The mitochondrial
tRNALeu(UUR) A-->G(3243) mutation was identified in 22 unrelated patients. The probands and their relatives were assessed clinically and by quantitative
mitochondrial DNA (
mtDNA) analysis. While 10 probands had clinical features consistent with the syndrome of
mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (
MELAS), usually associated with this mutation, 12 probands had other phenotypes including other
encephalopathies,
chronic progressive external ophthalmoplegia (
CPEO),
myoclonic epilepsy and ragged red fibres (
MERRF),
myopathy alone and diabetes and
deafness. Histochemical analyses of muscle biopsies showed a higher proportion of
cytochrome oxidase (COX) negative fibres, but fewer strongly COX reactive fibres, in patients with
CPEO compared with those with
MELAS. The proportion of mutant
mtDNA present in blood was significantly greater in symptomatic than asymptomatic subjects, and was correlated with age in both. This correlation was not observed in patients with the
tRNALys A-->G(8344) mutation. The proportion of mutant
mtDNA A-->G(3243) in muscle was always greater than that in blood. Significant correlations between proportion of mutant
mtDNA in blood and both age of onset of disease and a clinical severity score were observed. However, the proportion of mutant
mtDNA in blood in affected and unaffected cases overlapped, preventing use of the genetic-clinical correlation for prognostic or predictive purposes. The presence of intrafamilial clustering of phenotypes and the imperfect relationship between proportion of mutant
mtDNA and the presence or absence of disease suggests that other factors may determine the phenotype. To investigate this possibility further, the
tRNALeu(UUR) gene was sequenced in 23 probands and six relatives. In 28 patients the sequence was normal apart from the 3243 mutation, but in members of one family there was a homoplasmic T-->C transition at position 3290 which was not found in 140 controls or 50 other patients with
mitochondrial myopathy. The family with this transition had high levels of mutant
mtDNA A-->G(3243), with a unique phenotype of predominant skeletal
myopathy, suggesting that this second base change in
tRNALeu(UUR) may influence the clinical phenotype.