Journal Article

Gene–environment interactions in Leber hereditary optic neuropathy

Matthew Anthony Kirkman, Patrick Yu-Wai-Man, Alex Korsten, Miriam Leonhardt, Konstantin Dimitriadis, Ireneaus F. De Coo, Thomas Klopstock and Patrick Francis Chinnery

in Brain

Published on behalf of The Guarantors of Brain

Volume 132, issue 9, pages 2317-2326
Published in print September 2009 | ISSN: 0006-8950
Published online June 2009 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awp158

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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.3460G>A, m.11778G>A and m.14484T>C. 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.

Keywords: Leber hereditary optic neuropathy; mitochondrial DNA; alcohol; tobacco; epigenetics

Journal Article.  4886 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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