Auditory Neuropathy Spectrum Disorder Research Articles

Postoperative Auditory Progress in Cochlear-Implanted Children With Auditory Neuropathy.

This study aims to evaluate the effect of auditory neuropathy spectrum disorder (ANSD) on postoperative auditory perception and listening difficulties in pediatric cochlear implant (CI) recipients. The Children's Auditory Perception Test (CAPT) assesses auditory perception skills, and the Children's Home Inventory of Listening Difficulties (CHILD) Scale evaluates daily listening difficulties. The study involved pediatric CI recipients (n = 40) aged between 5 and 7 years, with and without diagnosis of ANSD. The research ensured homogeneity across various factors, including chronological age, age at diagnosis, age at initial implantation, bilateral simultaneous surgery, etiologies of hearing loss, and family education level. The findings have demonstrated that children without ANSD exhibited better performance in integrating visual-auditory stimuli and overall listening performance, distant sound source scores, and noisy environment scores (respectively p = .047, p = .001, p = .028, and p = .010). Additionally, children with better speech perception also have a better ability to integrate audiovisual stimuli (p = .005, r = .438). There are significant differences in postoperative listening skills and auditory perceptions between children with and without an ANSD who have CIs. Accordingly, children without an ANSD perform better.

Riboflavin transporter deficiency, the search for the undiagnosed: a retrospective data mining study

BackgroundRiboflavin transporter deficiency (RTD) is an inborn error of riboflavin transport causing progressive neurological symptoms if left untreated. While infants with symptomatic RTD rapidly deteriorate, presentation later in childhood or in adulthood is more gradual. Symptoms overlap with more common diseases, carrying a risk of misdiagnosis, and given the relatively recent discovery of the genetic basis of RTD in 2010 it is likely that older patients have not been tested. Treatment with oral riboflavin (vitamin B2) halts disease progression and can be lifesaving. We hypothesized that patients may have been left unrecognized at the time of presentation and therefore we performed a datamining study to detect undiagnosed RTD patients in a tertiary referral hospital.MethodsA systematic search in Electronic Health Records (EHR) of all patients visiting the Amsterdam University Medical Centers between January 2004 and July 2021 was performed by a medical data text-mining tool. Pseudonymized patient records, matching pre-defined search terms (hearing loss or auditory neuropathy spectrum disorders combined with key clinical symptoms or riboflavin) were screened and included if no definitive alternative diagnosis for symptoms indicating possible RTD was found. Included patients were offered genetic testing. We documented total number of patients with possible RTD, number of patients that underwent genetic testing for RTD and results of genetic testing.ResultsEHR of 2.288.901 patients were automatically screened. Thirteen patients with possible RTD were identified and offered genetic testing. Seven patients chose not to participate. Genetic testing was performed in 6 patients and was negative. The datamining did detect all previously known RTD patients in the hospital.ConclusionsBy screening a large cohort of patients of all ages in a tertiary referral hospital in a period spanning 17 years, no new RTD patients were found. Although not all suspected patients underwent genetic testing, our findings suggest that the prevalence of RTD is low and the chance of having missed this diagnosis in a tertiary referral hospital is limited.

Dissociation between caloric test and the video head impulse test in individuals with auditory neuropathy spectrum disorders.

Dissociation between caloric test and the video head impulse test in individuals with auditory neuropathy spectrum disorders.

A comparative study of auditory and non-auditory characteristics of congenital, early, and late-onset auditory neuropathy spectrum disorder

BackgroundThe study explored the differences in audiological and non-audiological characteristics between congenital, early-onset, and late-onset auditory neuropathy spectrum disorder (ANSD). Ninety-five individuals diagnosed with ANSD were included in the study. They were divided into three groups congenital ANSD—children (30 individuals, 60 ears), adults with early-onset ANSD (30 individuals, 56 ears), and adults with late-onset ANSD (35 individuals, 62 ears). The non-audiological characteristics (gender, laterality, and risk factors) and audiological characteristics (behavioral and electrophysiological measures) were compared between the three groups.ResultsDiscriminant analyses showed that the pure tone average, audiogram configuration, and speech thresholds were the best auditory predictors of onset-based group differences in ANSD (congenital and early-onset versus late-onset ANSD). While the congenital and early-onset group showed poorer pure-tone and speech thresholds, along with flat configuration, the late-onset group demonstrated relatively better thresholds and other configurations (rising, tent-shaped, cookie-bite). In addition, long latency responses were delayed or absent in children with congenital ANSD, indicative of onset coding deficits at the cortical level.ConclusionsThe study highlights the audiological differences between congenital, early-, and late-onset ANSD groups. These differences could be because of variations in etiology, pathophysiology, site of lesion, or genetic variability between the groups, which needs to be explored further.

