title: Audibility, speech perception and processing of temporal cues in ribbon synaptic disorders due to OTOF mutations.
abstract: Mutations in the OTOF gene encoding otoferlin result in a disrupted function of the ribbon synapses with impairment of the multivesicular glutamate release. Most affected subjects present with congenital hearing loss and abnormal auditory brainstem potentials associated with preserved cochlear hair cell activities (otoacoustic emissions, cochlear microphonics [CMs]). Transtympanic electrocochleography (ECochG) has recently been proposed for defining the details of potentials arising in both the cochlea and auditory nerve in this disorder, and with a view to shedding light on the pathophysiological mechanisms underlying auditory dysfunction. We review the audiological and electrophysiological findings in children with congenital profound deafness carrying two mutant alleles of the OTOF gene. We show that cochlear microphonic (CM) amplitude and summating potential (SP) amplitude and latency are normal, consistently with a preserved outer and inner hair cell function. In the majority of OTOF children, the SP component is followed by a markedly prolonged low-amplitude negative potential replacing the compound action potential (CAP) recorded in normally-hearing children. This potential is identified at intensities as low as 90 dB below the behavioral threshold. In some ears, a synchronized CAP is superimposed on the prolonged responses at high intensity. Stimulation at high rates reduces the amplitude and duration of the prolonged potentials, consistently with their neural generation. In some children, however, the ECochG response only consists of the SP, with no prolonged potential. Cochlear implants restore hearing sensitivity, speech perception and neural CAP by electrically stimulating the auditory nerve fibers. These findings indicate that an impaired multivesicular glutamate release in OTOF-related disorders leads to abnormal auditory nerve fiber activation and a consequent impairment of spike generation. The magnitude of these effects seems to vary, ranging from no auditory nerve fiber activation to an abnormal generation of EPSPs that occasionally trigger a synchronized electrical activity, resulting in high-threshold CAPs.
authors.affiliation: Department of Neurosciences, University of Padova, Via Giustiniani 2, 35128 Padova, Italy; Audiology and Phoniatrics Service, Treviso Regional Hospital, Piazza Ospedale 1, 31100 Treviso, Italy. Electronic address: rosamaria.santarelli@unipd.it.
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Santarelli
authors.affiliation: Servicio de Genética, Hospital Universitario Ramón y Cajal, IRYCIS, 28034 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28034 Madrid, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: del Castillo
authors.affiliation: Department of Neurosciences, University of Padova, Via Giustiniani 2, 35128 Padova, Italy; Audiology and Phoniatrics Service, Treviso Regional Hospital, Piazza Ospedale 1, 31100 Treviso, Italy.
authors.forename: Elona
authors.initials: E
authors.lastname: Cama
authors.affiliation: Department of Neurosciences, University of Padova, Via Giustiniani 2, 35128 Padova, Italy; Audiology and Phoniatrics Service, Treviso Regional Hospital, Piazza Ospedale 1, 31100 Treviso, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Scimemi
authors.affiliation: Department of Neurology, University of California, Irvine, CA 92697, USA.
authors.forename: Arnold
authors.initials: A
authors.lastname: Starr
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D001300:Audiometry, Evoked Response; D001306:Auditory Pathways / Q000378:metabolism / Q000503:physiopathology; D001309:Auditory Threshold; D003051:Cochlea / Q000294:innervation*; D019929:Cochlear Implantation; D003055:Cochlear Microphonic Potentials; D003056:Cochlear Nerve / Q000378:metabolism / Q000503:physiopathology*; D003463:Cues; D020022:Genetic Predisposition to Disease; D018698:Glutamic Acid / Q000378:metabolism; D006309:Hearing; D034381:Hearing Loss / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology / Q000534:rehabilitation; D006801:Humans; D008144:Loudness Perception; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D019986:Persons with Hearing Disabilities / Q000523:psychology; D010641:Phenotype; D011930:Reaction Time; D013065:Speech Intelligibility; D013067:Speech Perception; D009435:Synaptic Transmission; D013997:Time Factors
chemical_list: D008565:Membrane Proteins; C118457:OTOF protein, human; D018698:Glutamic Acid
keywords: Auditory neuropathy; Cochlear implant; Electrocochleography; Hearing aids; Ribbon synaptic disorders