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The cellular mechanisms of Leber's hereditary optic neuropathy (LHON) are poorly understood and there is little information on the onset of blindness and neurological degeneration. Here we define the relationship between oxidative stress and LHON pathogenicity at the cellular level. Venous blood was obtained from 14 patients with LHON, 21 asymptomatic maternal relatives and 30 normal individuals (controls). The level of free radicals in blood was assessed as luminol luminescence immediately and at 10 min after addition of phytohaemagglutinin. In LHON patients and their asymptomatic relatives, free radicals increased significantly immediately after adding phytohaemagglutinin compared with baseline and normal controls. After 10 min, however, there were no significant differences between and within the groups. These results suggest that the antioxidant capacity is reduced in the blood of patients with LHON and in asymptomatic relatives, and that oxidative stress plays a significant role in the pathogenesis of LHON.

We report here the clinical, genetic, and molecular characterization of five Chinese families with Leber's hereditary optic neuropathy (LHON). Clinical and genetic evaluations revealed the variable severity and age-of-onset in visual impairment in these families. Strikingly, there were extremely low penetrances of visual impairment in these Chinese families. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the distinct sets of mtDNA polymorphism, in addition to the identical ND4 G11696A mutation associated with LHON. Indeed, this mutation is present in homoplasmy only in the maternal lineage of those pedigrees but not other members of these families. In fact, the occurrence of the G11696A mutation in these several genetically unrelated subjects affected by visual impairment strongly indicates that this mutation is involved in the pathogenesis of visual impairment. Furthermore, the N405D in the ND5 and G5820A in the tRNA(Cys), showing high evolutional conservation, may contribute to the phenotypic expression of G11696A mutation in the WZ10 pedigree. However, there was the absence of functionally significant mtDNA mutations in other four Chinese pedigrees carrying the G11696A mutation. Therefore, nuclear modifier gene(s) or environmental factor(s) may play a role in the phenotypic expression of the LHON-associated G11696A mutation in these Chinese pedigrees.