Cochlear implantation in a child with auditory neuropathy spectrum disorder

Objective To report outcomes of cochlear implantation (CI) in a child with auditory neuropathy spectrum disorder (ANSD) and to provide preliminary clinical evidence of the efficacy of CI in ANSD patients.Methods A 4-year-old boy with diagnosed auditory neuropathy spectrum disorder (ANSD) received implantation of a Nucleus CI24R after an unsatisfactory trial of amplification.Post-implantation performance in both hearing sensitivity and speech recognition was assessed in different sessions.Aided hearing thresholds were tested by behavioral audiometry.Mandarin Early Speech Perception Test (MESP),Meaningful Auditory Integration Scale (MAIS),category of auditory performance (CAP) and Speech Intelligibility Rating (SIR) were used to assess the benefits in auditory skills or speech recognition the boy obtained from CI.The tests were administered before surgery and at 3 months and 7 months after opening.Results The boy demonstrated improved auditory sensitivity by using CI.Concerning speech recognition and communication,both speech audiometry and questionnaires showed an obvious benefit from CI.Conclusions CI has worked efficiently in this ANSD boy.But because of limited understanding of ANSD and rehabilitation effect by cochlear implantation in this condition,the clinical decision to implant should be cautious and only after a thorough evaluation.Meanwhile,well controlled and long term studies are needed to confirm the efficacy of cochlear implantation in patients with ANSD.

Profiles and predictors of onset based differences in vocal characteristics of adults with auditory neuropathy spectrum disorder(ANSD)

Purpose:Onset-based differences are understudied in Auditory Neuropathy Spectrum Disorder(ANSD)in dimensions such as voice,which is addressed in the study.The study aimed to profile and predict the best metrics of onset-related differences in acoustic vocal characteristics of early and late-onset ANSD patients.Methods:31 participants(15 early and 16 late-onset)aged 15e30 years diagnosed with ANSD were included in the study.The sustained phonation of vowel/i/recorded by the participants using android based smartphones of selected configuration was sent over email to the experimenter.Acoustic parameters(fundamental frequency,harmonic frequencies,jitter,shimmer,harmonic-to-noise ratio,cepstral peak prominence-CPP,and pitch sigma)were analysed using Praat software.Results:Results revealed significantly increased(p<0.05)fundamental frequency along with decreased F2 and F3 of/i/in the early-onset ANSD compared to the late-onset group,which can be explained based on differences in the pathophysiology of the disorder.Although not statistically significant,mean perturbations(jitter and shimmer),harmonic-to-noise ratio,cepstral peak prominence,and pitch sigma were more affected in the early-onset group,reflective of lowered auditory feedback and periodicity in their voice samples.Results of discriminant analysis marked the emergence of F2,F3,and CPP as the most sensitive metrics for onset-based group differences in voice characteristics.Conclusions:The findings from the study highlight the role of acoustical voice evaluation(especially CPP,F2&F3)in verifying the onset of ANSD disorder.The insights from the onset-based differences seen in vocal characteristics can indirectly help audiologists in deciding the management options for ANSD.

AIFM1 variants associated with auditory neuropathy spectrum disorder cause apoptosis due to impaired apoptosis-inducing factor dimerization

Auditory neuropathy spectrum disorder(ANSD)represents a variety of sensorineural deafness conditions characterized by abnormal inner hair cells and/or auditory nerve function,but with the preservation of outer hair cell function.ANSD represents up to 15%of individuals with hearing impairments.Through mutation screening,bioinformatic analysis and expression studies,we have previously identified several apoptosis-inducing factor(AIF)mitochondria-associated 1(AIFM1)variants in ANSD families and in some other sporadic cases.Here,to elucidate the pathogenic mechanisms underlying each AIFM1 variant,we generated AIF-null cells using the clustered regularly interspersed short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)system and constructed AIF-wild type(WT)and AIF-mutant(mut)(p.T260A,p.R422W,and p.R451Q)stable transfection cell lines.We then analyzed AIF structure,coenzyme-binding affinity,apoptosis,and other aspects.Results revealed that these variants resulted in impaired dimerization,compromising AIF function.The reduction reaction of AIF variants had proceeded slower than that of AIF-WT.The average levels of AIF dimerization in AIF variant cells were only 34.5%-49.7%of that of AIF-WT cells,resulting in caspase-independent apoptosis.The average percentage of apoptotic cells in the variants was 12.3%-17.9%,which was significantly higher than that(6.9%-7.4%)in controls.However,nicotinamide adenine dinucleotide(NADH)treatment promoted the reduction of apoptosis by rescuing AIF dimerization in AIF variant cells.Our findings show that the impairment of AIF dimerization by AIFM1 variants causes apoptosis contributing to ANSD,and introduce NADH as a potential drug for ANSD treatment.Our results help elucidate the mechanisms of ANSD and may lead to the provision of novel therapies.

Understanding auditory neuropathy spectrum disorder： a system- atic review in transgenic mouse models

Auditory neuropathy spectrum disorder is a unique group of hearing dysfunctions characterized by preserved outer hair cell function and abnormal neural conduction of the auditory pathway. However, the pathogenic mechanism underlying this disorder is not clear. We therefore performed a systematic review of genetic mouse models with different gene mutations to provide a valuable tool for better understanding of the process and the possible molecular mechanisms. Of the 18 articles retrieved, nine met the required criteria. All biochemical, histological, and electrophysiological results were recorded for each of the mouse models, as was the transgenic technology. This review provides a summary of different mouse models that may play an important role in the diagnosis and management of auditory neuropathy spectrum disorder in the future.

Audiological evaluation in Chinese patients with mitochondrial encephalomyopathies

Background Hearing impairment has been reported to be common in patients with mitochondrial disorders,a group of diseases characterized by pleiomorphic clinical manifestations due to defects in oxidative phosphorylation of mitochondria.This study aimed to investigate the audiological characteristics in a large cohort of patients with mitochondrial disease.Methods Comprehensive audiological evaluations,including pure tone audiometry,tympanometry,speech audiometry,otoacoustic emissions,electrocochleography and auditory brainstem evoked potentials,were performed in 73 Chinese patients with mitochondrial encephalomyopathy and with confirmed mitochondrial DNA （mtDNA） defects.Results Among the patients,71％ had hearing impairment.However,the incidence rate and severity of hearing impairment were much less in the chronic progressive external ophthalmoplegia （CPEO） subtype than in the mitochondrial encephalomyopathy,lactic acidosis,and stroke-like episodes （MELAS）,myoclonic epilepsy with ragged red fibers （MERRF） and Kearns-Sayre syndrome （KSS） subtypes.While most of our patients had a predominantly cochlea origin for the hearing deficit,five patients had an auditory neuropathy spectrum disorder and three patients had impairment of both cochlea and auditory codex.Conclusions Various portions of the auditory system could be involved in patients with mitochondrial diseases,including cochlea,auditory nerve,auditory pathway and cortex.Hearing loss was more associated with multisystem involvement.Genotype,mutant load of mtDNA and other unknown factors could contribute to heterogeneity of hearing impairment in mitochondrial disease.