To describe the clinical features of and identify the disease-causing mutation in a large Utah family segregating a dominantly inherited syndrome of optic atrophy, sensorineural hearing loss, ptosis, and ophthalmoplegia.

Observational case series.

Thirty individuals at risk for a syndrome of optic atrophy, sensorineural hearing loss, ptosis, and ophthalmoplegia in a single family underwent clinical examinations and venipuncture. Linkage analysis and mutation screening of the optic atrophy 1 gene (OPA1) were performed.

Eighteen individuals demonstrated characteristics of the syndrome. Genetic analysis identified a G→A substitution at nucleotide position 1334 in exon 14 of OPA1 causing an arginine-to-histidine change (R445H) in all affected members of the family. This change segregated with the disease phenotype in the study family with a LOD score of 7.02 at θ = 0 and was not found in 200 normal control subjects. Analysis of an unrelated Belgian family with a similar phenotype revealed the same R445H mutation segregating with the disease phenotype.

This study describes a mutation in OPA1 causing a unique syndrome of optic atrophy, sensorineural hearing loss, ptosis, and ophthalmoplegia. These results expand the spectrum of human disease associated with mutations of OPA1 and indicate that ophthalmologists caring for patients with optic atrophy should inquire about possible associated hearing loss. Although OPA1 is a nuclear gene, the gene product localizes to mitochondria, suggesting that mitochondrial dysfunction may be the final common pathway for many forms of syndromic and nonsyndromic optic atrophy, hearing loss, and external ophthalmoplegia.