RESPIRATORY-CHAIN FUNCTION IN LEBERS HEREDITARY OPTIC NEUROPATHY - LACK OF CORRELATION WITH CLINICAL-DISEASE

Leber's hereditary optic neuropathy (LHON; McKusick 308900) is a maternally inherited disease, characterized by acute or subacute loss of vision caused by severe bilateral optic neuropathy, usually around the age of 20 years. Approximately 50% of males and 20% of females in maternal lineages of LHON pedigrees develop optic atrophy. Wallace et al (1988) were the first to demonstrate the role of a mitochondrial DNA (mtDNA) point mutation (G-to-A change) at nucleotide position 11778 in the ND1 gene (coding for one of the subunits of complex I of the respiratory chain). In recent years, 10 more point mutations in mtDNA have been found to be related to this disease. LHON pedigrees are often characterized by a combination of different point mutations. The variable clinical penetrance in LHON pedigrees is surprising, and it is clear that other factors contribute to the development of clinical disease. Although all mtDNA point mutations affect genes coding for subunits of the respiratory chain, respiratory chain function has been studied in only a few LHON pedigrees (Parker et al 1989; Howell et al 1991; Larsson et al 1991; Majander et al 1991). It has recently been proposed that oxidative phosphorylation (OXPHOS) capacity has to decrease below a certain level, which is caused by the nature of the point mutation or combination of mutations (mutation pattern) and environmental factors, in combination with the decline in OXPHOS capacity owing to ageing, before optic atrophy develops (Brown et al 1992). To determine whether OXPHOS activity could be directly related to the development of clinical symptoms in LHON, we studied the integrity of the respiratory chain in cultured skin fibroblasts from LHON patients and maternally related, clinically unaffected, individuals.