Auditory Neuropathy as the Initial Phenotype for Patients With ATP1A3 c.2452 G &gt; A: Genotype–Phenotype Study and CI Management

Wenjia Wang,Fen Xiong,Linyi Xie,Jing Guan,Hongyang Wang,Lan Lan,Jin Li,Qiuju Wang

doi:10.3389/fcell.2021.749484

Abstract

Objective: The objective of this study is to analyze the genotype–phenotype correlation of patients with auditory neuropathy (AN), which is a clinical condition featuring normal cochlear responses and abnormal neural responses, and ATP1A3 c.2452 G > A (p.E818K), which has been generally recognized as a genetic cause of cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome.Methods: Four patients diagnosed as AN by clinical evaluation and otoacoustic emission and auditory brainstem responses were recruited and analyzed by next-generation sequencing to identify candidate disease-causing variants. Sanger sequencing was performed on the patients and their parents to verify the results, and short tandem repeat-based testing was conducted to confirm the biological relationship between the parents and the patients. Furthermore, cochlear implantation (CI) was performed in one AN patient to reconstruct hearing.Results: Four subjects with AN were identified to share a de novo variant, p.E818K in the ATP1A3 gene. Except for the AN phenotype, patients 1 and 2 exhibited varying degrees of neurological symptoms, implying that they can be diagnosed as CAPOS syndrome. During the 15 years follow-up of patient 1, we observed delayed neurological events and progressive bilateral sensorineural hearing loss in pure tone threshold (pure tone audiometry, PTA). Patient 2 underwent CI on his left ear, and the result was poor. The other two patients (patient 3 and patient 4, who were 8 and 6 years old, respectively) denied any neurological symptoms.Conclusion: ATP1A3 p.E818K has rarely been documented in the Chinese AN population. Our study confirms that p.E818K in the ATP1A3 gene is a multiethnic cause of AN in Chinese individuals. Our study further demonstrates the significance of genetic testing for this specific mutation for identifying the special subtype of AN with somewhat favorable CI outcome and offers a more accurate genetic counseling about the specific de novo mutation.

Highlights

Auditory neuropathy (AN) is a kind of hearing disorder involving different lesion sites beyond the outer hair cells (OHCs), ranging from the inner hair cells (IHCs) and synapses to auditory nerve and higher auditory centers (Rance and Starr, 2015; Moser and Starr, 2016)
We reported four Chinese AN patients carrying a de novo variant, p.E818K mutation of ATP1A3 gene, identified through generation sequencing (NGS)
A total of four AN cases with ATP1A3 variants were recruited in this study

Summary

Introduction

Auditory neuropathy (AN) is a kind of hearing disorder involving different lesion sites beyond the outer hair cells (OHCs), ranging from the inner hair cells (IHCs) and synapses to auditory nerve and higher auditory centers (Rance and Starr, 2015; Moser and Starr, 2016). Varying degrees of hearing loss are present in subjects with AN; their speech recognition rates are generally poor, disproportionate to the degree of hearing loss (Harrison et al, 2015; Rance and Starr, 2015; Moser and Starr, 2016). Considering postlingual-onset AN, many syndromic forms that cause sensory and motor neuropathy have been documented, including Charcot-Marie-Tooth disease, Friedreich’s ataxia, deafness-dystonia-optic neuropathy (DDON) syndrome, autosomal dominant optic atrophy (ADOA), and AUNX1 due to AIFM1 gene mutations in apoptosis-inducing factor (Han et al, 2017). Han et al (2017) explored the molecular etiology of three unrelated Korean subjects manifesting AN with postlingual onset, identified a mutation in c.2452. P.E818K in the ATP1A3 gene has rarely been documented in the Chinese population

Methods

Results

Discussion

Conclusion