Comparative Mapping of Vocal Parameters in Auditory Neuropathy Spectrum Disorder with and Without Use of Speech Processor in Bilateral Cochlear Implantation - A Pilot Study

Comparative Mapping of Vocal Parameters in Auditory Neuropathy Spectrum Disorder with and Without Use of Speech Processor in Bilateral Cochlear Implantation - A Pilot Study

Hearing loss secondary to variants in the OTOF gene

ObjectiveGenetic variants in the OTOF gene are responsible for non-syndromic hearing loss with an autosomal recessive inheritance pattern. The objective of our work was to evaluate the clinical characteristics of patients with biallelic pathogenic variants in OTOF and their evolution after treatment. MethodsA cohort of 124 patients with prelingual hearing loss, studied from 1996 to 2023, was included in this study. A genetic analysis was conducted to identify the type and frequency of variants in the OTOF gene and their relation to the clinical characteristics of the patients. ResultsThe homozygous p. Gln829* variant in the OTOF gene was detected in 3 probands (2.4 %) of a group of 124 individuals with prelingual hearing loss. Another 6 family members to a total of 9 individuals were finally included. All presented with severe/profound bilateral sensorineural hearing loss of congenital onset. Three of these individuals were diagnosed with auditory neuropathy spectrum disorder. One individual passed the OAE test during the screening program, and since he did not have risk factors for hearing loss that would warrant ABR testing, this led to a delay in his hearing loss diagnosis. Four individuals underwent cochlear implants (three bilateral) with good functional outcomes in three of them. However, in 17 familial cases with heterozygous variants, either no hearing loss was observed or it was within the expected range for their age. ConclusionsHearing loss secondary to the p.Gln829* variant of the OTOF gene is relatively rare in our medical area. Its presence in homozygosity is the cause of severe/profound bilateral prelingual sensorineural hearing loss, responsible for auditory neuropathy with a good response to cochlear implantation.

Measurement of thresholds using Chirp-ABR in children with auditory neuropathy spectrum disorder and sensorineural hearing loss

AimThis study explored the value of Chirp-auditory brainstem response (ABR) thresholds in assessing the hearing threshold of children diagnosed with auditory neuropathy spectrum disorder (ANSD). MethodsA total of 20 children with ANSD (40 ears, aged 1.5–7.0 years, median age 4.5 years) and 31 children with sensorineural hearing loss (SNHL) (52 ears, aged 0.9–8.0 years, median age 3.7 years) were included. Besides, 25 normal children (50 ears, aged 0.8–7.5 years, median age 4.6 years) were used as controls. Chirp-ABR and behavioral audiometry were performed simultaneously among three groups of children, allowing for a comparison of the thresholds obtained through both methods. ResultsIn ANSD children, the correlation (r-values) between the thresholds obtained from Chirp-ABR and behavioral audiometry at 500–4000 Hz were 0.84, 0.67, 0.59, and 0.60, respectively. The average threshold differences between two methods ranged from 9.7 to 13.3 dB at 500–4000 Hz. Notably, 20 % ears (8/40) exhibited considerable discrepancies (>30 dB) in thresholds at certain frequencies. For SNHL children, the r-values between two methods were 0.84, 0.89, 0.92, and 0.93, respectively. The average threshold differences between two methods were 5.7–8.2 dB at 500–4000 Hz. Similarly, in normal children, the average threshold differences between two methods ranged from 6.1 dB to 7.7 dB, the r-values were 0.81, 0.78, 0.80, and 0.80 at 500–4000 Hz, respectively. ConclusionChirp-ABR threshold is not suitable to predict the behavioral audiometry threshold in ANSD children. When there is a significant discrepancy (>30 dB) between Chirp-ABR thresholds and behavioral audiometry thresholds in hearing loss, ANSD should be highly suspected.

