Elongated EABR wave latencies observed in patients with auditory neuropathy caused by OTOF mutation

Abstract

ObjectivesWe sought to determine how the pathology altered electrically evoked auditory brainstem responses (EABRs) in patients with hearing loss by evaluating EABRs in auditory neuropathy patients with OTOF mutations comparing with various types of congenital deafness.MethodsWe included 15 patients with congenital hearing loss, grouped according to pathology: OTOF mutations (n = 4), GJB2 mutations (n = 4), SLC26A4 mutations (n = 4), or cytomegalovirus infections (n = 3). EABRs were recorded when patients underwent cochlear implantation surgery. We evaluated the latencies and amplitudes of the recorded EABRs and compared them statistically between four groups.ResultsThe EABR latencies of Wave III and Wave V, and of the interval between them, were significantly longer in the OTOF mutation group than in the GJB2 and SLC26A4 mutation groups (Wave III) and in all three other groups (Wave V and Wave III‐V latency); amplitudes were not significantly different between groups.ConclusionsOur results suggest OTOF mutations cause delayed (or slowed) postsynaptic neurotransmission, although the presumed mechanism involved reduced presynaptic transmission between hair cells and spiral ganglion neurons.Level of EvidenceMainly a case report

Central auditory maturation and behavioral outcomes after cochlear implantation in prelingual auditory neuropathy spectrum disorder related to OTOF variants (DFNB9): Lessons from pilot study

“…Indeed, wave III and wave V latencies obtained from cochlear implantees carrying the OTOF variants were significantly longer than those carrying the GJB2 or SLC26A4 variants, suggesting that postsynaptic (central to the SGNs) activity, such as CN synchrony, was still disturbed after implantation in DFNB9 subjects [ 21 ]. It was proposed that the prolonged disturbance in postsynaptic synchrony could be caused by insufficient presynaptic stimulation and/or delayed maturation of the nervous system, including both pre- and post-synaptic neuronal networks [ 21 ]. Collectively, earlier intervention could be crucial to auditory cortical maturation and successful behavioral outcomes of CI in subjects with OTOF variants.…”

“…This suggests that ANSD shows obvious heterogeneity, not only in the etiologies, but also in the amount of stimulus required for auditory cortical maturation. Recently, as evidenced by the electrically evoked ABR, OTOF variants were more closely associated with delayed postsynaptic neurotransmission [ 21 ]. The mechanism of peripheral neural dyssynchrony due to alteration of OTOF , which has been reported to be expressed exclusively in the IHC and affects the synapse between the IHCs and SGNs, can influence maturation of the auditory cortex requires further research.…”

“…Such observations convey that the sensitive period for neural plasticity significantly differs from gene to gene, favoring the former interpretation. Indeed, wave III and wave V latencies obtained from cochlear implantees carrying the OTOF variants were significantly longer than those carrying the GJB2 or SLC26A4 variants, suggesting that postsynaptic (central to the SGNs) activity, such as CN synchrony, was still disturbed after implantation in DFNB9 subjects [21]. It was proposed that the prolonged disturbance in postsynaptic synchrony could be caused by insufficient presynaptic stimulation and/or delayed maturation of the nervous system, including both pre-and post-synaptic neuronal networks [21].…”

“…Intriguingly, a recent electrophysiological study demonstrated that cochlear implantees with OTOF variants revealed significantly delayed ‘postsynaptic’ or more central neurotransmission with the device on, despite the presumed mechanism of DFNB9 involving ‘presynaptic’ transmission between hair cells and SGNs [ 21 ]. Additionally, the widespread expression of otoferlin, including in the brain, and its association subcellularly with the endosomal trans-Golgi network, may suggest a more ubiquitous role, likely influencing the development of both the central and peripheral auditory systems [ 22 ].…”

Flexible Real-Time Polymerase Chain Reaction-Based Platforms for Detecting Deafness Mutations in Koreans: A Proposed Guideline for the Etiologic Diagnosis of Auditory Neuropathy Spectrum Disorder

“…In addition, previous studies suggested that the sensitive period for successful CI outcomes for children with OTOF -related DFNB9 may be narrower than that for those with SLC26A4 - and GJB2 -related deafness [ 14 , 33 ]. Supporting this, abnormal cortical auditory evoked potentials and delayed postsynaptic neurotransmission in children with ANSD may reflect abnormal maturation of the central auditory system, necessitating early intervention [ 34 , 35 ]. Collectively, OTOF -related DFNB9 with early intervention, i.e., before the age of 24 months, is considered a good candidate for CI with a good prognosis for outcome.…”