evidence that suggests that neurocognitive, psychosocial, quality of life, growth, nutrition, bone pathology and maternal PKU outcomes are suboptimal. The time may be right for revisiting the 2000 NIH Consensus Statement in order to address a number of important issues related to PKU management, including treatment advancements for metabolic control in PKU, blood Phe variability, neurocognitive and psychological assessments, routine screening measures for nutritional biomarkers, and bone pathology.

  View details for DOI 10.1016/j.ymgme.2010.05.017

  View details for Web of Science ID 000283609600003

  View details for PubMedID 20678948

• Long-term outcome following pediatric liver transplantation for metabolic disorders PEDIATRIC TRANSPLANTATION Stevenson, T., Millan, M. T., Wayman, K., Berquist, W. E., Sarwal, M., Johnston, E. E., Esquivel, C. O., Enns, G. M. 2010; 14 (2): 268-275

  Abstract

  In order to determine long-term outcome, including survival, growth and development, following liver transplantation in children with metabolic disorders, we retrospectively reviewed charts of 54 children with metabolic disorders evaluated from 1989-2005 for presenting symptoms, transplantation timing and indications, survival, metabolic parameters, growth, and development. Thirty-three patients underwent liver transplantation (12 received combined liver-kidney transplants) at a median age of 21 months. At a median follow-up of 3.6 yr, patient survival was 100%, and liver and kidney allograft survival was 92%, and 100%, respectively. For the group as a whole, weight Z scores improved and body mass index at follow-up was in the normal range. Two yr post-transplantation, psychomotor development improved significantly (p < 0.01), but mental skills did not; however, both indices were in the low-normal range of development. When compared to patients with biliary atresia, children with metabolic disorders showed significantly lower mental developmental scores at one and two yr post-transplantation (p < 0.05), but psychomotor developmental scores were not significantly different. We conclude that, in patients with metabolic disorders meeting indications for transplantation, liver transplantation or combined liver-kidney transplantation (for those with accompanying renal failure) is associated with excellent long-term survival, improved growth, and improved psychomotor development.

  View details for DOI 10.1111/j.1399-3046.2009.01228.x

  View details for PubMedID 19671092

• Biomarkers of redox abnormalities in mitochondrial disorders and organic acidemias Atkuri, K. R., Cowan, T. M., Procaccio, V., Herzenberg, L. A., Enns, G. M. ELSEVIER SCI LTD. 2010: 206–7

  View details for DOI 10.1016/j.mito.2009.12.024

  View details for Web of Science ID 000274989300039

• EVIDENCE OF REDOX IMBALANCE IN A PATIENT WITH METHYLMALONIC ACIDEMIA (mut0) 33rd Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2010) Cusmano-Ozog, K., Moore, T., Niemi, A., Zadeh, N., Cowan, T. M., Enns, G. M. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2010: 210–11

  View details for Web of Science ID 000275140900037

• Nitrogen sparing therapy revisited 2009 3rd International Satellite on Urea Cycle Disorders Enns, G. M. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2010: S65–S71

  Abstract

  Although the protocol that most experienced metabolic centers in the United States follow for treating acute hyperammonemia in urea cycle disorders (UCDs) is similar to that proposed by Brusilow and Batshaw in the early 1980s, over the years a steady evolution has taken place. Continued developments in intensive care, surgical and hemodialysis techniques, fluid and electrolyte management, cardiovascular support, and emergency transport have contributed to improved management of acute hyperammonemia. Compared to historical data, survival of urea cycle patients has also improved following treatment with alternative pathway therapy, in addition to appropriate supportive care, including the provision of adequate calories to prevent catabolism and promote anabolism and hemodialysis if needed. However, overall neurological outcomes have been suboptimal. There are currently a number of exciting prospective new therapies on the horizon, including novel medications or cell-based treatments. Nevertheless, the therapeutic expertise that is currently in place at centers specializing in management of metabolic emergencies already has the potential to improve survival and outcome in these children significantly. The early identification of UCD patients so that transport to a metabolic treatment center may be carried out without delay continues to be a major area of focus and challenge.

  View details for PubMedID 20202877

• Future treatment strategies in phenylketonuria MOLECULAR GENETICS AND METABOLISM van Spronsen, F. J., Enns, G. M. 2010; 99: S90-S95

  Abstract

  Phenylketonuria (PKU) was the first inherited metabolic disease in which treatment was found to prevent clinical features of the disorder; dietary management was established almost 60 years ago. The institution of a low-phenylalanine (Phe) diet in the first few weeks of life was made possible by Guthrie neonatal screening, which further increased effectiveness of therapy. Indeed, neonatal diagnosis of PKU followed by institution of a low-Phe diet has been a remarkable success in preventing the devastating brain damage associated with untreated PKU. Nevertheless, significant difficulties exist in caring for PKU patients, including problems with adhering to the prescribed dietary regimen and the presence of neurocognitive deficits despite therapy. During the past few years, several ideas for new treatment strategies have emerged. This review aims to address these treatment strategies based on theoretical considerations of the biochemistry and pathogenesis of PKU. Recent times have seen the introduction of a wide array of novel treatments currently in clinical use, including more palatable medical foods, glycomacropeptide, large neutral amino acids, and tetrahydrobiopterin. Human trials are underway using an enzymatic therapeutic approach, while preclinical work continues in the fields of gene and cellular therapy. These therapeutic strategies propose to treat PKU at various levels, including nutritional intake, gut, liver, and blood-brain barrier, and have the potential to further improve outcome in PKU.

  View details for DOI 10.1016/j.ymgme.2009.10.008

  View details for Web of Science ID 000273758100016

  View details for PubMedID 20123478

• Pathological evidence of Wolman's disease following hematopoietic stem cell transplantation despite correction of lysosomal acid lipase activity BONE MARROW TRANSPLANTATION Gramatges, M. M., Dvorak, C. C., Regula, D. P., Enns, G. M., Weinberg, K., Agarwal, R. 2009; 44 (7): 449-450

  View details for DOI 10.1038/bmt.2009.57

  View details for Web of Science ID 000270933000007

  View details for PubMedID 19308038

• Hypoplastic Glomerulocystic Kidney Disease and Hepatoblastoma A Potential Association not Caused by Mutations in Hepatocyte Nuclear Factor 1 beta JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Abdul-Rahman, O. A., Edghill, E. L., Kwan, A., Enns, G. M., Hattersley, A. T. 2009; 31 (7): 527-529

  Abstract

  Hypoplastic glomerulocystic kidney disease is an autosomal dominant disorder caused by mutations in hepatocyte nuclear factor-1beta. Hepatoblastoma is a sporadic occurring tumor of embryonal origin that has been associated with the several overgrowth syndromes. We report a case of concomitant hypoplastic glomerulocystic kidney disease and hepatoblastoma. Review of the literature identified 4 other patients with a similar association. We propose that hypoplastic glomerulocystic kidney disease and hepatoblastoma represent a possible association, and we excluded mutations in hepatocyte nuclear factor-1beta in our patient as causative of this putative association.

  View details for Web of Science ID 000267567800014

  View details for PubMedID 19564751

• Clinical and Molecular Heterogeneity in Patients with the CblD Inborn Error of Cobalamin Metabolism JOURNAL OF PEDIATRICS Miousse, I. R., Watkins, D., Coelho, D., Rupar, T., Crombez, E. A., Vilain, E., Bernstein, J. A., Cowan, T., Lee-Messer, C., Enns, G. M., Fowler, B., Rosenblatt, D. S. 2009; 154 (4): 551-556

  Abstract

  To describe 3 patients with the cblD disorder, a rare inborn error of cobalamin metabolism caused by mutations in the MMADHC gene that can result in isolated homocystinuria, isolated methylmalonic aciduria, or combined homocystinuria and methylmalonic aciduria.Patient clinical records were reviewed. Biochemical and somatic cell genetic studies were performed on cultured fibroblasts. Sequence analysis of the MMADHC gene was performed on patient DNA.Patient 1 presented with isolated methylmalonic aciduria, patient 3 with isolated homocystinuria, and patient 2 with combined methylmalonic aciduria and homocystinuria. Studies of cultured fibroblasts confirmed decreased synthesis of adenosylcobalamin in patient 1, decreased synthesis of methylcobalamin in patient 3, and decreased synthesis of both cobalamin derivatives in patient 2. The diagnosis of cblD was established in each patient by complementation analysis. Mutations in the MMADHC gene were identified in all patients.The results emphasize the heterogeneous clinical, cellular and molecular phenotype of the cblD disorder. The results of molecular analysis of the MMADHC gene are consistent with the hypothesis that mutations affecting the N terminus of the MMADHC protein are associated with methylmalonic aciduria, and mutations affecting the C terminus are associated with homocystinuria.

