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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 strokelike 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? In this issue of JAMA Neurology, Maeda et al4 studied 2 pairs of monozygotic twins with m.3243A>G who developed MELAS syndrome. Their compelling case studies suggest that genetic factors play a major role in determining the clinical phenotype. In the first twin pair, both patients developed diabetes and deafness in their 30s, experienced a sudden cardiac arrest within a year of each other, subsequently developed congestive heart failure, and died at 53 and 54 years of age.4 In the second twin pair studied, both patients presented with hearing loss and with parietotemporal stroke-like episodes within a year of each other.4 Differences were also present between the twin pairs. In the first twin pair, 1 sibling had a unilateral occipital lesion and a cerebral infarction causing sudden death, whereas his brother had bitemporal lesions, developed akinetic mutism, and died of congestive heart failure. In the second twin pair, cerebral lesions were on opposite sides of the brain, and 1 patient developed hallucinations whereas his brother did not. Nevertheless, given the shared genetic composition in both individuals, this striking similarity in phenotypic signature suggests that the disease course is in large part determined by genetic factors. This report4 is supported by a previous monozygotic twin study by Spyropoulos et al,5 who also studied identical twins with an mtDNA mutation (m.14487T>C) in the MTND6 gene. Both brothers similarly experienced tonic-clonic seizures beginning 3 years apart, at 18 years and 21 years, which caused myoclonus of the right hand, altered color vision, bilateral ptosis, and transient white-matter lesions of the brain (albeit of different regions). The clinical pictures differed in the sensory numbness of the hand, hemiparesthesia, and frequency of seizures. Thus, both studies demonstrate that identical sets of mtDNA and nuclear DNA genes can produce strikingly similar clinical phenotypes.4,5 Whether the phenotype of m.3243A>G is established prior to organ formation at the zygote stage is an interesting question raised by Maeda et al,4 with important implications regarding the modifiability of the disease process. If indeed the mitochondrial disease process is “predestined” based on mtDNA heteroplasmy and nuclear DNA of the embryo, then this would cast somewhat of a shadow on the potential of prophylactic and therapeutic interventions to have meaningful clinical effectiveness. This would also suggest that modifiers of disease risk known to influence other conditions, including behavioral, dietary, and psychosocial factors, would be irrelevant to the pathogenesis of MELAS syndrome caused by m.3243A>G. However, there is evidence against a purely genetically determined course of mitochondrial disease. Animal models of mtDNA diseases indicate that diet, exercise, and environmental factors, such as hypoxia, can alter the course of mitochondrial disease, suggesting some modifiability.6 Likewise, Leber hereditary optic neuropathy (LHON) caused by mtDNA mutations appears to be exacerbated by smoking and possibly by alcohol consumption.7 Estrogen levels may also modify its pathogenesis, although more work is needed in this area. Another intriguing issue raised in the article by Maeda et al4 relates to tissue-specific segregation of m.3243A>G. If heteroplasmy was determined solely by the initial proportion of mutant and normal mtDNA molecules in the oocyte, then all tissues would be expected to have equal heteroplasmy levels. Related article Opinion

Disentangling (Epi)Genetic and Environmental Contributions to the Mitochondrial 3243A>G Mutation Phenotype