Mitochondrial diseases in North America: An analysis of the NAMDC Registry

Emanuele Barca; Yuelin Long; Victoria Cooley; Robert Schoenaker; Valentina Emmanuele; Salvatore DiMauro; Bruce H Cohen; Amel Karaa; Georgirene D Vladutiu; Richard Haas; Johan L K Van Hove; Fernando Scaglia; Sumit Parikh; Jirair K Bedoyan; Susanne D DeBrosse; Ralitza H Gavrilova; Russell P Saneto; Gregory M Enns; Peter W Stacpoole; Jaya Ganesh; Austin Larson; Zarazuela Zolkipli-Cunningham; Marni J Falk; Amy C Goldstein; Mark Tarnopolsky; Andrea Gropman; Kathryn Camp; Danuta Krotoski; Kristin Engelstad; Xiomara Q Rosales; Joshua Kriger; Johnston Grier; Richard Buchsbaum; John L P Thompson; Michio Hirano

doi:10.1212/NXG.0000000000000402

Mitochondrial diseases in North America: An analysis of the NAMDC Registry

Neurol Genet. 2020 Mar 2;6(2):e402. doi: 10.1212/NXG.0000000000000402. eCollection 2020 Apr.

Authors

Emanuele Barca¹, Yuelin Long¹, Victoria Cooley¹, Robert Schoenaker¹, Valentina Emmanuele¹, Salvatore DiMauro¹, Bruce H Cohen¹, Amel Karaa¹, Georgirene D Vladutiu¹, Richard Haas¹, Johan L K Van Hove¹, Fernando Scaglia¹, Sumit Parikh¹, Jirair K Bedoyan¹, Susanne D DeBrosse¹, Ralitza H Gavrilova¹, Russell P Saneto¹, Gregory M Enns¹, Peter W Stacpoole¹, Jaya Ganesh¹, Austin Larson¹, Zarazuela Zolkipli-Cunningham¹, Marni J Falk¹, Amy C Goldstein¹, Mark Tarnopolsky¹, Andrea Gropman¹, Kathryn Camp¹, Danuta Krotoski¹, Kristin Engelstad¹, Xiomara Q Rosales¹, Joshua Kriger¹, Johnston Grier¹, Richard Buchsbaum¹, John L P Thompson¹, Michio Hirano¹

Affiliation

¹ Department of Neurology (E.B., V.E., S.D., K.E., X.Q.R., M.H.), Columbia University Medical Center, New York; Department of Biostatistics (Y.L., V.C., J.K., J. Grier, R.B., J.L.P.T.), Mailman School of Public Health, Columbia University, New York; Radboudumc (R.S.), Nijmegen, The Netherlands; Department of Pediatrics (B.H.C.), Northeast Ohio Medical University and Akron Children's Hospital; Genetics Unit (A.K.), Massachusetts General Hospital, Boston; Department of Pediatrics (G.D.V.), State University of New York at Buffalo; Departments of Neurosciences and Pediatrics (R.H.), University of California at San Diego; Department of Pediatrics (J.L.K.V.H., A.L.), University of Colorado School of Medicine, Aurora; Department of Molecular and Human Genetics (F.S.), Baylor College of Medicine, Houston, TX; Texas Children's Hospital (F.S.), Houston; Joint BCM-CUHK Center of Medical Genetics (F.S.), Prince of Wales Hospital, ShaTin, New Territories, Hong Kong; Department of Neurology (S.P.), Cleveland Clinic, OH; Departments of Genetics and Genome Sciences and Pediatrics (J.K.B., S.D.D.), and Center for Human Genetics, University Hospitals Cleveland Medical Center, Case Western Reserve University, OH; Departments of Neurology and Clinical Genomics (R.H.G.), Mayo Clinic, Rochester, MN; Department of Neurology (R.P.S.), University of Washington, Seattle Children's Hospital; Department of Pediatrics (G.M.E.), Stanford University, Palo Alto, CA; Department of Medicine (P.W.S.), University of Florida at Gainesville; Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai (J. Ganesh), New York; Mitochondrial Medicine Frontier Program (Z.Z.-C., M.J.F., A.C.G.), Division of Human Genetics, The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine; University of Pennsylvania Perelman School of Medicine (Z.Z.-C.), Philadelphia; Department of Neurology (M.T.), McMasters University, Toronto, Ontario, Canada; Department of Neurology (A.G.), Children's National Health Network, Washington, DC; Office of Dietary Supplements (K.C.), National Institutes of Health, Bethesda, MD; and Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.K.), National Institutes of Health, Bethesda, MD.

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.

Abstract

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