Sir, Autosomal dominant optic atrophy (DOA) is a common cause of inherited visual failure affecting at least 1 in 35 000 of the general population (Yu-Wai-Man et al ., 2010 a ). Pathogenic OPA1 mutations account for about 60% of all cases, causing bilateral, symmetrical optic atrophy secondary to the highly tissue-specific loss of one cell type - the retinal ganglion cell (Lenaers et al ., 2009). Although optic nerve degeneration remains the defining feature of DOA, we recently reported in Brain that up to 20% of patients with OPA1 mutations will also develop additional neuromuscular complications including deafness, ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia (Yu-Wai-Man et al ., 2010 b ). In two earlier studies, also published in Brain (Amati-Bonneau et al ., 2008; Hudson et al ., 2008), we described for the first time the intriguing association of these syndromal DOA+ variants with multiple mitochondrial DNA deletions and cytochrome c oxidase (COX)-negative skeletal muscle fibres (Zeviani, 2008). Interestingly, these mitochondrial defects were subsequently identified in OPA1 patients with pure optic nerve involvement, but at levels four times lower compared with the DOA+ group (Yu-Wai-Man et al ., 2010 b ). The involvement of other tissue types in DOA+ could therefore be a direct consequence of the greater accumulation of these secondary mitochondrial DNA abnormalities, the latter potentiating an already compromised mitochondrial oxidative reserve due to the mutant OPA1 protein. To determine whether this was the case, we used in vivo phosphorus magnetic resonance spectroscopy (31P-MRS) to specifically measure mitochondrial oxidative function in a subgroup of OPA1 patients from our original reports, correlating our findings with the histochemical and mitochondrial DNA defects identified in skeletal muscle biopsies, and thus extending our previous observations (Yu-Wai-Man et al ., 2010 b ). For this 31P-MRS study, we selected 17 …