A MITOCHONDRIAL-DNA TRNA(VAL) POINT MUTATION ASSOCIATED WITH ADULT-ONSET LEIGH-SYNDROME

Subacute necrotizing encephalomyelopathy (Leigh syndrome) is associate d with a number of mitochondrial DNA (mtDNA) abnormalities. We studied a family with maternally inherited encephalomyelopathy. Two siblings developed adult-onset Leigh syndrome. Muscle biopsy specimens showed e nhanced succinic dehydrogenase activity and cytochrome oxidase-negativ e fibers. We sequenced the ATPase-and transfer RNA (tRNA)-encoding gen es of mtDNA and identified a novel mtDNA valine tRNA mutation at base pair 1644. This transversion was heteroplasmic in blood and muscle in all individuals studied, and the proportion of mutant mtDNA correlated with disease severity. This is the first heteroplasmic transversion w ithin a mtDNA tRNA gene and the second pathogenic mtDNA tRNA(Val) muta tion to be associated with human disease.