LHON, mtDNA mutations

Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disease and the first linked to maternal inheritance through a mutation in the mtDNA. LHON is characterized by bilateral subacute loss of central vision caused by focal degeneration of the retinal ganglion cell layer and of the optic nerve. After initial symptoms, both eyes are usually affected within 6 months. Approximately 50% to 60% of males and only 8% to 32% of females who possess the mtDNA mutation will actually develop this optic neuropathy. Nuclear-encoded factors that affect mtDNA expression, mtDNA products, or mitochondrial metabolism may modify the phenotypic expression of LHON. Genetic coimseling in LHON is complicated in that the amount of mutant mtDNA transmitted by heteroplasmic females cannot be predicted, and testing cannot predict which individuals will develop visual symptoms. ... 

LHON is a disorder caused by OXPHOS deficiency. Although more than 27 mutations have been associated with this disease, mtDNA mutations G3460A, G11778A, and... 

T14484C represent 95% of those identified. Mutation G11778A was the first described, is the most common, and accounts for at least 50% of cases. In most affected individuals, LHON mutations appear to be homoplasmic, with only mutant mtDNA detected, but in 15% of cases, the mutations are heteroplasmic, with a mixture of both normal and mutant mtDNA detected. Each of the common mutations affects a subrmit of the nicotinamide adenine dinucleotide ubiquinone oxidoreductase in complex I of the OXPHOS pathway. The mechanism by which these mutations cause the LHON phenotype is not well understood. ... 

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