  View details for DOI 10.1016/j.jpeds.2008.10.043

  View details for Web of Science ID 000264808000020

  View details for PubMedID 19058814

• A novel homozygous SCO2 mutation, p.G193S, causing fatal infantile cardioencephalomyopathy CLINICAL NEUROPATHOLOGY Mobley, B. C., Enns, G. M., Wong, L., Vogel, H. 2009; 28 (2): 143-149

  Abstract

  Cytochrome c oxidase (COX) deficiency is a frequent cause of mitochondrial disease in infants. Mutations in the COX assembly gene SCO2 cause fatal infantile cardioencephalomyopathy. All patients reported to date with SCO2 deficiency share a common p.E140K mutation in at least 1 allele. In order to further the understanding of the genotype-phenotype spectrum associated with fatal infantile cardioencephalomyopathy, we describe a novel homozygous SCO2 mutation p.G193S in a patient with fatal infantile cardioencephalomyopathy born to consanguineous parents of Indian ancestry.

  View details for Web of Science ID 000264437100011

  View details for PubMedID 19353847

• Successful pregnancy and cesarean delivery via noninvasive ventilation in mitochondrial myopathy JOURNAL OF PERINATOLOGY Yuan, N., El-Sayed, Y. Y., Ruoss, S. J., Riley, E., Enns, G. M., Robinson, T. E. 2009; 29 (2): 166-167

  Abstract

  We report a case study of a 22-year-old woman with mitochondrial thymidine kinase 2 deficiency and chronic respiratory failure due to severe neuromuscular weakness requiring noninvasive positive pressure ventilation (NIPPV) since 12 years of age. During pregnancy and cesarean delivery, she was successfully supported with NIPPV. A multidisciplinary team approach should be used in pregnant patients with these disorders with specific attention to management of pulmonary complications, selection of route of delivery, anesthesia, and analgesia.

  View details for DOI 10.1038/jp.2008.178

  View details for Web of Science ID 000263492700016

  View details for PubMedID 19177045

• Cell-based therapies for metabolic liver disease MOLECULAR GENETICS AND METABOLISM Enns, G. M., Millan, M. T. 2008; 95 (1-2): 3-10

  Abstract

  Liver transplantation is an important therapeutic option for many individuals with metabolic liver disease. Nevertheless, the invasive nature of surgery and limitations of donor organ availability have led to the search for alternatives to whole-organ transplantation. Cell-based therapies have been a particularly active area of investigation in recent years. Hepatocyte transplantations have been performed for a variety of indications, including acute liver failure, end-stage liver disease, and inborn errors of metabolism. Individuals with inborn errors of metabolism who have undergone hepatocyte transplantation have shown clinical improvement and partial correction of the underlying metabolic defect. In most cases, sustained benefits have not been observed. This may be related to inadequate cell dose, variations in the quality of hepatocyte preparations, rejection of the transplanted cells, or senescence of transplanted hepatocytes. Though initial proof of concept with hepatocyte transplantation has been demonstrated by a number of investigators, wide application of this technology has been hindered by the inability to secure a reliable and well-characterized cell source(s) for transplantation and by the challenges of sustained engraftment and expansion of transplanted cells in vivo. Cell-based therapies, including those based on stem cells or more differentiated progenitor cells, may represent the future of cell transplantation for treatment of metabolic liver disease.

  View details for DOI 10.1016/j.ymgme.2008.06.001

  View details for PubMedID 18640065

• Neurologic Damage and Neurocognitive Dysfunction in Urea Cycle Disorders SEMINARS IN PEDIATRIC NEUROLOGY Enns, G. M. 2008; 15 (3): 132-139

  Abstract

  Although the survival of patients who have urea cycle disorders has improved with the use of modalities such as alternative pathway therapy and hemodialysis, neurologic outcome is suboptimal. Patients often manifest with a variety of neurologic abnormalities, including cerebral edema, seizures, cognitive impairment, and psychiatric illness. Current hypotheses of the pathogenesis underlying brain dysfunction in these patients have focused on several lines of investigation, including the role of glutamine in causing cerebral edema, mitochondrial dysfunction leading to energy failure and the production of free radicals, and altered neurotransmitter metabolism. Advances in understanding the pathogenetic mechanisms underlying brain impairment in urea cycle disorders may lead to the development of therapies designed to interfere with the molecular cascade that ultimately leads to cerebral edema and other brain pathological findings.

  View details for DOI 10.1016/j.spen.2008.05.007

  View details for PubMedID 18708004

• Maternal phenylketonuria PEDIATRICS Saal, H. M., Braddock, S. R., Bull, M. J., Enns, G., Gruen, J. R., Mendelsohn, N. J., Saul, R. A. 2008; 122 (2): 445-449

  View details for DOI 10.1542/peds.2008-1485

  View details for Web of Science ID 000258142500028

• Dopa-responsive dystonia presenting as delayed and awkward gait PEDIATRIC NEUROLOGY Cheyette, B. N., Cheyette, S. N., Cusmano-Ozog, K., Enns, G. M. 2008; 38 (4): 273-275

  Abstract

  Dopa-responsive dystonia is a hereditary disease characterized by inadequate dopamine production. Autosomal-dominant cases result from mutations in the GCH1 gene, encoding guanosine triphosphate (GTP)-cyclohydrolase 1. The most common presenting manifestation is dystonia of a lower extremity, often worsening late in the day. The onset and clinical severity are variable, sometimes even within a single family. Gender effects on allele penetrance have been reported. We present a male toddler with dopa-responsive dystonia caused by an autosomal-dominant GCH1 mutation. Three other family members were also found to carry the mutation, with widely different functional consequences.

  View details for DOI 10.1016/j.pediatrneurol.2007.12.005

  View details for Web of Science ID 000254646800009

  View details for PubMedID 18358407

• Central nervous system therapy for lysosomal storage disorders NEUROSURGICAL FOCUS Enns, G. M., Huhn, S. L. 2008; 24 (3-4)

  Abstract

  Most lysosomal storage disorders are characterized by progressive central nervous system impairment, with or without systemic involvement. Affected individuals have an array of symptoms related to brain dysfunction, the most devastating of which is neurodegeneration following a period of normal development. The blood-brain barrier has represented a significant impediment to developing therapeutic approaches to treat brain disease, but novel approaches-including enzyme replacement, small-molecule, gene, and cell-based therapies-have given children afflicted by these conditions and those who care for them hope for the future.

  View details for DOI 10.3171/FOC/2008/24/3-4/E11

  View details for PubMedID 18341388

• Health supervision for children with neurofibromatosis PEDIATRICS Schaefer, G. B., Bull, M. J., Enns, G. M., Gruen, J. R., Hersh, J. H., Mendelsohn, N. J., Saal, H. M. 2008; 121 (3): 633-642

  Abstract

  Neurofibromatosis 1 is a multisystem disorder that primarily involves the skin and nervous system. Its population prevalence is 1 in 3500. The condition usually is recognized in early childhood, when cutaneous manifestations are apparent. Although neurofibromatosis 1 is associated with marked clinical variability, most affected children do well from the standpoint of their growth and development. Some features of neurofibromatosis 1 are present at birth, and others are age-related abnormalities of tissue proliferation, which necessitate periodic monitoring to address ongoing health and developmental needs and to minimize the risk of serious medical complications. This clinical report provides a review of the clinical criteria needed to establish a diagnosis, the inheritance pattern of neurofibromatosis 1, its major clinical and developmental manifestations, and guidelines for monitoring and providing intervention to maximize the growth, development, and health of an affected child.

