Clinical and biochemical heterogeneity associated with an A to G mitochondrial DNA mutation at position 3251 in tRNALeu.

The index case is a 16 year-old-boy of normal intelligence who developed a progressive proximal myopathy with severe muscle pain four years ago. A muscle biopsy RRF and decreased complex I activity. Lactate levels in blood and in CSF and MR images of the brain were normal. A hetero-plasmic A to G transition at nucleotide 3251 in the tRNA leucine gene was present in almost 95% of the muscle mtDNA molecules of our patient. His 19-year-old-sister, who has been suffering from myoclonic epilepsy, intermittent vomiting and headaches, as well as his mother who complains of moderate proximal weakness, fatigability and headaches were also found to be heteroplasmic in leukocyte mtDNA for this tRNALeu mutation. A mutation load of 90% was seen in the muscle tissue of the mother, but complex I activity was normal. This mutation was previously reported in two unrelated families with a predominant clinical presentation of proximal myopathy, but some members of our family have more signs of a MELAS presentation. The A3251G mutation is clearly associated with phenotypic variability. Also, it has to be stressed that mitochondrial encephalomyopathies with high levels of pathogenic mutant mtDNA are not always associated with impaired oxidation phosphorylation levels. Furthermore, lactic acidosis is not an associated sign in this severe for of mitochondrial encephalomyopathy.