Clinical, biochemical and molecular genetic features of Leber's hereditaryoptic neuropathy

Leber's hereditary optic neuropathy (LHON) has traditionally been considere d a disease causing severe and permanent visual loss in young adult males. In nearly all families with LHON it is associated with one of three pathoge nic mitochondrial DNA (mtDNA) mutations, at bp 11778, 3460 or 14484. The av ailability of mtDNA confirmation of a diagnosis of LHON has demonstrated th at LHON occurs with a wider range of age at onset and more commonly in fema les than previously recognised. In addition, analysis of patients grouped a ccording to mtDNA mutation has demonstrated differences both in the clinica l features of visual failure and in recurrence risks to relatives associate d with each of the pathogenic mtDNA mutations. Whilst pathogenic mtDNA muta tions are required for the development of LHON, other factors must be repon sible for the variable penetrance and male predominance of this condition. Available data on a number of hypotheses including the role of an additiona l X-linked visual loss susceptibility locus, impaired mitochondrial respira tory chain activity, mtDNA heteroplasmy, environmental factors and autoimmu nity are discussed. Subacute visual failure is seen in association with all three pathogenic LHON mutations. However, the clinical and experimental da ta reviewed suggest differences in the phenotype associated with each of th e three mutations which may reflect variation in the disease mechanisms res ulting in this common end-point. (C) 1999 Elsevier Science B.V. All rights reserved.