Novel Variant of FDXR as a Molecular Etiology of Postlingual Post-Synaptic Auditory Neuropathy Spectrum Disorder via Mitochondrial Dysfunction: Reiteration of the Correlation between Genotype and Cochlear Implantation Outcomes.

FDXR encodes the mitochondrial ferredoxin reductase, which is associated with auditory neuropathy spectrum disorder (ANSD) and optic atrophy. Only two studies have described FDXRrelated hearing loss. The auditory rehabilitation outcomes of this disease entity have not been investigated, and the pathophysiologic mechanism is not well elucidated. Here we report a hearingimpaired subject with co-segregation of the FDXR variant and post-synaptic type ANSD, who underwent cochlear implantation (CI) with favorable outcomes. We suggest a possible pathophysiologic mechanism of adult-onset ANSD via mitochondrial dysfunction. A 35-year-old woman was ascertained to have ANSD. Exome sequencing identified the genetic cause of hearing loss, and functional study measuring mitochondrial activity was performed to provide molecular evidence of pathophysiology. Expression of FDXR in the mouse cochlea was evaluated by immunohistochemistry. Intraoperatively, electrically-evoked compound action potential (ECAP) responses were measured, and mapping parameters were adjusted accordingly. Audiological outcomes were monitored for over 1 year. In lymphoblastoid cell lines (LCLs) carrying a novel FDXR variant, decreased ATP and MtMP levels and increased ROS levels were observed compared to control LCLs. These dysfunctions were restored by administering mitochondria isolated from umbilical cord mesenchymal stem cells, confirming the pathogenic potential of this variant via mitochondrial dysfunction. Partial ECAP responses during CI and FDXR expression in the mouse cochlea indicate that FDXR-related ANSD is postsynaptic. By increasing the pulse width during mapping, the patient's CI outcomes showed significant improvement over 1-year post-CI. Post-synaptic ANSD due to a novel FDXR variant linked to mitochondrial dysfunction was identified first in a Korean, and 1-year post CI outcomes were reported for the first time in the literature. Excellent audiologic results were obtained, and our results reiterate the correlation between genotype and CI outcomes in ANSD.

Assessing Neural Synchrony in the Cochlear Nerve to Electrical Stimulation in Children With Auditory Neuropathy Spectrum Disorder.

This study reported phase locking values (PLVs) that quantified the trial-to-trial phase coherence of electrically evoked compound action potentials in children with auditory neuropathy spectrum disorders (ANSD) and children with Gap Junction Beta 2 (GJB2) mutations, a patient population without noticeable cochlear nerve damage. PLVs were measured at three electrode locations in 11 children with ANSD and 11 children with GJB2 mutations. Smaller PLVs indicated poorer neural synchrony. A linear mixed-effects model was used to compare PLVs measured at different electrode locations between participant groups. After controlling for the stimulation level effect, children with ANSD had smaller PLVs than children with GJB2 mutations at all three electrode locations. Cochlear-implanted children with ANSD show poorer peripheral neural synchrony than children with GJB2 mutations.

Predictors of cochlear implant outcomes in pediatric auditory neuropathy: A matched case-control study.

Current evidence supports the benefits of cochlear implants (CIs) in children with hearing loss, including those with auditory neuropathy spectrum disorder (ANSD). However, there is limited evidence regarding factors that hold predictive value for intervention outcomes. This retrospective case-control study consisted of 66 children with CIs, including 22 with ANSD and 44 with sensorineural hearing loss (SNHL) matched on sex, age, age at CI activation, and the length of follow-up with CIs (1:2 ratio). The case and control groups were compared in the results of five open-set speech perception tests, and a Forward Linear Regression Model was used to identify factors that can predict the post-CI outcomes. There was no significant difference in average scores between the two groups across five outcome measures, ranging from 88.40% to 95.65%. The correlation matrix revealed that younger ages at hearing aid fitting and CI activation positively influenced improvements in speech perception test scores. Furthermore, among the variables incorporated in the regression model, the duration of follow-up with CIs, age at CI activation, and the utilization of two CIs demonstrated prognostic significance for improved post-CI speech perception outcomes. Children with ANSD can achieve similar open-set speech perception outcomes as children with SNHL. A longer CI follow-up, a lower age at CI activation, and the use of two CIs are predictive for optimal CI outcome.

