Gene–environment interactions in Leber hereditary optic neuropathy

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

¹Mitochondrial Research Group, Institute for Ageing and Health, The Medical School, Newcastle University, UK
²Department of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
³Department of Child Neurology, Erasmus Medical Center, University Medical Center Rotterdam, The Netherlands
⁴Department 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: [email protected]

Received February 15, 2009. Revised May 10, 2009. Accepted May 11, 2009. Advance Access publication June 12, 2009

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Brain 132(9):p 2317-2326, September 2009.

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.