  View details for DOI 10.1542/peds.2007-3364

  View details for Web of Science ID 000253780100025

  View details for PubMedID 18310216

• Progressive cerebral vascular degeneration with mitochondrial encephalopathy AMERICAN JOURNAL OF MEDICAL GENETICS PART A Longo, N., Schrijver, I., Vogel, H., Pique, L. M., Cowan, T. M., Pasquali, M., Steinberg, G. K., Hedlund, G. L., Ernst, S. L., Gallagher, R. C., Enns, G. M. 2008; 146A (3): 361-367

  Abstract

  MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) is a maternally inherited disorder characterized by recurrent cerebral infarctions that do not conform to discreet vascular territories. Here we report on a patient who presented at 7 years of age with loss of consciousness and severe metabolic acidosis following vomiting and dehydration. She developed progressive sensorineural hearing loss, myopathy, ptosis, short stature, and mild developmental delays after normal early development. Biochemical testing identified metabolites characteristic of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (hexanoylglycine and suberylglycine), but also severe lactic acidemia (10-25 mM) and, in urine, excess of lactic acid, intermediates of the citric cycle, and marked ketonuria, suggesting mitochondrial dysfunction. She progressed rapidly to develop temporary cortical blindness. Brain imaging indicated generalized atrophy, more marked on the left side, in addition to white matter alterations consistent with a mitochondrial disorder. Magnetic resonance angiography indicated occlusion of the left cerebral artery with development of collateral circulation (Moyamoya syndrome). This process worsened over time to involve the other side of the brain. A muscle biopsy indicated the presence of numerous ragged red fibers. Molecular testing confirmed compound heterozygosity for the common mutation in the MCAD gene (985A>G) and a second pathogenic mutation (233T>C). MtDNA testing indicated that the muscle was almost homoplasmic for the 3243A>T mutation in tRNALeu, with a lower mutant load (about 50% heteroplasmy) in blood and skin fibroblasts. These results indicate that mitochondrial disorders may be associated with severe vascular disease resulting in Moyamoya syndrome. The contribution of the concomitant MCAD deficiency to the development of the phenotype in this case is unclear.

  View details for DOI 10.1002/ajmg.a.31841

  View details for Web of Science ID 000253008300014

• An unusual case of Pompe disease presenting as muscular dystrophy Cusmano-Ozog, K., Vogel, H., Cowan, T., Enns, G. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2008: S18

  View details for DOI 10.1016/j.ymgme.2007.10.031

  View details for Web of Science ID 000253358500036

• Clinical and molecular features of mitochondrial DNA depletion due to mutations in deoxyguanosine kinase HUMAN MUTATION Dimmock, D. P., Zhang, Q., Dionisi-Vici, C., Carrozzo, R., Shieh, J., Tang, L. Y., Truong, C., Schmitt, E., Sifry-Platt, M., Lucioli, S., Santorelli, F. M., Ficicioglu, C. H., Rodriguez, M., Wierenga, K., Enns, G. M., Longo, N., Lipson, M. H., Valiance, H., Craigen, W. J., Scaglia, F., Wong, L. 2008; 29 (2): 330-331

  Abstract

  Published mutations in deoxyguanosine kinase (DGUOK) cause mitochondrial DNA depletion and a clinical phenotype that consists of neonatal liver failure, nystagmus and hypotonia. In this series, we have identified 15 different mutations in the DGUOK gene from 9 kindreds. Among them, 12 have not previously been reported. Nonsense, splice site, or frame-shift mutations that produce truncated proteins predominate over missense mutations. All patients who harbor null mutations had early onset liver failure and significant neurological disease. These patients have all died before 2-years of age. Conversely, two patients carrying missense mutations had isolated liver disease and are alive in their 4th year of life without liver transplant. Five subjects were detected by newborn screening, with elevated tyrosine or phenylalanine. Consequently, this disease should be considered if elevated tyrosine is identified by newborn screening. Mitochondrial DNA content was below 10% of controls in liver in all but one case and modestly reduced in blood cells. With this paper a total of 39 different mutations in DGUOK have been identified. The most frequent mutation, c.763_c.766dupGATT, occurs in 8 unrelated kindreds. 70% of mutations occur in only one kindred, suggesting full sequencing of this gene is required for diagnosis. The presentation of one case with apparent viral hepatitis, without neurological disease, suggests that this disease should be considered in patients with infantile liver failure regardless of the presence of neurological features or apparent infectious etiology.

  View details for DOI 10.1002/humu.9519

  View details for Web of Science ID 000253033000018

  View details for PubMedID 18205204

• Inborn error of metabolism presenting as malformation syndrome: Hydrocephalus as a manifestation of cobalamin D disease Western Regional Meeting of the American-Federation-for-Medical-Research Bernstein, J. A., Lee-Messer, C., Cusmano, K., Rosenblatt, D. S., Cowan, T., Enns, G. M. LIPPINCOTT WILLIAMS & WILKINS. 2008: 196–96

  View details for Web of Science ID 000252793300290

• Glutaric acidemia type I: a neurosurgical perspective JOURNAL OF NEUROSURGERY Hou, L. C., Veeravagu, A., Hsu, A. R., Enns, G. M., Huhn, S. L. 2007; 107 (2): 167-172

  Abstract

  Glutaric acidemia type I (GA-I) is a rare, autosomal recessive metabolic disorder that leads to severe dystonia, basal ganglia degeneration, and bilaterally enlarged anterior middle cranial fossae. The current management of this disease includes early diagnosis with newborn screening, prevention of catabolism, carnitine supplementation, and a strict dietary protein restriction. Neurosurgical evaluation and intervention may be necessary in patients with structural lesions associated with this disease. In this report, the authors present two pediatric patients with GA-I and discuss the neurosurgical aspects of this rare medical disorder.

  View details for DOI 10.3171/PED-07/08/167

  View details for PubMedID 18459892

• Cobalamin C disease identified by expanded newborn screening: The California experience. Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2007) Cusmano-Ozog, K., Lorey, F., LEVINE, S., Martin, M., Nicholas, E., Packman, S., Rosenblatt, D. S., Cederbaum, S. D., Cowan, T. M., Enns, G. M. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2007: 240–40

  View details for Web of Science ID 000245179500012

• Early identification and aggressive treatment of cobalamin C disease. Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2007) Cusmano-Ozog, K., Martin, M., Nicholas, E., Packman, S., Rosenblatt, D. S., Cowan, T. M., Enns, G. M. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2007: 249–50

  View details for Web of Science ID 000245179500036

• Cobalamin c disease and expanded newborn screening: The California experience. 8th Conference of the Western Student Medical Research Forum/Western Section of the American-Federation-for-Medical-Research/Western Association-of-Physicians/Western-Society-for-Pediatric-Research/Western-Society-for-Clinical-Investigation Cusmano-Ozog, K., Lorey, F., LEVINE, S., Martin, M., Nicholas, E., Packman, S., Rosenblatt, D. S., Cowan, T. M., Enns, G. M. LIPPINCOTT WILLIAMS & WILKINS. 2007: S90–S90

  View details for Web of Science ID 000247692400092

• Systemic hyalinosis: A distinctive early childhood-onset disorder characterized by mutations in the anthrax toxin receptor 2 gene (ANTRX2) PEDIATRICS Shieh, J. T., Swidler, P., Martignetti, J. A., Ramirez, M. C., Balboni, I., Kaplan, J., Kennedy, J., Abdul-Rahman, O., Enns, G. M., Sandborg, C., Slavotinek, A., Hoyme, H. E. 2006; 118 (5): E1485-E1492

