The mitochondrial DNA transfer RNA(Lys)A-->G(8344) mutation and the syndrome of myoclonic epilepsy with ragged red fibres (MERRF). Relationship of clinical phenotype to proportion of mutant mitochondrial DNA.

The mitochondrial DNA (mtDNA) transfer RNA (tRNA)Lys A-->G(8344) mutation was identified in seven patients. These patients and their relatives were assessed clinically; in one family the mutation was deduced to be present in four generations. The phenotype in index cases was consistent with the syndrome of myoclonic epilepsy with ragged red fibres, with the core clinical features of myoclonus, ataxia and seizures. Amongst other features, progressive external ophthalmoplegia, Leigh's syndrome and stroke-like episodes were observed, well recognized in mitochondrial myopathies but novel manifestations of this genotype. Samples of blood and muscle were analysed for the proportion of mutant mtDNA using an oligonucleotide hybridization technique. The proportion of mutant mtDNA in blood was significantly greater in symptomatic than asymptomatic cases. Furthermore, the proportion of mutant mtDNA in blood correlated with age of onset of disease and clinical severity assessed by a simple scale. Study of disease associated with the tRNA(Lys) A-->G(8344) mutation provides further insight into the pathogenesis and transmission of mitochondrial diseases. Quantification of the proportion of mtDNA in tissues demonstrates that this is a major factor determining the course of disease, but other, as yet unidentified factors are also likely to play a role.