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Gene-environment interactions in Leber hereditary optic neuropathy

Lookup NU author(s): Matthew Kirkman, Dr Patrick Yu Wai Man, Professor Patrick Chinnery

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Abstract

Leber hereditary optic neuropathy (LHON) is a genetic disorder primarily due to mutations of mitochondrial DNA (mtDNA). Environmental factors are thought to precipitate the visual failure and explain the marked incomplete penetrance of LHON, but previous small studies have failed to confirm this to be the case. LHON has no treatment, so identifying environmental triggers is the key to disease prevention, whilst potentially revealing new mechanisms amenable to therapeutic manipulation. To address this issue, we conducted a large, multicentre epidemiological study of 196 affected and 206 unaffected carriers from 125 LHON pedigrees known to harbour one of the three primary pathogenic mtDNA mutations: m.3460GA, m.11778GA and m.14484TC. A comprehensive history of exposure to smoking, alcohol and other putative environmental insults was collected using a structured questionnaire. We identified a strong and consistent association between visual loss and smoking, independent of gender and alcohol intake, leading to a clinical penetrance of 93 in men who smoked. There was a trend towards increased visual failure with alcohol, but only with a heavy intake. Based on these findings, asymptomatic carriers of a LHON mtDNA mutation should be strongly advised not to smoke and to moderate their alcohol intake.

Publication metadata

Author(s): Kirkman MA, Yu Wai Man P, Korsten A, Leonhardt M, Dimitriadis K, De Coo IF, Klopstock T, Chinnery PF

Publication type: Article

Publication status: Published

Journal: Brain

Year: 2009

Volume: 132

Issue: 9

Pages: 2317-2326

Date deposited: 19/03/2010

ISSN (print): 0006-8950

ISSN (electronic): 1460-2156

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/brain/awp158

DOI: 10.1093/brain/awp158

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