Walsh & Hoyt: Autosomal-Dominant Optic Atrophy, Deafness and Ophthalmoplegia

Treft et al. described a syndrome affecting 23 members of five generations of a Utahfamily characterized by optic atrophy, deafness, ptosis, ophthalmoplegia, dystaxia, and myopathy. The visual loss was first noted between the ages of 6 and 19 years, with an average age of onset of 11 years. Visual loss was occasionally sudden in onset but always progressive to the 20/30 to 20/400 range. Electroretinograms were abnormal, although retinal pigmentary changes were absent, suggesting the combination of a primary retinal degeneration and a primary optic neuropathy. Hearing loss was sensorineural and progressive, with onset in the first or second decades. Ophthalmoplegia, dystaxia, and myopathy occurred in midlife. One muscle biopsy showed ragged red fibers. Male-to-male transmission confirmed autosomal-dominant inheritance. An unrelated family from Belgium was reported witha similar phenotype. Both these families have recently been genetically confirmed to carry the R445H mutation in the OPA1 gene, previously reported in a single Japanese patient with optic atrophy and a single French woman with optic atrophy and deafness. Other OPA1 mutations in this region (the GTPase domain) have been associated with monosymptomatic autosomal-dominant optic atrophy (Kjers disease). These findings underscore the importance of mitochondrial dysfunction, whether the result of nuclear or mitochondrial DNA defects, as a final common pathway for many forms of syndromic and nonsyndromic optic atrophy.