Autosomal dominant optic atrophy with OPA1 gene mutations accompanied by auditory neuropathy and other systemic complications in a Japanese cohort

PURPOSE: This study aimed to describe the genetic and clinical characteristics of four Japanese patients with autosomal dominant optic atrophy (DOA) accompanied by auditory neuropathy and other systemic complications (i.e., DOA-plus disease). METHODS: Four patients from four independent families underwent comprehensive ophthalmic and auditory examinations and were diagnosed with DOA-plus disease. The disease-causing gene variants in the OPA1 gene were identified by direct sequencing. The genetic and clinical data of 48 DOA patients without systemic complications—that is, with simple DOA—were compared to those of DOA-plus patients. RESULTS: DOA-plus patients noticed a decrease in vision before the age of 14 and hearing impairment 3 to 13 years after the development of visual symptoms. Two patients had progressive external ophthalmoplegia, and one patient had vestibular dysfunction and ataxia. The DOA-plus phenotypes accounted for 13.3% (4/30) of the families with the OPA1 gene mutations. Each DOA-plus patient harbored one of the monoallelic mutations in the OPA1 gene: c.1334G>A, p.R445H, c.1618A>C, p.T540P, and c.892A>C, p.S298R. Missense mutations accounted for 100% (4/4) of the DOA-plus families and only 11.5% (3/26) of the families with simple DOA. CONCLUSIONS: All the patients with the DOA-plus phenotype carried one of the missense mutations in the OPA1 gene. They all had typical ocular symptoms and signs of DOA in their first or second decade, and other systemic complications—such as auditory neuropathy, vestibular dysfunction, and ataxia—followed the ocular symptoms. We should consider the occurrence of extraocular complications in cases with DOA, especially when they carry the missense mutations in the OPA1 gene.