Mitochondrial diseases in North America: An analysis of the NAMDC Registry.,Neurology Genetics

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Mitochondrial diseases in North America: An analysis of the NAMDC Registry.
Neurology Genetics ( IF 3.0 ) Pub Date : 2020-04-01 , DOI: 10.1212/nxg.0000000000000402
Emanuele Barca ₁ , Yuelin Long ₁ , Victoria Cooley ₁ , Robert Schoenaker ₁ , Valentina Emmanuele ₁ , Salvatore DiMauro ₁ , Bruce H Cohen ₁ , Amel Karaa ₁ , Georgirene D Vladutiu ₁ , Richard Haas ₁ , Johan L K Van Hove ₁ , Fernando Scaglia ₁ , Sumit Parikh ₁ , Jirair K Bedoyan ₁ , Susanne D DeBrosse ₁ , Ralitza H Gavrilova ₁ , Russell P Saneto ₁ , Gregory M Enns ₁ , Peter W Stacpoole ₁ , Jaya Ganesh ₁ , Austin Larson ₁ , Zarazuela Zolkipli-Cunningham ₁ , Marni J Falk ₁ , Amy C Goldstein ₁ , Mark Tarnopolsky ₁ , Andrea Gropman ₁ , Kathryn Camp ₁ , Danuta Krotoski ₁ , Kristin Engelstad ₁ , Xiomara Q Rosales ₁ , Joshua Kriger ₁ , Johnston Grier ₁ , Richard Buchsbaum ₁ , John L P Thompson ₁ , Michio Hirano ₁

Affiliation

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.

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.

中文翻译：

北美的线粒体疾病：对 NAMDC 登记处的分析。

客观的

描述参加北美线粒体疾病联盟 (NAMDC) 登记的线粒体疾病 (MtDs) 参与者的临床、生化和遗传特征。

方法

这项横断面、多中心、回顾性数据库分析评估了 2011 年 9 月至 2018 年 12 月参加 NAMDC 登记的参与者的表型和分子特征。NAMDC 是一个由 17 个具有 MtD 专业知识的中心组成的网络，包括成人和儿科专家。

结果

1,553 名参与者中有 1,440 名拥有足够的临床数据进行分析。在这项研究中，我们仅纳入了具有分子遗传学诊断的参与者 (n = 666)。发病年龄从婴儿期到成年期。最常见的诊断是多系统疾病（113 名参与者），只有少数参与者被诊断出患有经典线粒体综合征。最常见的经典综合征是 Leigh 综合征（97 人）和线粒体脑肌病、乳酸性酸中毒和中风样发作（71 人）。线粒体 DNA 中的致病性变异（414 名参与者）比致病性核基因变异（252 名参与者）更常见。鉴定了 65 个核基因的致病变异，其中POLG1和PDHA1是最常受影响的。仅在单个参与者中报告了 38 个基因的致病变异。

结论

NAMDC 注册数据证实了 MtDs 参与者的临床、生化和遗传特征的高度可变性。这项研究通过提供北美 MtD 参与者的第一个全面描述，成为未来加强 MtD 研究和临床护理的重要资源。

更新日期：2020-04-01

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