  Abstract

  We sought to further characterize the phenotype and facilitate clinical recognition of systemic hyalinosis in children who present with chronic pain and progressive contractures in early childhood.We report on 3 children who presented in infancy with symptoms and signs that initially were not recognized to be those of systemic hyalinosis. Although the children were evaluated for a variety of problems, including lysosomal storage disorders and nonaccidental trauma, all eventually underwent genetic analysis of the anthrax toxin receptor 2 gene (ANTRX2) and were diagnosed as having systemic hyalinosis.We describe the recognizable but variable clinical phenotype of systemic hyalinosis and associated mutations in ANTRX2. Affected individuals presented in early infancy with severe pain and progressive contractures. Initial diagnostic evaluations were unrevealing; however, hyperpigmented skin over bony prominences, skin nodules, and fleshy perianal masses suggested a diagnosis of systemic hyalinosis. ANTRX2 analysis confirmed the diagnosis in each case. Although 2 of the children died in infancy as a result of complications of chronic diarrhea, the third child has survived into midchildhood. These data suggest that some ANTRX2 mutations, such as that identified in the long-term survivor, may be associated with a less severe course of disease.Although some aspects of systemic hyalinosis may resemble lysosomal storage disorders, the clinical features of systemic hyalinosis are distinctive, and detection of an ANTRX2 mutation can confirm the diagnosis. Early recognition of affected individuals should allow for aggressive pain control and expectant management of the multiple associated problems, including gastrointestinal dysfunction.

  View details for DOI 10.1542/peds.2006-0824

  View details for PubMedID 17043134

• Introduction to the newborn screening fact sheets PEDIATRICS Kaye, C. I., Schaefer, G. B., Bull, M. J., Enns, G. M., Gruen, J. R., Hersh, J. H., Mendelsohn, N. J., Saal, H. M., Goldberg, J. D., Hanson, J. W., Lloyd-Puryear, M. A., Rasmussen, S. A., Spire, P., Accurso, F., La Franchi, S., Lane, P. A., Northrup, H., Pang, S., Watson, M. 2006; 118 (3): 1304-1312

  Abstract

  Newborn screening fact sheets were last revised in 1996 by the Committee on Genetics of the American Academy of Pediatrics. These fact sheets have been revised again because of advances in the field, including technologic innovations such as tandem mass spectrometry, as well as greater appreciation of ethical issues such as informed consent. The fact sheets provide information to assist pediatricians and other professionals who care for children in performing their essential role within the newborn screening public health system. The newborn screening system consists of 5 parts: (1) newborn testing; (2) follow-up of abnormal screening results to facilitate timely diagnostic testing and management; (3) diagnostic testing; (4) disease management, which requires coordination with the medical home and genetic counseling; and (5) continuous evaluation and improvement of the newborn screening system. The following disorders are reviewed in the newborn screening fact sheets (which are available at www.pediatrics.org/cgi/content/full/118/3/e934): biotinidase deficiency, congenital adrenal hyperplasia, congenital hearing loss, congenital hypothyroidism, cystic fibrosis, galactosemia,homocystinuria, maple syrup urine disease, medium-chain acyl-coenzyme A dehydrogenase deficiency, phenylketonuria, sickle cell disease and other hemoglobinopathies,and tyrosinemia.

  View details for DOI 10.1542/peds.2006-1782

  View details for Web of Science ID 000240959100058

  View details for PubMedID 16960984

• Immunohistochemical analysis of cytochrome oxidase deficiency using fixed tissues Vogel, H., Masek, M., Gallagher, R., Enns, G. BLACKWELL PUBLISHING. 2006: S167

  View details for Web of Science ID 000239938600373

• Genitopatellar syndrome: expanding the phenotype and excluding mutations in LMX1B and TBX4. American journal of medical genetics. Part A Abdul-Rahman, O. A., La, T. H., Kwan, A., Schlaubitz, S., Barsh, G. S., Enns, G. M., Hudgins, L. 2006; 140 (14): 1567-1572

  Abstract

  Genitopatellar syndrome is a newly described disorder characterized by absent/hypoplastic patellae, lower extremity contractures, urogenital anomalies, dysmorphic features, skeletal anomalies, and agenesis of the corpus callosum. More recently, cardiac anomalies and ectodermal dysplasia have been suggested as additional features of this syndrome. We report on two additional patients with genitopatellar syndrome and expand the spectrum of anomalies to include radio-ulnar synostosis. Since there exists significant overlap in the skeletal phenotype between genitopatellar syndrome and both the nail-patella and short patella syndromes, mutation screening of their causative genes, LMX1B and TBX4, was performed. Although there still does not appear to be an identifiable molecular etiology in genitopatellar syndrome, mutations in these two candidate genes have been excluded in our patients. Since both LMX1B and TBX4 are involved in a common molecular pathway, it is likely that the causative gene of genitopatellar syndrome functions within the same developmental process.

  View details for PubMedID 16761293

• Genitopatellar syndrome: Expanding the phenotype and excluding mutations in LMX1B and TBX4 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Abdul-Rahman, O. A., La, T. H., Kwan, A., Schlaubitz, S., Barsh, G. S., Enns, G. M., Hudgins, L. 2006; 140A (14): 1567-1572

  Abstract

  Genitopatellar syndrome is a newly described disorder characterized by absent/hypoplastic patellae, lower extremity contractures, urogenital anomalies, dysmorphic features, skeletal anomalies, and agenesis of the corpus callosum. More recently, cardiac anomalies and ectodermal dysplasia have been suggested as additional features of this syndrome. We report on two additional patients with genitopatellar syndrome and expand the spectrum of anomalies to include radio-ulnar synostosis. Since there exists significant overlap in the skeletal phenotype between genitopatellar syndrome and both the nail-patella and short patella syndromes, mutation screening of their causative genes, LMX1B and TBX4, was performed. Although there still does not appear to be an identifiable molecular etiology in genitopatellar syndrome, mutations in these two candidate genes have been excluded in our patients. Since both LMX1B and TBX4 are involved in a common molecular pathway, it is likely that the causative gene of genitopatellar syndrome functions within the same developmental process.

  View details for DOI 10.1002/ajmg.a.31258

  View details for Web of Science ID 000238799900011

• Glutaryl-CoA dehydrogenase deficiency and newborn screening: Retrospective analysis of a low excretor provides further evidence that some cases may be missed MOLECULAR GENETICS AND METABOLISM Gallagher, R. C., Cowan, T. M., Goodman, S. I., Enns, G. A. 2005; 86 (3): 417-420

  Abstract

  Glutaryl-CoA dehydrogenase deficiency (GA-I) is associated with the onset of irreversible, disabling dystonia between 3 and 18 months of age. Presymptomatic identification and treatment can prevent the devastating disability associated with this disorder. We report the retrospective analysis of the newborn blood spot of an affected child with a low excretor phenotype. The level of glutarylcarnitine was below the newborn screening program cut-off. This suggests that some cases of GA-I may be missed by newborn screening by tandem mass spectrometry.

  View details for DOI 10.1016/j.ymgme.2005.08.005

  View details for PubMedID 16183314

• Identification of three novel mutations in the dihydropyrimidine dehydrogenase gene associated with altered pre-mRNA splicing or protein function (vol 386, pg 319, 2005) BIOLOGICAL CHEMISTRY Van Kuilenburg, A. B., Meinsma, R., Beke, E., Bobba, B., Boffi, P., Enns, G. M., Witt, D. R., Dobritzsch, D. 2005; 386 (10): 1075

  View details for DOI 10.1515/BC.2005.123

  View details for Web of Science ID 000232953000014

• Management of methylmalonic acidaemia by combined liver-kidney transplantation JOURNAL OF INHERITED METABOLIC DISEASE Nagarajan, S., Enns, G. M., Millan, M. T., Winter, S., Sarwal, M. M. 2005; 28 (4): 517-524

  Abstract

  Methylmalonic acidaemia (MMA) is a rare autosomal recessive inborn error of metabolism that typically presents in infancy with recurrent episodes of metabolic acidosis, developmental delay and failure to thrive. The disease course is complicated by the development of chronic tubulointerstitial nephritis progressing to end-stage renal disease in adolescence. We describe two adolescents with cobalamin-nonresponsive MMA (mut0) who developed polyuria, chronic tubulointerstitial nephritis, dystonia but normal synthetic liver function. Both patients received combined liver-kidney transplantation (CLKT), preceded by a single pretransplant haemodialysis for clearance of methylmalonic acid. Post CLKT there was 95-97% reduction in serum and urine methylmalonic acid, leading to significant liberalization of dietary protein intake and a consequent increase in body mass index, muscle strength and energy. In addition, renal function normalized and clinical neurological status stabilized. We propose that CLKT be considered as a therapeutic option early in the course of cobalamin-nonresponsive MMA. Progressive tubulointerstitial nephritis with disabling polyuria is a confounder in patient management even in the absence of end-stage renal disease. Successful CLKT restores methylmalonyl-CoA mutase enzyme levels in the liver and kidney, improves clearance of methylmalonic acid with resultant dietary protein liberalization, and offers excellent graft and patient outcomes with improvement in quality of life.

