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Editorial |

Disentangling (Epi)Genetic and Environmental Contributions to the Mitochondrial 3243A>G Mutation Phenotype Phenotypic Destiny in Mitochondrial Disease?

Martin Picard, PhD1,2; Michio Hirano, MD1
[+] Author Affiliations
1H. Houston Merritt Center, Columbia Translational Neuroscience Initiative, Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York
2Division of Behavioral Medicine, Department of Psychiatry, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York
JAMA Neurol. 2016;73(8):923-925. doi:10.1001/jamaneurol.2016.1676.
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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 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?

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Life Span Perspective and Variable Mitochondrial DNA Heteroplasmy Across Tissues

A, The single-cell zygote contains a certain percentage of mutant and normal mitochondrial DNA (mtDNA) molecules, termed mtDNA heteroplasmy. In monozygotic twins, this mutation load is distributed equally into the blastocysts, leading to early embryos of equal heteroplasmy levels prior to organ formation. The article by Maeda et al4 shows near equal mtDNA mitochondrial 3243A>G mutation (m.3243A>G) heteroplasmy between most tissues of a pair of adult twins, suggesting that genetics and initial heteroplasmy levels play a determinant role in dictating later-life heteroplasmy and clinical phenotype. The report4 also documents substantial heteroplasmy differences across tissues, indicating that tissue-specific factors affect m.3243A>G expansion across the life span. B, Association between the average mtDNA m.3243A>G heteroplasmy levels in the 3 autopsied patients studied in Maeda et al4 and mitochondrial content across mouse tissues, representing energy demand.8 This association suggests that nongenetic factors are involved in the segregation of mutant and normal mtDNA molecules during development. Central nervous system tissues are indicated by the light red circle.

aTissues differing by greater than 10% in heteroplasmy levels between monozygotic twins.

bCorrelation coefficient excluding central nervous system tissues: r2 = 0.91; P < .05.

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