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

Leber's hereditary optic neuropathy (LHON; McKusick 308900) is a mater nally inherited disease, characterized by acute or subacute loss of vi sion caused by severe bilateral optic neuropathy, usually around the a ge of 20 years. Approximately 50% of males and 20% of females in mater nal lineages of LHON pedigrees develop optic atrophy. Wallace et al (1 988) were the first to demonstrate the role of a mitochondrial DNA (mt DNA) point mutation (G-to-A change) at nucleotide position 11778 in th e ND1 gene (coding for one of the subunits of complex I of the respira tory chain). In recent years, 10 more point mutations in mtDNA have be en found to be related to this disease. LHON pedigrees are often chara cterized by a combination of different point mutations. The variable c linical penetrance in LHON pedigrees is surprising, and it is clear th at other factors contribute to the development of clinical disease. Al though all mtDNA point mutations affect genes coding for subunits of t he respiratory chain, respiratory chain function has been studied in o nly a few LHON pedigrees (Parker et al 1989; Howell et al 1991; Larsso n et al 1991; Majander et al 1991). It has recently been proposed that oxidative phosphorylation (OXPHOS) capacity has to decrease below a c ertain level, which is caused by the nature of the point mutation or c ombination of mutations (mutation pattern) and environmental factors, in combination with the decline in OXPHOS capacity owing to ageing, be fore optic atrophy develops (Brown et al 1992). To determine whether O XPHOS activity could be directly related to the development of clinica l symptoms in LHON, we studied the integrity of the respiratory chain in cultured skin fibroblasts from LHON patients and maternally related , clinically unaffected, individuals.