Background: Myoclonic epilepsy with ragged-red fibres (MERRF) and mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) are established phenotypes of mitochondrial encephalomyopathy. The m.8356T>C transition in the mitochondrial tRNA(Lys) gene is a pathogenic mutations of MERRF. The m.3243A>G transition in the mitochondrial tRNA(Leu) gene is detected in most MELAS patients. Although previous analyses of double mutations in mitochondrial DNA (mtDNA) were useful for discussing their nature, many unsolved questions remain.
Objective: To describe the clinical and genetic features of a family with the above mtDNA double-point mutations and discuss the role of double mtDNA mutations in diverse clinical features in the family.
Patients and methods: The proband was a 23-year-old woman with MERRF harbouring m.8356T>C and m.3243A>G transitions in mitochondrial tRNA genes. We assessed clinical aspects of her and those of her three relatives and performed mutation analyses on their mtDNA.
Results: Phenotypes of the four patients were MERRF, MERRF/MELAS overlap syndrome and asymptomatic carrier. We hypothesise that the course of the phenotype of this family begins with MERRF and is followed by MELAS. This double mutation was heteroplasmic in blood of all four patients but with different rates in each patient, while m.8356T>C appeared homoplasmic and m.3243A>G was heteroplasmic in muscle of the two examined cases. No other mutations were detected in the total mtDNA sequence in this family.
Conclusions: This is the first reported case of a double-point mutation in mtDNA, both of which were heteroplasmic and pathogenic for the established phenotypes.