  View details for DOI 10.1007/s10545-005-0517-8

  View details for Web of Science ID 000229220200008

  View details for PubMedID 15902554

• Postpartum "psychosis" in mild argininosuccinate synthetase deficiency OBSTETRICS AND GYNECOLOGY Enns, G. M., O'Brien, W. E., Kobayashi, K., Shinzawa, H., Pellegrino, J. E. 2005; 105 (5): 1244-1246

  Abstract

  Urea cycle disorders are relatively rare but well-established causes of postpartum coma and death. Such clinical presentations have been reported previously in ornithine transcarbamylase and carbamyl phosphate synthetase deficiencies.We describe a woman, without prior symptoms of metabolic disease, who presented with hyperammonemia and psychiatric symptoms in the postpartum period. Initial diagnoses included acute fatty liver of pregnancy and postpartum psychosis. She was later found to have argininosuccinate synthetase deficiency after further metabolic investigations. Rare heterozygous mutations in the argininosuccinate synthetase gene were identified.Urea cycle disorders may present initially with postpartum psychiatric symptoms and may represent an underrecognized cause of "postpartum psychosis." We recommend obtaining metabolic studies in women with neurologic or severe psychiatric symptoms in the postpartum period.

  View details for DOI 10.1097/01.AOG.0000157769.90230.24

  View details for PubMedID 15863597

• Identification of three novel mutations in the dihydropyrimidine dehydrogenase gene associated with altered pre-mRNA splicing or protein function BIOLOGICAL CHEMISTRY van Kuilenburg, A. B., Meinsma, R., Beke, E., Bobba, B., Boffi, P., Enns, G. M., Witt, D. R., Dobritzsch, D. 2005; 386 (4): 319-324

  Abstract

  Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases uracil and thymine, as well as of the widely used chemotherapeutic drug 5-fluorouracil (5FU). Analysis of the DPD gene ( DPYD ) in two patients presenting with complete DPD deficiency and the parents of an affected child showed the presence of three novel mutations, including one splice site mutation IVS11 + 1G-->T and the missense mutations 731A-->C (E244V) and 1651G-->A (A551T). The G-->T mutation in the invariant GT splice donor site flanking exon 11 (IVS11 + 1G-->T) created a cryptic splice site within exon 11. As a consequence, a 141-bp fragment encoding the aminoacid residues 400-446 of the primary sequence of the DPD protein was missing in the mature DPD mRNA. Analysis of the crystal structure of pig DPD suggested that the E244V mutation might interfere with the electron flow between NADPH and the pyrimidine binding site of DPD. The A551T point mutation might prevent binding of the prosthetic group FMN and affect folding of the DPD protein. The identification of these novel mutations in DPYD will allow the identification of patients with an increased risk of developing severe 5FU-associated toxicity.

  View details for DOI 10.1515/BC.2005.038

  View details for Web of Science ID 000228817700002

  View details for PubMedID 15899693

• Two cases of transient 5-oxoprolinuria resolving with antioxidant therapy. Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2005) Huguenin, S. M., Gallagher, R. C., Lyons, M. J., Kwan, T., Enns, G. M., Cowan, T. M. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2005: 223–24

  View details for Web of Science ID 000227648400059

• Mutations in POMT1 are found in a minority of patients with Walker-Warburg syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Currier, S. C., Lee, C. K., Chang, B. S., Bodell, A. L., Pai, G. S., Job, L., Lagae, L. G., Al-Gazali, L. I., Eyaid, W. M., Enns, G., Dobyns, W. B., Walsh, C. A. 2005; 133A (1): 53-57

  Abstract

  Walker-Warburg syndrome (WWS) is an autosomal recessive disorder of infancy characterized by hydrocephalus, agyria, retinal dysplasia, congenital muscular dystrophy, and over migration of neurons through a disrupted pial surface resulting in leptomeningeal heterotopia. Although previous work identified mutations in the o-mannosyl transferase, POMT1, in 6 out of 30 WWS families [Beltran-Valero de Bernabe et al., 2002], the incidence of POMT1 mutations in WWS is not known. We sequenced the entire coding region of POMT1 in 30 consecutive, unselected patients with classic WWS. Two novel heterozygous mutations were found in two patients from non-consanguineous parents, whereas 28 other patients failed to show any POMT1 mutations. One patient was found to be heterozygous for a transition, g.1233T > A, which predicts p.Y352X. A second patient was found also to be heterozygous for a transition g.1790C > G, which predicts p.S537R. As an additional determination of the frequency of the POMT1 mutations in WWS, we tested for linkage of WWS to POMT1 in six consanguineous families. All six demonstrated heterozygosity and negative LOD scores at the POMT1 locus. From these data we show that POMT1 is an uncommon cause of WWS, the incidence of coding region mutations in this population of WWS being less than 7%. We conclude that while the incidence of POMT1 mutations in WWS can be as high as 20% as reported by Beltran-Valero de Bernabe et al. [2002] and it can be as low as approximately 7%, as reported here.

  View details for DOI 10.1002/ajmg.a.30487

  View details for Web of Science ID 000226619200010

  View details for PubMedID 15637732

• Mild developmental delay in terminal chromosome 6p deletion AMERICAN JOURNAL OF MEDICAL GENETICS PART A Chen, K. M., Cherry, A. M., Hahn, J. S., Enns, G. M. 2004; 129A (2): 201-205

  Abstract

  Deletions involving the short arm of chromosome 6 are relatively rare. Although features of this condition are variable, common findings include developmental delay, ocular abnormalities, hearing loss, and cardiac defects. In an effort to define further the clinical variability of this condition, we report a 6-year-old female with a de novo terminal deletion of chromosome 6 at band 6p24, with mild gross motor delays and normal cognition.

  View details for DOI 10.1002/ajmg.a.30127

  View details for PubMedID 15316977

• Terminal 22q deletion syndrome: A newly recognized cause of speech and language disability in the autism spectrum PEDIATRICS Manning, M. A., Cassidy, S. B., Clericuzio, C., Cherry, A. M., Schwartz, S., Hudgins, L., Enns, G. M., Hoyme, H. E. 2004; 114 (2): 451-457

  Abstract

  Cryptic subtelomeric chromosome rearrangements account for 6% to 10% of idiopathic mental retardation. As cytogenetic and molecular techniques have become more sophisticated, the number of genetic syndromes attributed to these microdeletions has increased. To date, 64 patients have been described in the literature with a more recently recognized microdeletion syndrome, del 22q13.3. The purpose of this study is to present 11 new cases of this recently described syndrome to delineate further the phenotype and to alert the clinician to another genetic condition that should be considered in the differential diagnosis of early hypotonia, delayed speech acquisition, and autistic behavior.Eleven patients were evaluated in 3 academic institutions. Clinical features and results of cytogenetic testing were recorded and tabulated. Reasons for referral for genetic evaluation included developmental delay, severe expressive speech and language delay, and dysmorphic features.Age of presentation ranged from 5 months to 46 years. There were 10 female patients and 1 male patient. All of the patients exhibited delayed motor development, some degree of hypotonia, and severe expressive speech and language delay. Dysmorphic facial features included epicanthal folds, large cupped ears, underdeveloped philtrum, loss of cupid's bow, and full supraorbital ridges. Six patients exhibited autistic-like behaviors. Microscopically visible chromosome deletions were observed in 6 patients. In the remainder, the deletion was detected with the use of fluorescence in situ hybridization.Hypotonia and developmental delay are nonspecific findings observed in many malformation and genetic syndromes. However, in association with severe speech and language delay and autistic-like behavior, this phenotype may be a significant indication to consider the 22q13 deletion syndrome as a potential cause.

