The expanding clinical spectrum of dominant optic atrophy

Autosomal dominant optic atrophy (DOA) is the most common inherited optic nerve disorder in the population and OPA1 is the major causative gene, accounting for about 60% of families. Visual loss starts in early childhood secondary to the highly tissue‐specific loss of one cell type – the retinal ganglion cell. Although progressive visual failure remains the defining feature of DOA, we recently described the expanding phenotypic spectrum associated with OPA1 disease. Up to 20% of mutational carriers developed a more severe “DOA+” phenotype characterised by prominent neuromuscular features such as deafness, myopathy, peripheral neuropathy, ataxia, and chronic progressive external ophthalmoplegia. Interestingly, we found a three‐fold increased risk of developing the more severe DOA+ phenotype with missense OPA1 mutations involving the GTPase domain compared with other mutational subgroups. Histochemical and molecular characterisation of skeletal muscle biopsies revealed the presence of cytochrome c oxidase deficient fibres and clear evidence of mitochondrial DNA instability. Dissecting the disease mechanisms leading to optic atrophy and multisystem tissue involvement in DOA will have important therapeutic implications.