Epidemiology, aetiology and diagnosis of congenital hearing loss via hearing screening of 153 913 newborns.

Congenital hearing loss (HL), one of the most common paediatric chronic conditions, significantly affects speech and language development. Its early diagnosis and medical intervention can be achieved via newborn hearing screening. However, data on the prevalence and aetiology of congenital HL in infants who fail newborn hearing screening are limited. The sample population included 153 913 infants who underwent newborn hearing screening, and the prevalence of congenital HL, defined as moderate to profound bilateral HL (BHL) or unilateral HL (UHL) (≥40 dB HL), in one prefecture of Japan was measured to minimize the loss-to-follow-up rate, a common factor affecting the screening procedure. Comprehensive aetiological investigation, including physiology, imaging, genetic tests, and congenital cytomegalovirus screening, was performed on children diagnosed with congenital HL. The calculated prevalence of congenital HL was 1.62 per 1000 newborns (bilateral, 0.84; unilateral, 0.77). More than half of the cases with congenital bilateral or severe to profound UHL showed genetic aetiology or cochlear nerve deficiency (CND), respectively. Approximately 4% and 6% of the cases of congenital BHL and UHL were associated with congenital cytomegalovirus infection and auditory neuropathy spectrum disorder, respectively. This is an epidemiological and comprehensive aetiological study of congenital HL, as determined via newborn hearing screening according to its severity and laterality, in a large-scale general population of a developed country. Our findings can serve as a reference for optimizing care and intervention options for children with HL and their families.

Transmembrane proteins with unknown function (TMEMs) as ion channels: electrophysiological properties, structure, and pathophysiological roles.

A transmembrane (TMEM) protein with an unknown function is a type of membrane-spanning protein expressed in the plasma membrane or the membranes of intracellular organelles. Recently, several TMEM proteins have been identified as functional ion channels. The structures and functions of these proteins have been extensively studied over the last two decades, starting with TMEM16A (ANO1). In this review, we provide a summary of the electrophysiological properties of known TMEM proteins that function as ion channels, such as TMEM175 (KEL), TMEM206 (PAC), TMEM38 (TRIC), TMEM87A (GolpHCat), TMEM120A (TACAN), TMEM63 (OSCA), TMEM150C (Tentonin3), and TMEM43 (Gapjinc). Additionally, we examine the unique structural features of these channels compared to those of other well-known ion channels. Furthermore, we discuss the diverse physiological roles of these proteins in lysosomal/endosomal/Golgi pH regulation, intracellular Ca2+ regulation, spatial memory, cell migration, adipocyte differentiation, and mechanical pain, as well as their pathophysiological roles in Parkinson's disease, cancer, osteogenesis imperfecta, infantile hypomyelination, cardiomyopathy, and auditory neuropathy spectrum disorder. This review highlights the potential for the discovery of novel ion channels within the TMEM protein family and the development of new therapeutic targets for related channelopathies.

The human OPA1delTTAG mutation induces adult onset and progressive auditory neuropathy in mice

Dominant optic atrophy (DOA) is one of the most prevalent forms of hereditary optic neuropathies and is mainly caused by heterozygous variants in OPA1, encoding a mitochondrial dynamin-related large GTPase. The clinical spectrum of DOA has been extended to a wide variety of syndromic presentations, called DOAplus, including deafness as the main secondary symptom associated to vision impairment. To date, the pathophysiological mechanisms underlying the deafness in DOA remain unknown. To gain insights into the process leading to hearing impairment, we have analyzed the Opa1delTTAG mouse model that recapitulates the DOAplus syndrome through complementary approaches combining morpho-physiology, biochemistry, and cellular and molecular biology. We found that Opa1delTTAG mutation leads an adult-onset progressive auditory neuropathy in mice, as attested by the auditory brainstem response threshold shift over time. However, the mutant mice harbored larger otoacoustic emissions in comparison to wild-type littermates, whereas the endocochlear potential, which is a proxy for the functional state of the stria vascularis, was comparable between both genotypes. Ultrastructural examination of the mutant mice revealed a selective loss of sensory inner hair cells, together with a progressive degeneration of the axons and myelin sheaths of the afferent terminals of the spiral ganglion neurons, supporting an auditory neuropathy spectrum disorder (ANSD). Molecular assessment of cochlea demonstrated a reduction of Opa1 mRNA level by greater than 40%, supporting haploinsufficiency as the disease mechanism. In addition, we evidenced an early increase in Sirtuin 3 level and in Beclin1 activity, and subsequently an age-related mtDNA depletion, increased oxidative stress, mitophagy as well as an impaired autophagic flux. Together, these results support a novel role for OPA1 in the maintenance of inner hair cells and auditory neural structures, addressing new challenges for the exploration and treatment of OPA1-linked ANSD in patients.