  View details for PubMedID 15286229

• Head imaging abnormalities in dihydropyrimidine dehydrogenase deficiency JOURNAL OF INHERITED METABOLIC DISEASE Enns, G. M., Barkovich, A. J., van Kuilenburg, A. B., Manning, M., Sanger, T., Witt, D. R., Van Gennip, A. H. 2004; 27 (4): 513-522

  Abstract

  Dihydropyrimidine dehydrogenase (DPD) deficiency is a rare autosomal recessive disorder of pyrimidine metabolism. Patients may present with a wide range of neurological symptoms during the first years of life. Head imaging abnormalities have been reported only rarely and include diffuse cerebral atrophy and white-matter hyperintensity. The pathogenesis of the white-matter abnormalities is unknown, although environmental factors and altered energy metabolism may be involved. To further understanding of the spectrum of brain abnormalities associated with DPD deficiency, we report a 17-month-old girl, born to a consanguineous Pakistani couple, who had a history of encephalopathy, prolonged hypoventilation, developmental delay and failure to thrive. Head MRI showed prominent sulci and abnormal T2 prolongation in the cerebral white matter and brainstem. Thus, DPD deficiency may feature prominent brain abnormalities involving the cerebral white matter and brainstem. Anoxic stress may have contributed to the clinical presentation and brain findings in this case. In order to define more clearly the contribution of DPD deficiency to the pathogenesis of these MRI abnormalities, we recommend performing detailed analysis of urine pyrimidine metabolites in patients who have such findings.

  View details for Web of Science ID 000223177000010

  View details for PubMedID 15303009

• Methotrexate/misoprostol embryopathy: Report of four cases resulting from failed medical abortion Bryan D Hall Festschrift 2003 Adam, M. P., Manning, M. A., Beck, A. E., Kwan, A., Enns, G. M., Clericuzio, C., Hoyme, H. E. WILEY-LISS. 2003: 72–78

  Abstract

  Methotrexate, a methyl derivative of aminopterin, is a folic acid antagonist and a known human teratogen; misoprostol is a synthetic prostaglandin E1 analog that causes uterine contractions. Recently, there has been resurgence in the use of methotrexate in combination with misoprostol or of methotrexate alone for the treatment of unwanted or ectopic pregnancies, respectively. This report documents the findings in four infants who were exposed prenatally to methotrexate alone or in combination with misoprostol in a failed attempt at medical abortion or treatment of ectopic pregnancy. All patients demonstrated growth deficiency, with growth parameters <10th centile, and all displayed features consistent with methotrexate and/or misoprostol embryopathy. Since an increasing number of medical abortions are being performed, it is important for physicians to recognize the associated teratogenic effects of these abortifacients. Data from the patients herein described should prompt obstetricians and other health care practitioners who prescribe these medications to counsel their patients regarding these risks, especially if the treatment regimen fails to induce an abortion.

  View details for DOI 10.1002/ajmg.a.20503

  View details for PubMedID 14556250

• Compensatory amplification of mtDNA in a patient with a novel deletion/duplication and high mutant load JOURNAL OF MEDICAL GENETICS Wong, L. J., Perng, C. L., Hsu, C. H., Bai, R. K., Schelley, S., Vladutiu, G. D., Vogel, H., Enns, G. M. 2003; 40 (11)

  View details for Web of Science ID 000186682000022

  View details for PubMedID 14627692

  View details for PubMedCentralID PMC1735312

• Congenital disorder of glycosylation Ic in patients of Indian origin MOLECULAR GENETICS AND METABOLISM Newell, J. W., Seo, N. S., Enns, G. M., McCraken, M., Mantovani, J. F., Freeze, H. H. 2003; 79 (3): 221-228

  Abstract

  Congenital disorder of glycosylation type Ic (CDG-Ic) is caused by mutations in ALG6, encoding an alpha 1,3-glucosyltransferase. The most frequent mutation found in this gene (C998T resulting in an A333V substitution) has until now been found only in patients of European origin. Here we describe the first occurrence of this CDG-Ic mutation in patients of Indian origin. Of three Indian patients described in this study, patient 1 was homozygous and patient 2 heterozygous for the A333V mutation. In patient 2 we also found a new mutation, IVS3+2_3insT, just 3bp away from the previously described IVS3+5G>A substitution; both mutations resulted in exon 3 skipping. We screened a panel of >350 genomic DNA samples from an ethnically diverse American population to determine the frequency of the A333V mutation. None of the samples carried this mutation, indicating the frequency of patients carrying this homozygous mutation should be <1 in 5x10(5). The discovery of the common CDG-Ic mutation A333V in an Indian population raises questions as to its ethnic origin.

  View details for DOI 10.1016/S1096-7192(03)00089-1

  View details for Web of Science ID 000184304300010

  View details for PubMedID 12855228

• Severe liver disease in urea cycle disorders. Western Regional Meeting of the American-Federation-for-Medical-Research Traynor, J. D., Tuchman, M., Manning, M. A., Goodman, S. I., Enns, G. M. LIPPINCOTT WILLIAMS & WILKINS. 2003: S118–S118

  View details for Web of Science ID 000180569600164

• Bilateral cystic lung disease in a monoamnionic twin of an anencephalic: A case of glial heterotopia in the lungs. Western Regional Meeting of the American-Federation-for-Medical-Research Anderson, J. M., Adams, M. L., Morgan, T., Robinson, T., Enns, G. M., Keller, K. A., Sylvester, K. G., Hintz, S. R. LIPPINCOTT WILLIAMS & WILKINS. 2003: S119–S120

  View details for Web of Science ID 000180569600170

• Clinical and molecular features of congenital disorder of glycosylation in patients with type 1 sialotransferrin pattern and diverse ethnic origins JOURNAL OF PEDIATRICS Enns, G. M., Steiner, R. D., Buist, N., Cowan, C., Leppig, K. A., McCracken, M. F., Westphal, V., Freeze, H. H., O'Brien, J. F., Jaeken, J., Matthijs, G., Behera, S., Hudgins, L. 2002; 141 (5): 695-700

  Abstract

  To increase awareness of congenital disorders of glycosylation (CDG), we report the features of patients with a variety of clinical presentations ranging from mild hypotonia and strabismus to severe neurologic impairment.Nine North American patients with CDG type I and different ethnic origins were studied.All patients had transferrin isoelectric focusing studies with a type 1 sialotransferrin pattern. Molecular analysis showed the previously described R141H, V231M, and T237M PMM2 mutations in four patients as well as 3 rare mutations (DeltaC389, L104V, and IVS1 -1 G-->A) in the PMM2 gene in two Asian patients.The clinical features of these patients with diverse ethnic backgrounds confirm the variable course of CDG type I. Screening for CDG should be considered in children with relatively mild neurologic impairment, especially if they have suggestive findings such as cerebellar hypoplasia and abnormal fat distribution.

  View details for DOI 10.1067/mpd.2002.128658

  View details for PubMedID 12410200

• Post-partum "psychosis" in mild argininosuccinate synthetase deficiency. 52nd Annual Meeting of the American-Society-of-Human-Genetics Enns, G. M., O'Brien, W. E., Kobayashi, K., Shinzawa, H., Hart, K., Gao, H. Z., Tabata, A., Saheki, T. CELL PRESS. 2002: 425–25

  View details for Web of Science ID 000178025801483

• The adolescent with an inborn error of metabolism: medical issues and transition to adulthood. Adolescent medicine (Philadelphia, Pa.) Enns, G. M., Packman, W. 2002; 13 (2): 315-?

