SLC17A8 encoding VGLUT3, if altered, has been shown to cause ANSD in mice 27, 28 however, to date, phenotypes of ANSD have not been reported in human subjects with SLC17A8-induced hearing loss 29, 30. Only mutations from DIAPH3 as the cause of AUNA1 25, 26 have been anecdotally reported from familial ANSD cases, leaving a substantial portion of non-syndromic and sporadic forms of ANSD still unanswered with respect to the molecular etiology. However, there are not many reported genes related to non-syndromic, progressive ANSD with postlingual onset. 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. The predominance of OTOF mutations has also been established in Koreans as they were reported to account for up to 85% of the Korean population with prelingual ANSD with normal cochlear nerve 15. Among them, OTOF mutations occupy a major part of prelingual ANSD in many Caucasian populations 14. GJB2 and mitochondrial 12SrRNA mutations have also been reported to be related to this phenotype 10, 11, 12, 13. Only a few genes have been associated with prelingual genetic ANSD, including autosomal recessive OTOF (DFNB9 the otoferlin gene, NM_001287489) and PJVK genes (DFNB59 the pejvakin gene, NM_001042702) 6, 7, 8, 9. The etiologies of ANSD are highly diverse, including hypoxia, infection, kernicterus, cytotoxic oncologic drug, and genetic factors 4, 5.Īs for prelingual genetic ANSD, there seems to be less diversity compared with postlingual-onset genetic ANSD. Subjects with ANSD have varying degrees of hearing losses however, they generally present poor speech recognition that is disproportionate to the degree of hearing loss and difficulty hearing in noise 1, 2, 3. 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.Īuditory 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). Based on this, cochlear implantation (CI) was performed in the first proband, leading to remarkable benefits. This ANSD phenotype was compatible with known expression of ATP1A3 mainly in the synapse between afferent nerve and inner hair cells. 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. However, hearing loss induced by CAPOS has never been characterized to date. 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. Three out of 106 sporadic progressive hearing losses turned out to manifest ANSD. Thus, we aimed to evaluate the prevalence and molecular etiologies of these cases. The etiologies and prevalence of sporadic, postlingual-onset, progressive auditory neuropathy spectrum disorder (ANSD) have rarely been documented.
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