Abstract
The etiologies and prevalence of sporadic, postlingual-onset, progressive auditory neuropathy spectrum disorder (ANSD) have rarely been documented. Thus, we aimed to evaluate the prevalence and molecular etiologies of these cases. Three out of 106 sporadic progressive hearing losses turned out to manifest ANSD. Through whole exome sequencing and subsequent bioinformatics analysis, two out of the three were found to share a de novo variant, p.E818K of ATP1A3, which had been reported to cause exclusively CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) syndrome. However, hearing loss induced by CAPOS has never been characterized to date. Interestingly, the first proband did not manifest any features of CAPOS, except subclinical areflexia; however, the phenotypes of second proband was compatible with that of CAPOS, making this the first reported CAPOS allele in Koreans. This ANSD phenotype was compatible with known expression of ATP1A3 mainly in the synapse between afferent nerve and inner hair cells. Based on this, cochlear implantation (CI) was performed in the first proband, leading to remarkable benefits. Collectively, the de novo ATP1A3 variant can cause postlingual-onset auditory synaptopathy, making this gene a significant contributor to sporadic progressive ANSD and a biomarker ensuring favorable short-term CI outcomes.
Highlights
The etiologies and prevalence of sporadic, postlingual-onset, progressive auditory neuropathy spectrum disorder (ANSD) have rarely been documented
Auditory neuropathy spectrum disorder (ANSD) is a type of hearing loss characterized by electrophysiological findings of an impaired or absent response in auditory brainstem responses (ABR), despite evidence of intact outer hair cell function as supported by the presence of cochlear microphonics and/or detectable otoacoustic emission (OAE)
We identified that sensorineural hearing loss (SNHL) in CAPOS syndrome (OMIM #601388), comprising of cerebellar ataxia, areflexia, pes cavus, optic atrophy, and hearing loss[31,32,33,34,35,36,37], can fit into the category of ANSD and manifest in a non-syndromic manner
Summary
The etiologies and prevalence of sporadic, postlingual-onset, progressive auditory neuropathy spectrum disorder (ANSD) have rarely been documented. The first proband did not manifest any features of CAPOS, except subclinical areflexia; the phenotypes of second proband was compatible with that of CAPOS, making this the first reported CAPOS allele in Koreans This ANSD phenotype was compatible with known expression of ATP1A3 mainly in the synapse between afferent nerve and inner hair cells. As for postlingual-onset ANSD, a lot of syndromic forms that cause sensory and motor neuropathy have been documented in adults with ANSD, including Charcot-Marie-Tooth disease[2,16,17], Friedreich’s ataxia[18,19], deafness-dystonia-optic neuropathy (DDON) syndrome[20], autosomal dominant optic atrophy (ADOA)[21,22], and AUNX1 due to mutations in apoptosis-inducing factor[23,24]. We aimed to explore the molecular etiology of three unrelated subjects manifesting sporadic, progressive ANSD with postlingual onset. We identified that sensorineural hearing loss (SNHL) in CAPOS syndrome (OMIM #601388), comprising of cerebellar ataxia, areflexia, pes cavus, optic atrophy, and hearing loss[31,32,33,34,35,36,37], can fit into the category of ANSD and manifest in a non-syndromic manner
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