Mitochondrial diseases are a group of heterogeneous disorders caused by inherited mutations in the mitochondrial genome (mtDNA) and nuclear genome. Typically, mutations in the mtDNA are maternally inherited and cause respiratory chain defects and account for a substantial fraction of childhood and adult neurometabolic disease, with an estimated prevalence of 1:5000 (0.02%).1 The most common mtDNA mutation is the mitochondrial 3243A>G mutation (m.3243A>G) in the MTTL1 gene (OMIM 590050), which encodes the transfer RNA tRNALeu(UUR).1 This mutation is associated with multiple clinical and psychiatric manifestations, including diabetes, deafness, exercise intolerance, myopathy, cardiomyopathy, lactic acidosis, ophthalmoplegia, and neurological symptoms such as seizures, dementia, and myoclonus.2,3 In the most severe cases, m.3243A>G causes mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, which is associated with disability and early death.2,3 Within families, affected individuals vary widely in terms of age at onset—ranging from less than 1 year to more than 50 years of age—spectrum of clinical manifestations, and disease progression. In fact, some individuals are asymptomatic despite carrying equivalent mtDNA mutation levels in blood and/or urine.2,3 The origin of such broad phenotypic variability has been a 2-decade conundrum in mitochondrial medicine. How can patients carrying an identical mtDNA mutation exhibit such broad differences in symptoms, age at onset, and disease course? And to what extent is the disease phenotype genetically determined and environmentally modulated?
Picard M, Hirano M. Disentangling (Epi)Genetic and Environmental Contributions to the Mitochondrial 3243A>G Mutation PhenotypePhenotypic Destiny in Mitochondrial Disease?. JAMA Neurol. 2016;73(8):923-925. doi:10.1001/jamaneurol.2016.1676