The role of APOE in the phenotypic expression of Leber hereditary optic neuropathy.

Leber hereditary optic neuropathy (LHON, MIM 535000) is a mitochondrial genetic disease that causes blindness in young adults, with an estimated prevalence of 1 in 25 000 in the north east of England. It classically presents as bilateral subacute loss of central vision owing to the focal neurodegeneration of the retinal ganglion cell layer. There is marked cell body and axonal degeneration, with associated demyelination and atrophy observed from the optic nerves to the lateral geniculate bodies. 3 Over 95% of cases are principally the result of one of three “primary” mtDNA point mutations, G3460A, G11778A, and T14484C, which all involve genes encoding complex I subunits of the mitochondrial respiratory chain. However, only ∼50% of male and ∼10% of female LHON carriers will develop the optic neuropathy. This marked incomplete penetrance and gender bias clearly indicates that additional factors are required for the phenotypic expression of the pathogenic mtDNA mutations in LHON. Segregation analysis initially suggested that a nuclear encoded modifier locus on the X chromosome could account for these intriguing features. 7 However, attempts to map this X linked susceptibility locus using standard linkage analysis have so far not been successful. Furthermore, the Bu and Rotter segregation model could not be replicated in every LHON population. It is therefore likely that the phenotypic expression of the primary mtDNA LHON mutations is dependent upon the complex interaction of multiple susceptibility factors, which may include nuclear modifier genes and environmental agents. There is a strong association between APOE genotype and a number of common neurodegenerative conditions, including Alzheimer disease and dementia with Lewy bodies. The APOE e4 allele is associated with an increased lifetime risk and an earlier age of onset for these disorders, whereas the e2 allele appears to have a protective effect. The mechanisms behind these effects remain unclear, but there is emerging evidence that APOE has a wide range of important functions in the central nervous system (CNS) besides its postulated role in amyloid plaque and neurofibrillary tangle formation. It has been implicated in the modulation of neuronal response to oxidative stress and also as an important neurotrophic factor inducing recovery after acute neuronal injury. APOE is produced by Muller cells within the retina and then secreted into the vitreous humour, after which it is taken up by retinal ganglion cells and rapidly transported to the optic nerve. 16 It is therefore possible that APOE genotype could modulate the expression of the primary mtDNA LHON mutations. Here, we present the results of a family based association study that investigated whether APOE genotype influenced the risk of visual loss and/or the age of onset in LHON pedigrees from two different background populations.