Preparing for Otoferlin gene therapy trials: A survey of NHS Paediatric Audiology and Cochlear Implant services on diagnosis and management of Auditory Neuropathy Spectrum Disorder

ObjectivesGene therapy for monogenic hearing loss is on the horizon. The first trials in patients with Auditory Neuropathy Spectrum Disorder (ANSD) due to pathogenic variants in the Otoferlin (OTOF) gene will open this year. In the UK, the new NHS Genomic Medicine Service (GMS) offers genetic testing in each child diagnosed with congenital or early onset sensorineural hearing loss. This survey study aims to map preexisting clinical pathways for the diagnosis and management of children with ANSD and identify opportunities for improvement in early identification of OTOF- related ANSD. MethodsA Google form with 24 questions in English covering the ANSD clinical pathway was developed with clinicians involved in the diagnosis and management ANSD. The survey was disseminated via email to all Lead clinicians of NHS Tertiary Paediatric Audiology and Cochlear Implant Services within the UK. ResultsData was received from 27 (34 %) NHS Tertiary Paediatric Audiology Services and 8 (n = 57 %) Paediatric Cochlear Implant Services. Services follow existing national guidance and provide multidisciplinary care with structured patient pathways for referral, diagnosis, and management of children with ANSD and multidisciplinary input throughout. Clinicians are aware of the genetic causes of ANSD and new processes for genetic testing, but do not uniformly refer children with ANSD for testing for OTOF pathogenic variants. As such, they had difficulty estimating numbers of children with OTOF pathogenic variants under their care. ConclusionThose results highlight the urgency of implementing hearing gene panel sequencing for all children with ANSD to provide opportunities for early diagnosis and candidacy for OTOF gene therapy trials.

Auditory Neuropathy Spectrum Disorder in Individuals with Sickle Cell Anemia: Case Study.

The present study attempted to understand the association between Auditory neuropathy spectrum disorder (ANSD) and Sickle cell anemia (SCA) and to recognize possible causative factors for the presence of ANSD in SCA individuals. Two cases, 24 years male and 17years female with a laboratory-confirmed diagnosis of Sickle cell anemia underwent detailed audiological evaluation i.e., pure tone audiometry, speech audiometry, immittance audiometry, otoacoustic emission, and auditory brainstem responses. Audiological evaluation revealed a bilateral moderate low-frequency sensorineural hearing loss in male and bilateral moderately severe sensorineural Hearing loss in female case with elevated Speech Recognition Threshold and poor Speech Identification Scores. 'A' type tympanogram with the absence of Acoustic reflexes and the presence of Otoacoustic emission with no distinct and reproducible peak V in Auditory Brainstem Response (ABR) at 90 dBnHL with the presence of ringing cochlear microphonics on polarity reversal collectively indicating bilateral ANSD in both cases. ANSD and SCA are reported to have a genetic basis of etiology. There might be possibilities that one genetic condition may be common in manifesting both conditions or one genetic condition can cause the presence of another genetic condition or can exaggerate the evolution of another genetic condition. Also, abnormal ABR findings indicate the possibility of neuropathological involvement in isolation or in combination with genetic abnormalities that need detailed investigation to understand non-genetic causative factors. Thus, paved the path for further research in this line and might provide better rehabilitative options.

Outcomes of Cochlear Implant Recipient With ANSD: Intra and Post Operative Findings, Progress in Audition and Speech Skills.

