Leber hereditary optic neuropathy: Does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation?

Leber hereditary optic neuropathy (LHON) is a major cause of inherited blindness in young males. Approximately 1 in 7 individuals with LHON harbor a mixture of mutated and wild-type (normal) mtDNA (heteroplasmy), and the risks of developing blindness in heteroplasmic LHON individuals are not well characterized. MtDNA is inherited exclusively down the maternal line, and although the risks of a relative within a homoplasmic LHON pedigree are relatively well established, the risks of transmission in heteroplasmic LHON pedigrees have not been studied in detail. We analyzed 17 independent pedigrees that harbor the most prevalent LHON mutation: G11778A. The pedigrees were influenced by incomplete ascertainment bias, which was reduced by omitting the affected probands from the analysis. We made the following observations: (1) The frequency of blindness in males was related to the mutation load in that individual's blood. (2) Mothers with < or = 80% mutant mtDNA in blood were less likely to have clinically affected sons than mothers with 100% mutant mtDNA in their blood. (3) Within individual lineages, changes in mutation load from one generation to the next were largely determined by random genetic drift in these pedigrees. This study provides insights into the mutation load, or threshold, necessary for expression of the optic neuropathy, the relationship between mutation load in the mother and the risk of blindness in her children, and the complex inheritance of heteroplasmic mtDNA defects.