Dominant Optic Atrophy: Novel OPA1 Mutations and Revised Prevalence Estimates

Autosomal-dominant optic atrophy (DOA) is the most common inherited optic nerve disorder seen in clinical practice. So far, 2 causative genes have been identified in patients with DOA; OPA1, which accounts for 50%–60% of cases, and OPA3, which is relatively rare having been identified in only isolated families in association with premature cataracts. OPA1 mutations have a high penetrance rate, but the disease phenotype is characterized by marked intra- and interfamilial variability. Patients classically present with increasing visual difficulties in early childhood and there is a high rate of progression to blind registration. As a result of the selective involvement of the retinal ganglion cells within the papillomacular bundle, the optic disc often has a characteristic temporal wedge of pallor. Although optic nerve involvement is a cardinal feature of OPA1 disease, extraocular manifestations are being increasingly recognized and the term DOA plus (DOA+) has been coined to describe these more severe syndromal variants. In a major collaborative survey involving diagnostic and research centers in northern Europe, about 20% of OPA1 carriers had developed neurologic deficits, ranging from early-onset sensorineural deafness to peripheral neuropathy, ataxia, myopathy, and late-onset chronic progressive external ophthalmoplegia. These findings have obvious practical implications for the multidisciplinary care of affected patients and the wider aspects of genetic counseling for familial carriers.