Auditory neuropathy spectrum disorder (ANSD) is a distinct type of SNHL that is characterized by the presence of otoacoustic emissions and/or cochlear microphonics. Cochlear implantation was initially not recommended for ANSD children, later studies showed variable outcomes among ANSD. CI is currently the intervention option of choice for many children with ANSD who are unable to obtain benefit from conventional amplification. To review experiences with some of the preoperative and postoperative findings in a child who was diagnosed with auditory neuropathy and provided with cochlear implant. To describe changes in auditory function, which enabled to have significant improvement in hearing and communication skills through auditory verbal therapy (AVT) and regular follow ups. Pre and postoperative, findings in cochlear implant recipient who was diagnosed with ANSD. Child received complete medical examinations, including related consultations in audiology, otorhinolaryngology, paediatrics, neurology, psychology, speech language pathology, and radiology. A 3-year-old-female have brought to the hospital with a C/o not responding to sounds, name call and unable to speak. Medical and Audiological evaluations were initiated. The hearing assessments of thechild included appropriate behavioural audiometric techniques, objective measures of middle ear function, acoustic reflex studies, transient evoked (TEOAE), distortion product (DPOAE) otoacoustic emissions and auditory brainstem responses (ABR). Implanted with (HiRes Ultra CI HiFocus SlimJ Electrode), and objective measures were recorded intraoperatively electrode impedances and neural response telemetry (NRT) to assess the outcomes technically. These intraoperative objective measures were used to help program the speech processor for the child. Postoperatively, child has had regular follow-up with otorhinolaryngologist to assure complete healing of the surgical incision, to assess their general medical conditions, and audiologist for switch-on (speech processor) followed by mapping. The hearing and communication skills have been assessed, also continued Auditory Verbal Therapy (AVT) on a regular basis. Postoperatively, objective measures were recorded in regular intervals and monitored with therapy outcomes. The child has shown significant improvement in sound detection, speech perception abilities, communication skills and shown evidence of progression of good NRT results, which were recorded and had no postoperative complications. Experience with cochlear implantation for child diagnosed with ANSD that effectively received and benefited from CI. A detailed and careful evaluations, audiological follow-ups and tailored rehabilitation plans, can be considered as a beneficial management approach for CI, especially who diagnosed with ANSD. The regular use of cochlear implant in this diagnosis can lead to a clear increase in speech comprehension, development and overall progress in quality of life. Success or lack of success with a CI appears to be somewhat dependent on the specific site of lesion (pre- or post-synaptic). Currently there are no clinical measures available to diagnose the specific site of lesion. Indeed, CI appears to be an effective rehabilitation modality for ANSD patients. This may be explained by the fact that the implanted electrode delivers synchronized electrical impulses directly to the auditory nerve, bypassing the presynaptic IHCs and its synapse involved in the unsynchronized firing of the auditory nerve described in ANSD. However, genetic studies that have proven to be essential in the knowledge of underlying mechanisms of ANSD represent a promising therapeutic approach in the management of ANSD.

Predicting the Impact of OTOF Gene Missense Variants on Auditory Neuropathy Spectrum Disorder.

Auditory neuropathy spectrum disorder (ANSD) associated with mutations of the OTOF gene is one of the common types of sensorineural hearing loss of a hereditary nature. Due to its high genetic heterogeneity, ANSD is considered one of the most difficult hearing disorders to diagnose. The dataset from 270 known annotated single amino acid substitutions (SAV) related to ANSD was created. It was used to estimate the accuracy of pathogenicity prediction using the known (from dbNSFP4.4) method and a new one. The new method (ConStruct) for the creation of the protein-centric classification model is based on the use of Random Forest for the analysis of missense variants in exons of the OTOF gene. A system of predictor variables was developed based on the modern understanding of the structure and function of the otoferlin protein and reflecting the location of changes in the tertiary structure of the protein due to mutations in the OTOF gene. The conservation values of nucleotide substitutions in genomes of 100 vertebrates and 30 primates were also used as variables. The average prediction of balanced accuracy and the AUC value calculated by the 5-fold cross-validation procedure were 0.866 and 0.903, respectively. The model shows good results for interpreting data from the targeted sequencing of the OTOF gene and can be implemented as an auxiliary tool for the diagnosis of ANSD in the early stages of ontogenesis. The created model, together with the results of the pathogenicity prediction of SAVs via other known accurate methods, were used for the evaluation of a manually created set of 1302 VUS related to ANSD. Based on the analysis of predicted results, 16 SAVs were selected as the new most probable pathogenic variants.

Cortical Auditory Evoked Potential Testing in Children With Auditory Neuropathy Spectrum Disorder.

