OPA1-related auditory neuropathy: site of lesion and outcome of cochlear implantation

Dominant optic atrophy (DOA) is associated with pathogenic mutations in the nuclear gene encoding for the OPA1 protein in about 60-70% of cases. Besides optic atrophy, patients carrying OPA1 mutations present with hearing loss, ataxia, sensorimotor neuropathy, external ophthalmoplegia and mitochondrial myopathy. In this study we characterized the hearing dysfunction in OPA1- linked disorders and provided effective rehabilitative options to improve speech perception. We studied two groups of OPA1 subjects, one comprising 11 patients (13-79 years) carrying OPA1 mutations inducing haploinsufficiency (OPA1-H), the other, 10 subjects (5-58 years) harboring OPA1 missense mutations (OPA1-M). Both groups underwent pure tone and speech perception evaluation, and otoacoustic emissions (OAEs) and auditory brainstem response (ABR) recording. Cochlear potentials were recorded through transtympanic electrocochleography from the OPA1-M group and were compared to recordings obtained from 20 normally-hearing controls and from 19 subjects with cochlear hearing loss. Eight OPA1-M patients underwent cochlear implantation. Speech perception measures and electrically-evoked auditory nerve and brainstem responses were obtained after one year of cochlear implant use. Nine out of 11 patients included in the OPA1-H group had normal hearing function. In contrast, all but one OPA1-M subject displayed impaired speech perception, abnormal ABRs and presence of OAEs consistent with auditory neuropathy. In electrocochleography recordings, cochlear microphonic had enhanced amplitudes while summating potential showed normal latency and peak amplitude consistent with preservation of both outer and inner hair cell activities. After cancelling the cochlear microphonic, the synchronized neural response seen in both normally-hearing controls and hearing-impaired subjects was replaced by a prolonged, low-amplitude negative potential that decreased in both amplitude and duration during rapid stimulation consistent with neural generation. The use of cochlear implant improved speech perception in all patients. Brainstem potentials were recorded in response to electrical stimulation in five subjects out of six, whereas no compound action potential was evoked from the auditory nerve through the cochlear implant. These findings indicate that underlying the hearing impairment in patients carrying OPA1 missense mutations is a disordered synchrony in auditory nerve fiber activity resulting from neural degeneration affecting the terminal dendrites. Cochlear implantation improves speech perception and synchronous activation of auditory pathways by by-passing the site of lesion