Revelation of a new mitochondrial DNA mutation (G12147A) in a MELAS/MERFF phenotype

Background: A 26-year-old man presented at onset with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) and later with a phenotype for MELAS and myoclonic epilepsy and ragged red fiber disease (MELAS/MERRF). Objective: To identify the possible defects in the mitochondrial genome in blood and muscle samples of the patient. Design: Case study of a patient clinically exhibiting strokelike episodes and then epilepsy with myoclonic features, ataxia, and dementia. Setting: Research unit of a university hospital. Main Outcome Measures: Electromyographic, morphologic, and biochemical studies of muscle and molecular analysis of blood and muscle to investigate mitochondrial DNA (mtDNA) size and quantity. Results: Morphologically, we found abnormal mitochondrial proliferation with several cytochrome-c oxidase (COX)-negative fibers in muscle biopsy specimens; the analysis of serial sections showed a decreased immunoreactivity for the mtDNA-encoded subunits COXII and, partially, COX1. Biochemically, we found a partial and isolated COX deficiency. The complete mtDNA sequence analysis identified 3 sequence changes, 2 of which were reported polymorphisms. The remaining change, a G12147A transition in the transfer RNA(His) gene, appeared to be the likely pathogenic mutation. Conclusions: Our data propose that the G12147A change, the first mutation in the transfer RNA(His) gene associated with an overlapped MELAS/MERFF phenotype, is the cause of the encephalomyopathy in this patient interfering with the overall mitochondrial protein synthesis.