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 an impaired 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.\ud 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, 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 by comparison with 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.\ud 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

Timing of cochlear implantation in auditory neuropathy patients with OTOF mutations: Our experience with 10 patients

“…One showed favourable speech perception performance 3 years after implantation; the other's speech perception performance was mediocre. Santarelli et al performed disyllabic recognition testing in six ANSD patients with biallelic OTOF mutations and reported that all six patients attained speech perception scores of 90%‐100% at 1‐1.5 year after surgery.…”

“…Recent studies have shown that genetic testing is of great help in determining the site of pathology in paediatric sensorineural hearing impairment (SNHI) . Specifically, mutations in the OTOF gene, a common cause of clinical ANSD, are an indicator that the pathology is confined to the synapse; post‐synaptic neurons and nerve fibres are preserved for electrical stimulation of CI. In this study, we retrospectively analysed CI outcomes in 10 patients with OTOF mutations to explore the utility of genetic diagnosis to help determine the timing of cochlear implantation in patients with ANSD.…”

Auditory neuropathy — neural and synaptic mechanisms

“…We are only beginning to obtain insight into the protein structure of ferlins 55,56 . To date, approximately 90 pathogenic mutations of OTOF have been reported; the majority of these muta tions are assumed to be nonsense or truncation mutations that cause inactivation of otoferlin 57 , result ing in DFNB9type hearing impairment. Otoferlin knockout mice are likely to be an appropriate animal model for DFNB9 (REFS 19,30).…”

Auditory Neuropathy Spectrum Disorders: From Diagnosis to Treatment: Literature Review and Case Reports

“…The term of "auditory neuropathy" was then proposed to initially describe hereditary sensorimotor neuropathies [8]. Later, several authors suggested the more comprehensive term of "auditory neuropathy/auditory dys-synchrony" (AN/AD) or "auditory neuropathies" to underline the loss of temporal coding due to an abnormal synchronization at different levels of the peripheral neural pathways [7,[9][10][11].…”