In the present report, we reviewed the role of cortical auditory evoked potentials (CAEPs) as an objective measure during the evaluation and management process in children with auditory neuropathy spectrum disorder (ANSD). We reviewed the results of CAEP recordings in 66 patients with ANSD aged between 2 months and 12 years and assessed the relationship between their characteristics (prevalence, morphology, latencies, and amplitudes) and various clinical features, including the mode of medical management. Overall, the CAEPs were present in 85.2% of the ears tested. Factors such as prematurity, medical complexity, neuronal issues, or presence of syndromes did not have an effect on the presence or absence of CAEPs. CAEP latencies were significantly shorter in ears with cochlear nerve deficiency than in ears with a normal caliber nerve. Three different patterns of CAEP responses were observed in patients with bilateral ANSD and present cochlear nerves: (a) responses with normal morphology and presence of both P1-P2complex and N2 components, (b) responses with abnormal morphology and presence of the N2 component but undefined P1-P2complex peak, and (c) entirely absent responses. None of the patients with normal, mild, or moderate degree of hearing loss had a complete absence of CAEP responses. No significant differences were uncovered when comparing the latencies across unaided and aided children and children who later received cochlear implants. The CAEP protocol used in our ANSD program did inform about the presence or absence of central auditory stimulation. Absent responses typically fit into an overall picture of complete auditory deprivation and all of these children were ultimately offered cochlear implants after failing to develop oral language. Present responses, on the other hand, were acknowledged as a sign of some degree of auditory stimulation but always interpreted with caution given that prognostic implications remain unclear.

Cochlear Implantation in Children with Auditory Neuropathy: Meta-Analysis

Plain Language SummaryAuditory neuropathy (AN) is associated with fluctuations in rates of speech discrimination. With respect to treatment, we have variable results in the literature about development of speech perception and skills, in children with AN and cochlear implant (CI) rehabilitation. To compare their results with sensorineural hearing loss children due to other causes was the objective of this study, which was performed a systematic literature review with meta-analysis that shown there was no evidence allowing the conclusion that the two groups were different from each other about results in speech performance after 1 year of CI placement. So, this study demonstrated that CI provides the comparable benefit to children with auditory neuropathy spectrum disorder in comparison to children with neurosensory hearing loss associated with other causes in their speech development.

NADH improves AIF dimerization and inhibits apoptosis in iPSCs-derived neurons from patients with auditory neuropathy spectrum disorder

Auditory neuropathy spectrum disorder (ANSD) is a hearing impairment involving disruptions to inner hair cells (IHCs), ribbon synapses, spiral ganglion neurons (SGNs), and/or the auditory nerve itself. The outcomes of cochlear implants (CI) for ANSD are variable and dependent on the location of lesion sites. Discovering a potential therapeutic agent for ANSD remains an urgent requirement. Here, 293T stable transfection cell lines and patient induced pluripotent stem cells (iPSCs)-derived auditory neurons carrying the apoptosis inducing factor (AIF) p.R422Q variant were used to pursue a therapeutic regent for ANSD. Nicotinamide adenine dinucleotide (NADH) is a main electron donor in the electron transport chain (ETC). In 293T stable transfection cells with the p.R422Q variant, NADH treatment improved AIF dimerization, rescued mitochondrial dysfunctions, and decreased cell apoptosis. The effects of NADH were further confirmed in patient iPSCs-derived neurons. The relative level of AIF dimers was increased to 150.7 % (P = 0.026) from 59.2 % in patient-neurons upon NADH treatment. Such increased AIF dimerization promoted the mitochondrial import of coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4), which further restored mitochondrial functions. Similarly, the content of mitochondrial calcium (mCa2+) was downregulated from 136.7 % to 102.3 % (P = 0.0024) in patient-neurons upon NADH treatment. Such decreased mCa2+ levels inhibited calpain activity, ultimately reducing the percentage of apoptotic cells from 30.5 % to 21.1 % (P = 0.021). We also compared the therapeutic effects of gene correction and NADH treatment on hereditary ANSD. NADH treatment had comparable restorative effects on functions of ANSD patient-specific cells to that of gene correction. Our findings offer evidence of the molecular mechanisms of ANSD and introduce NADH as a potential therapeutic agent for ANSD therapy.