Hearing Dysfunction in a Large Family Affected by Dominant Optic Atrophy (OPA8-Related DOA): A Human Model of Hidden Auditory Neuropathy.

Maria Lucia Valentino,Piero Barboni,Anna Monteleone,Chiara La Morgia,Valerio Carelli,Pietro Scimemi,Rosamaria Santarelli

doi:10.3389/fnins.2019.00501

Abstract

Hidden auditory neuropathy is characterized by reduced performances in challenging auditory tasks with the preservation of hearing thresholds, resulting from diffuse loss of cochlear inner hair cell (IHC) synapses following primary degeneration of unmyelinated terminals of auditory fibers. We report the audiological and electrophysiological findings collected from 10 members (4 males, 6 females) of a large Italian family affected by dominant optic atrophy, associated with the OPA8 locus, who complained of difficulties in understanding speech in the presence of noise. The patients were pooled into two groups, one consisting of 4 young adults (19–50 years) with normal hearing thresholds, and the other made up of 6 patients of an older age (55–72 years) showing mild hearing loss. Speech perception scores were normal in the first group and decreased in the second. Otoacoustic emissions (OAEs) and cochlear microphonics (CMs) recordings were consistent with preservation of outer hair cell (OHC) function in all patients, whereas auditory brainstem responses (ABRs) showed attenuated amplitudes in the first group and severe abnormalities in the second. Middle ear acoustic reflexes had delayed peak latencies in all patients in comparison with normally hearing individuals. Transtympanic electrocochleography (ECochG) recordings in response to 0.1 ms clicks at intensities from 120 to 60 dB peak equivalent SPL showed a reduction in amplitude of both summating potential (SP) and compound action potential (CAP) together with delayed CAP peak latencies and prolonged CAP duration in all patients in comparison with a control group of 20 normally hearing individuals. These findings indicate that underlying the hearing impairment in OPA8 patients is hidden AN resulting from diffuse loss of IHCs synapses. At an early stage the functional alterations only consist of abnormalities of ABR and ECochG potentials with increased latencies of acoustic reflexes, whereas reduction in speech perception scores become apparent with progression of the disease. Central mechanisms increasing the cortical gain are likely to compensate for the reduction of cochlear input.

Highlights

Dominant optic atrophy (DOA) is amongst the most common inherited optic neuropathies, with a prevalence of about 1 in 25,000–30,000 (Lenaers et al, 2012; Yu-Wai-Man and Chinnery, 2013), and is characterized by a slowly progressive bilateral visual loss beginning in childhood (Kjer, 1959)
Our study demonstrates that the hearing dysfunction in OPA8 patients is underlain by hidden auditory neuropathy due to degeneration of synaptic contacts between hair cells and auditory nerve fibers
This results in abnormalities of the evoked auditory nerve (SP, compound action potential (CAP)) and auditory brainstem responses (ABRs) potentials, which constitutes the first sign of the disease, whereas hearing thresholds and speech perception appear to be largely unaffected at an early stage

Summary

Introduction

Dominant optic atrophy (DOA) is amongst the most common inherited optic neuropathies, with a prevalence of about 1 in 25,000–30,000 (Lenaers et al, 2012; Yu-Wai-Man and Chinnery, 2013), and is characterized by a slowly progressive bilateral visual loss beginning in childhood (Kjer, 1959). The genetic basis of DOA not linked to OPA1 mutations is increasingly being elucidated, and a growing list of other genes involved in the recurrent association of syndromic DOA and sensorineural deafness is being reported. This includes OPA3 with the peculiar association with cataracts (Reynier et al, 2004; Sergouniotis et al, 2015), Wolframin 1 (Eiberg et al, 2006; Rendtorff et al, 2011), MFN2 (Rouzier et al, 2012), SPG7 (Klebe et al, 2012), and DNM1L (Gerber et al, 2017). Almost all these genes encode proteins involved in mitochondrial functions, affecting mitochondrial dynamics and oxidative phosphorylation (Yu-Wai-Man et al, 2016)

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