Reply: Parsing the differences in affected with LHON: genetic versus environmental triggers of disease conversion.

Abstract

Sir, Carelli and colleagues (2016) draw attention to an interesting feature of a figure that we published in a Brain article on the role of environmental factors in precipitating visual loss in Leber's hereditary optic neuropathy (LHON), which is an important cause of inherited mitochondrial blindness (Kirkman et al. , 2009 a ). Our original study involved 125 LHON families. One hundred and ninety-six affected and 206 unaffected LHON carriers harbouring one of three common mitochondrial DNA (mtDNA) mutations (m.11778A>G, m.3460A>G, and m.14484T>C) were recruited. All the participants took part in a standardized phone-based interview to collect information on lifestyle habits, in particular smoking and alcohol consumption. Overall, our study showed a strong consistent relationship between smoking and the risk of visual failure in LHON that was independent of gender and alcohol intake. Rather strikingly, the clinical penetrance of the LHON mtDNA mutations was 93% in the males who smoked compared within the 50% overall lifetime risk generally quoted in the literature (Newman et al. , 1991). Figure 3 in our original study (Kirkman et al. , 2009 b ) showed the proportion of LHON mutation carriers that remained symptom-free as a function of age, stratified by their tobacco consumption, both cumulative (Fig. 3A) and the maximum intensity (Fig. 3B). Figure 3A showed an unexpected and unexplained feature that was noticed by reviewers of the manuscript, and subsequently highlighted in the accompanying Scientific Commentary (Newman, 2009). Curiously, for individuals under 50 years of age, the clinical penetrance of the pathogenic LHON mtDNA mutations appeared to be lower in those individuals who have had the highest cumulative smoking exposure up to that age. However, all other statistical analyses gave a consistent message that smoking was a major risk factor for precipitating visual failure in LHON. Of note, when considering maximum intensity of …