title: OPA1-related auditory neuropathy: site of lesion and outcome of cochlear implantation.
abstract: Hearing impairment is the second most prevalent clinical feature after optic atrophy in dominant optic atrophy associated with mutations in the OPA1 gene. 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 (seven males; age range 13-79 years) carrying OPA1 mutations inducing haploinsufficiency, the other, 10 subjects (three males; age range 5-58 years) carrying OPA1 missense mutations. Both groups underwent audiometric assessment with pure tone and speech perception evaluation, and otoacoustic emissions and auditory brainstem response recording. Cochlear potentials were recorded through transtympanic electrocochleography from the group of patients harbouring OPA1 missense mutations and were compared to recordings obtained from 20 control subjects with normal hearing and from 19 subjects with cochlear hearing loss. Eight patients carrying OPA1 missense mutations underwent cochlear implantation. Speech perception measures and electrically-evoked auditory nerve and brainstem responses were obtained after 1 year of cochlear implant use. Nine of 11 patients carrying OPA1 mutations inducing haploinsufficiency had normal hearing function. In contrast, all but one subject harbouring OPA1 missense mutations displayed impaired speech perception, abnormal brainstem responses and presence of otoacoustic emissions 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 subjects with cochlear hearing loss 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 but one patient. Brainstem potentials were recorded in response to electrical stimulation in five of six subjects, 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 fibre activity resulting from neural degeneration affecting the terminal dendrites. Cochlear implantation improves speech perception and synchronous activation of auditory pathways by bypassing the site of lesion.
authors.affiliation: 1 Department of Neurosciences, University of Padova, Via Giustiniani 2, 35128 Padova, Italy 2 Audiology and Phoniatrics Service, Treviso Regional Hospital, Piazza Ospedale 1, 31100 Treviso, Italy rosamaria.santarelli@unipd.it.
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Santarelli
authors.affiliation: 1 Department of Neurosciences, University of Padova, Via Giustiniani 2, 35128 Padova, Italy 2 Audiology and Phoniatrics Service, Treviso Regional Hospital, Piazza Ospedale 1, 31100 Treviso, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Rossi
authors.affiliation: 1 Department of Neurosciences, University of Padova, Via Giustiniani 2, 35128 Padova, Italy 2 Audiology and Phoniatrics Service, Treviso Regional Hospital, Piazza Ospedale 1, 31100 Treviso, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Scimemi
authors.affiliation: 1 Department of Neurosciences, University of Padova, Via Giustiniani 2, 35128 Padova, Italy 2 Audiology and Phoniatrics Service, Treviso Regional Hospital, Piazza Ospedale 1, 31100 Treviso, Italy.
authors.forename: Elona
authors.initials: E
authors.lastname: Cama
authors.affiliation: 3 Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy 4 IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Via Altura 3, 40139 Bologna, Italy.
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Valentino
authors.affiliation: 3 Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy 4 IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Via Altura 3, 40139 Bologna, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: La Morgia
authors.affiliation: 3 Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy 4 IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Via Altura 3, 40139 Bologna, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Caporali
authors.affiliation: 3 Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy 4 IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Via Altura 3, 40139 Bologna, Italy.
authors.forename: Rocco
authors.initials: R
authors.lastname: Liguori
authors.affiliation: 1 Department of Neurosciences, University of Padova, Via Giustiniani 2, 35128 Padova, Italy 2 Audiology and Phoniatrics Service, Treviso Regional Hospital, Piazza Ospedale 1, 31100 Treviso, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Magnavita
authors.affiliation: 2 Audiology and Phoniatrics Service, Treviso Regional Hospital, Piazza Ospedale 1, 31100 Treviso, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Monteleone
authors.affiliation: 2 Audiology and Phoniatrics Service, Treviso Regional Hospital, Piazza Ospedale 1, 31100 Treviso, Italy.
authors.forename: Ariella
authors.initials: A
authors.lastname: Biscaro
authors.affiliation: 1 Department of Neurosciences, University of Padova, Via Giustiniani 2, 35128 Padova, Italy 2 Audiology and Phoniatrics Service, Treviso Regional Hospital, Piazza Ospedale 1, 31100 Treviso, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Arslan
authors.affiliation: 3 Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy 4 IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Via Altura 3, 40139 Bologna, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001300:Audiometry, Evoked Response; D001309:Auditory Threshold / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D019929:Cochlear Implantation; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006313:Hearing Loss, Central / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D017084:Otoacoustic Emissions, Spontaneous; D013067:Speech Perception / Q000502:physiology; D015898:Tomography Scanners, X-Ray Computed; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human
keywords: OPA1-related hearing impairment; auditory neuropathy; cochlear implants; electrocochleography; speech perception