  Abstract

  As patients with inborn errors of metabolism survive longer, understanding of potential medical and psychiatric complications adolescence and adulthood has increased. In general, detailed therapeutic guidelines for specific metabolic disorders are not available, and medical management must be tailored to the individual patient. Close interaction between the biochemical genetics clinic staff, primary care physician, mental health professional, and other specialists is necessary to formulate an integrated care plan. The education of the patient and family is a critical function of the biochemical genetics clinic, and transition from dependence on parents or other care providers to full independence is gradual. The ultimate goal is for the patient to have the essential knowledge and motivation required to cope responsibly with dietary and medical therapeutic regimens by adolescence or early adulthood. Specific illustrative inborn errors of metabolism are discussed (aminoacidemias, urea cycle defects, organic acidemias, fatty acid oxidation defects, disorders of carbohydrate metabolism, lysosomal storage disorders) in light of potential problems encountered in adolescence and adulthood, including issues involving pregnancy and long-term medical, psychosocial, and psychiatric complications.

  View details for PubMedID 11986039

• Early neonatal diagnosis of long-chain 3-hydroxyacyl coenzyme A dehydrogenase and mitochondrial trifunctional protein deficiencies MOLECULAR GENETICS AND METABOLISM Hintz, S. R., Matern, D., Strauss, A., Bennett, M. J., Hoyme, H. E., Schelley, S., Kobori, J., Colby, C., Lehman, N. L., Enns, G. M. 2002; 75 (2): 120-127

  Abstract

  Tandem mass spectrometry (MS/MS) has been introduced in several newborn screening programs for the detection of a large number of inborn errors of metabolism, including fatty acid oxidation disorders (FAOD). Early identification and treatment of FAOD have the potential to improve outcome and may be life-saving in some cases; an estimated 5% of sudden infant deaths are attributable to undiagnosed disorders of fatty acid oxidation. We report very early neonatal presentations of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (TFP) deficiencies confirmed by molecular analysis. Both patients had cardiorespiratory collapse and hypoglycemia, without a history of maternal pregnancy complications. Retrospective MS/MS analysis of the original newborn screening blood spots revealed characteristic acylcarnitine profiles. These cases are among the earliest reported presentations of LCHAD and TFP deficiencies and further illustrate the potential of MS/MS as a valuable tool for newborn screening of FAOD. However, timely analysis and reporting of results to clinicians are essential, because these disorders can manifest in the first few days of life.

  View details for DOI 10.1006/mgme.2001.3282

  View details for PubMedID 11855930

• Redefining a case of Jarcho-Levin syndrome as Oculo-Auriculo-Vertebral Spectrum. Cheng, S. F., Enns, G. M., Golabi, M., Blumberg, B., Kostiner, D. R. CELL PRESS. 2001: 300–300

  View details for Web of Science ID 000171648900686

• Functional analysis of novel mutations in a congenital disorder of glycosylation Ia patient with mixed Asian ancestry MOLECULAR GENETICS AND METABOLISM Westphal, V., Enns, G. M., McCracken, M. F., Freeze, H. H. 2001; 73 (1): 71-76

  Abstract

  Congenital disorders of glycosylation (CDG) are caused by autosomal recessive mutations in genes affecting N-glycan biosynthesis. Mutations in the PMM2 gene, which encodes the enzyme phosphomannomutase (mannose 6-phosphate <--> mannose 1-phosphate), give rise to the most common form: CDG-Ia. These patients typically present with dysmorphic features and neurological abnormalities, cerebellar hypoplasia, ataxia, hypotonia, and coagulopathy, in addition to feeding problems. However, the clinical symptoms vary greatly. The great majority of known CDG-Ia patients are of European descent where the most common mutant alleles originated. This ethnic bias can also be explained by lack of global awareness of the disorder. Here we report an Asian patient with prominent systemic features that we diagnosed with CDG-Ia resulting from two new mutations in the PMM2 gene (310C --> G resulting in L104V and an intronic mutation IVS1-1G --> A). The latter mutation seems to result in lower mRNA levels, and the L104V has been functionally analyzed in a yeast expression system together with known mutations. The Filipino and Cambodian origins of the parents show that CDG-Ia mutations occur in these ethnic groups as well as in Caucasians.

  View details for Web of Science ID 000168761300009

  View details for PubMedID 11350185

• Clinical course and biochemistry of sialuria JOURNAL OF INHERITED METABOLIC DISEASE Enns, G. M., Seppala, R., Musci, T. J., Weisiger, K., Ferrell, L. D., Wenger, D. A., Gahl, W. A., Packman, S. 2001; 24 (3): 328-336

  Abstract

  Sialuria is a rare inborn error of metabolism in which excessive free sialic acid (N-acetylneuraminic acid, NeuAc) is synthesized. A defect in the feedback inhibition of UDP-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase by the end-product of the sialic acid synthetic pathway, CMP-NeuAc, is the mechanism underlying this overproduction. Recent evidence suggests that sialuria is an autosomal dominant disorder. Only five patients have been documented to have such an enzymatic defect. We report a longitudinal study of one of the original sialuria patients, to age 11 years. Although he has coarse features and massive hepatomegaly, he has shown normal growth and relatively normal development. Pulmonary function testing showed minimal small airway obstruction. At 11 years, he developed intermittent abdominal pain and transient transaminase elevation above his baseline. Sialuria should be considered in the differential diagnosis of a patient with a phenotype suggestive of a mucopolysaccharidosis or oligosaccharidosis in the absence of developmental regression or prominent dysostosis multiplex. We recommend close monitoring of liver and pulmonary function in sialuria patients.

  View details for Web of Science ID 000169331400002

  View details for PubMedID 11486897

• Natural history of branchio-oto-renal (BOR) syndrome. Hudgins, L., Jones, M. C., Olney, R. S., Enns, G. M., Schelley, S. L. CELL PRESS. 2000: 56–56

  View details for Web of Science ID 000089400700237

• Molecular correlations in phenylketonuria: Mutation patterns and corresponding biochemical and clinical phenotypes in a heterogeneous California population PEDIATRIC RESEARCH Enns, G. M., Martinez, D. R., Kuzmin, A. I., Koch, R., Wakeem, C. K., Woo, S. L., Eisensmith, R. C., Packman, S. 1999; 46 (5): 594-602

  Abstract

  We studied 133 California phenylketonuria (PKU) patients and one obligate heterozygote to delineate the molecular basis of PKU in a population with greater ethnic diversity than in previous studies, and to determine whether a correlation exists between genotype and clinical phenotype, with the latter defined by both the diagnostic pretreatment blood phenylalanine (PHE) level and cognitive (IQ) test scores. To determine PAH genotypes, we used PCR-mediated amplification, denaturing gradient gel electrophoresis, and direct sequencing on dried whole blood samples. Where possible, mutation severity was defined according to predicted in vitro PAH enzyme activity estimated by using Cos cell expression analysis for a given mutation. We then asked whether mutation severity, as defined by such expression analysis, correlated with pretreatment PHE levels or with IQ test results. A mutation was identified in 236 (88%) of 267 mutant alleles. Seventeen new mutant alleles were found; A47E, T81P, I102T, E182G, T328D, Y343P, K371R, Y387H, A389E, E422K, IVS9nt5, IVS11nt20, delS70, del364-368/del198-220, delF299, delT323, and -1C/T. In striking contrast to a number of studies in other populations, in this study, based on predicted PAH activity, we observed no correlation between mutation severity and pretreatment PHE levels. There was also no correlation between genotype and IQ. We conclude that in samples collected from an ethnically heterogeneous population, there is no correlation of mutation severity with either pretreatment PHE levels or IQ measurement in treated patients. We caution that genetic counseling in PKU should incorporate the notion that prognosis may not be predicted with precision based on mutation analysis in a given patient.

