Brain Advance Access published online on June 12, 2009
Brain, doi:10.1093/brain/awp158
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Gene–environment interactions in Leber hereditary optic neuropathy
1 Mitochondrial Research Group, Institute for Ageing and Health, The Medical School, Newcastle University, UK 2 Department of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne, UK 3 Department of Child Neurology, Erasmus Medical Center, University Medical Center Rotterdam, The Netherlands 4 Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany
Correspondence to:
Prof. Patrick Francis Chinnery, Mitochondrial Research Group, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK E-mail: P.F.Chinnery{at}ncl.ac.uk
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.
Key Words: Leber hereditary optic neuropathy; mitochondrial DNA; alcohol; tobacco; epigenetics
Received February 15, 2009. Revised May 10, 2009. Accepted May 11, 2009.