Mitochondrial diseases in North America

Abstract

ObjectiveTo describe clinical, biochemical, and genetic features of participants with mitochondrial diseases (MtDs) enrolled in the North American Mitochondrial Disease Consortium (NAMDC) Registry. MethodsThis 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. ResultsOne 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. ConclusionsThe 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. Cohort studies following collection(s): This article, along with others on similar topics, appears in the Permissions & Licensing http://ng.neurology.org/misc/about.xhtml#permissions its entirety can be found online at: Information about reproducing this article in parts (figures,tables) or in Reprints http://ng.neurology.org/misc/addir.xhtml#reprintsusInformation about ordering reprints can be found online:reserved. Online

Specifications of the ACMG/AMP standards and guidelines for mitochondrial DNA variant interpretation

“…| 2049 clinical syndromes (MELAS, MERRF, MIDD, NARP, Pearson, KSS, CPEO, CPEO plus, Leigh syndrome spectrum, LHON, and primary lactic acidosis). However, given the strict clinical criteria of several of these syndromes that many individuals with pathogenic mtDNA variants do not meet (Barca et al, 2020), an individual can also be defined as affected if one "red flag" feature is present along with two or more nonspecific features (Haas et al, 2007), or they have three or more nonspecific features with suggestive lab abnormalities (Haas et al, 2008).…”

Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity

“…One of the most frequent causes of inherited mitochondrial disease is the heteroplasmic m.3243A>G mutation in the MT-TL1 gene encoding the mitochondrial leucyl-tRNA 1 gene (10)(11)(12). This variant is responsible for nearly 80% of cases of mitochondrial encephalomyopathy lactic acidosis and strokelike episodes (MELAS), one of the most common mtDNA disorders, which typically presents before age 40 years with myopathy, headaches, vomiting, hearing loss, seizures, lactic acidosis, and stroke-like episodes (10,13).…”

Effect of rapamycin on mitochondria and lysosomes in fibroblasts from patients with mtDNA mutations

“…MELAS is one of the most common maternallyinherited mitochondrial disorder, with accumulations of point mutations in the mtDNA (8,9) and a prevalence rate estimated to be 6 per 10,000 people (10). As mitochondria are essential to nearly every cell in the body, the disease affects the brain, heart, muscles, gastrointestinal tract, endocrine function, pulmonary and renal systems (11,12). Due to such a wide range of symptoms and genetic features, conducting controlled clinical trials with therapeutic agents is challenging (12)(13)(14)(15)(16).…”