  View details for Web of Science ID 000083247000017

  View details for PubMedID 10541324

• Apparent cyclophosphamide (cytoxan) embryopathy: A distinct phenotype? AMERICAN JOURNAL OF MEDICAL GENETICS Enns, G. M., Roeder, E., Chan, R. T., Catts, Z. A., Cox, V. A., Golabi, M. 1999; 86 (3): 237-241

  Abstract

  Cyclophosphamide (CP) is an alkylating agent widely used in treating cancer and autoimmune disease. CP is classified as a pregnancy risk factor D drug and is teratogenic in animals, but population studies have not conclusively demonstrated teratogenicity in humans. Six isolated reports of prenatally exposed infants with various congenital anomalies exist, but to date no specific phenotype has been delineated. The purpose of this report is to document a new case of in utero CP exposure with multiple congenital anomalies and to establish an apparent CP embryopathy phenotype. The mother had systemic lupus erythematosus and cyclophosphamide exposure in the first trimester. She also took nifedipine, atenolol, clonidine, prednisone, aspirin, and potassium chloride throughout pregnancy. The infant had growth retardation and multiple anomalies including microbrachycephaly, coronal craniosynostosis, hypotelorism, shallow orbits, proptosis, blepharophimosis, small, abnormal ears, unilateral preauricular pit, broad, flat nasal bridge, microstomia, high-arched palate, micrognathia, preaxial upper limb and postaxial lower limb defects consisting of hypoplastic thumbs, and bilateral absence of the 4th and 5th toes. Chromosomes were apparently normal. The reported cases of in utero exposure to cyclosposphamide shared the following manifestations with our patient: growth deficiency, developmental delay, craniosynostosis, blepharophimosis, flat nasal bridge, abnormal ears, and distal limb defects including hypoplastic thumbs and oligodactyly. We conclude that (a) cyclophosphamide is a human teratogen, (b) a distinct phenotype exists, and (c) the safety of CP in pregnancy is in serious question.

  View details for Web of Science ID 000082714300008

  View details for PubMedID 10482872

• Progressive neurological deterioration and MRI changes in cblC methylmalonic acidaemia treated with hydroxocobalamin JOURNAL OF INHERITED METABOLIC DISEASE Enns, G. M., Barkovich, A. J., Rosenblatt, D. S., Fredrick, D. R., Weisiger, K., Ohnstad, C., Packman, S. 1999; 22 (5): 599-607

  Abstract

  Cobalamin C (cblC) defects result in decreased activity of both methylmalonyl-CoA mutase and N5-methyltetrahydrofolate:homocysteine methyltransferase (methionine synthase), with subsequent methylmalonic acid-uria and homocystinuria. Patients typically show failure to thrive, developmental delay and megaloblastic anaemia. Vitamin B12 therapy has been beneficial in some cases. We report a now 4-year-old Hispanic girl with cblC disease documented by complementation analysis, with progressive neurological deterioration and worsening head MRI changes while on intramuscular hydroxocobalamin begun at age 3 weeks. Oral carnitine and folic acid were added at age 1 year. Blood levels of methylmalonic acid were reduced to treatment ranges. In the absence of acute metabolic crises, she developed microcephaly, progressive hypotonia and decreased interactiveness. Funduscopic examination was normal at age 13 months. At age 19 months, she developed nystagmus, and darkly pigmented fundi and sclerotic retinal vessels were observed on examination. Her neonatal head MRI was normal. By age 1 year, the MRI showed diffuse white-matter loss with secondary third and lateral ventricle enlargement, a thin corpus callosum, and normal basal ganglia. At age 15 months, progression of the white-matter loss, as well as hyperintense globi pallidi, were present. Interval progression of both grey- and white-matter loss was seen at age 27 months. We therefore caution that progressive neurological deterioration and head MRI abnormalities may still occur in cblC disease, despite early initiation of hydroxocobalamin therapy and improvement in toxic metabolite concentrations in physiological fluids.

  View details for Web of Science ID 000080750600004

  View details for PubMedID 10399092

• Severe congenital anomalies requiring transplantation in children with Kabuki syndrome AMERICAN JOURNAL OF MEDICAL GENETICS Ewart-Toland, A., Enns, G. M., Cox, V. A., Mohan, G. C., Rosenthal, P., Golabi, M. 1998; 80 (4): 362-367

  Abstract

  Kabuki syndrome (KS) is a rare multiple malformation disorder characterized by developmental delay, distinct facial anomalies, congenital heart defects, limb and skeletal anomalies, and short stature. Renal anomalies have been reported in a few cases of KS, but to our knowledge, hepatic anomalies have not. Here, we document two cases of KS requiring liver or kidney transplantation: one with severe hepatic and renal anomalies and one with severe renal anomalies. Both cases had the characteristic facial appearance of children with KS, postnatal growth deficiency, and developmental delay. At birth, case 1 presented with hypoglycemia, ileal perforation, right hydroureter, and hydronephrosis. The patient subsequently developed hyperbilirubinemia, hepatic abscess, and cholangitis. At age 8 months, he underwent a liver transplant. Hepatic pathology diagnosed neonatal sclerosing cholangitis. Case 2 presented with renal failure at age 6 years. Renal ultrasound study showed markedly dysplastic kidneys requiring transplantation. In addition to characteristic findings of KS, she had coronal synostosis and was shown to have immune deficiency and an autoimmune disorder manifesting as Hashimoto thyroiditis and vitiligo. We conclude: 1) severe hepatic and renal anomalies leading to organ failure can occur in KS; 2) patients with neonatal sclerosing cholangitis should be examined closely for features of KS; 3) coronal synostosis may occur in KS; and 4) immune deficiency and autoimmune disorder can be associated with KS.

  View details for Web of Science ID 000077302900011

  View details for PubMedID 9856564

• Congenital diaphragmatic defects and associated syndromes, malformations, and chromosome anomalies: A retrospective study of 60 patients and literature review AMERICAN JOURNAL OF MEDICAL GENETICS Enns, G. M., Cox, V. A., Goldstein, R. B., Gibbs, D. L., Harrison, M. R., Golabi, M. 1998; 79 (3): 215-225

  Abstract

  Congenital diaphragmatic defects (CDDs) may occur in malformation syndromes of varied causes. Syndromic cases of CDDs due to chromosomal defects, autosomal recessive, autosomal dominant, or X-linked inheritance have been described. In order to determine the frequency and nature of syndromes, malformations, and chromosome abnormalities associated with CDDs, we reviewed the records of all patients with CDDs evaluated over a 4-year period. During the 4-year interval, a total of 60 patients was evaluated. Of these, 29 had a therapeutic or spontaneous abortion, and 31 received postnatal care. On prenatal ultrasonography, 20 of 60 (33%) of patients with CDDs had additional anomalies. Additional anomalies, besides CDDs, were present in 15 of 31 (48%) of liveborn patients on newborn evaluation. In total, 16 patients with multiple anomalies were evaluated. Of these, 12 of 16 (75%) had additional abnormalities detected by prenatal ultrasonography. The 4 of 16 (25%) without additional anomalies on prenatal sonography had multiple anomalies found neonatally, lethal multiple pterygium syndrome being diagnosed in one case. Prenatal chromosome analysis was performed in 7 of 16 patients, and all had postnatal karyotypes. All initial karyotypes were normal. Tetrasomy 12p was documented on postnatal fibroblast analysis in one case who had percutaneous umbilical blood sampling (PUBS). Syndromes diagnosed postnatally in 7 of 16 patients (44%) include: Fryns syndrome (2), Simpson-Golabi-Behmel syndrome (2), tetrasomy 12p (1), Brachmann-de Lange syndrome (1), and lethal multiple pterygium syndrome (1). We were unable to make a specific diagnosis in 9 of 16 patients (56%) with multiple malformations. In patients with CDDs, a normal prenatal karyotype, especially if obtained by PUBS, and absence of other detected abnormalities by fetal ultrasonography, do not exclude the presence of other major anomalies, including chromosome abnormalities and severe multiple malformation syndromes.

  View details for Web of Science ID 000076065100013

  View details for PubMedID 9788565