Leigh syndrome caused by a novel m.4296G>A mutation in mitochondrial tRNA isoleucine

Leigh syndrome is a severe neurodegenerative disease with heterogeneous genetic etiology. We report a novel m.4296GA variant in the mitochondrial tRNA isoleucine gene in a child with Leigh syndrome, mitochondrial proliferation, lactic acidosis, and abnormal respiratory chain enzymology. The variant is present at75% heteroplasmy in blood and cultured fibroblasts from the proband,5% in asymptomatic maternal relatives, and is absent in 3000 controls. It is located in the highly conserved anticodon region of tRNA(Ile) where three other pathogenic changes have been described. We conclude that there is strong evidence to classify m.4296GA as a pathogenic mutation causing Leigh syndrome.