Auditory Neuropathy Spectrum Disorder Research Articles

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.

Case Report: Transient Auditory Neuropathy (TAN) with resurgence of electrophysiologic waveforms observed between the neonatal period and age 3 years

Auditory neuropathy spectrum disorder (ANSD) is a spectrum of conditions marked by diminished auditory function and believed to be caused by the impaired neural transmission of auditory stimulation in the setting of functional outer hair cells (Rance1). There are reports of “spontaneously resolving” or “transient” ANSD (TAN) in the literature. In this case report of TAN, we demonstrate the resurgence of the ABR waveform morphology over a 3-year period to reveal electrophysiologic testing consistent with the subject’s functional hearing level by age 3 years.

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

Background: Auditory neuropathy (AN) is a nosological entity of unknown etiology, which is associated with fluctuations in rates of speech discrimination. Its diagnosis is based on presence of otoacoustic emissions and lack of, or abnormal, brainstem auditory evoked potential. 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. Objectives: Comparatively assessing results recorded for the development of auditory and speech skills in children with auditory neuropathy spectrum disorder (ANSD), who were subjected to cochlear implantation, in comparison to results recorded for children with sensorineural hearing loss associated with other causes was the objective of this study. Method: A systematic literature review with meta-analysis was performed, with studies published from 1975 to 2023. Results: Nineteen studies were included in the systematic review, and eight were selected for the meta-analysis, which showed 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. Conclusion: Therefore, this study shows that CI provides the comparable benefit to children with ANSD 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.

Indicators for cochlear implantation in children with auditory neuropathy spectrum disorder: A systematic review.

ANSD refers to a group of auditory diseases demonstrating intact outer hair cells and desynchronized neural firings of the auditory nerve. A cochlear implant is a promising intervention strategy for severe to profound sensorineural hearing loss (SNHL). However, due to its variable outcomes in children with ANSD, a consensus has yet to be reached on its performance. This study aimed to review the literature to determine the efficacy of cochlear implants in children with ANSD and to determine prognostic indicators. The study identifies the pre-operative and post-operative predictors of success for CI in children with ANSD. The review was carried out using PRISMA guidelines. This resulted in 9630 topic-related articles. Among these, 17 articles met the inclusion and exclusion criteria that were included for the study. The quality and potential risks associated with each article were evaluated using the quality impact assessment protocol (QUIPS) tool. A review of 17 articles was conducted to highlight these predictors. Most selected studies included case reports, case series, cohorts, and comparisons between children with ANSD and SNHL. Assessment of study quality reported an overall low risk of bias. The overall result showed cochlear implant would be an effective option for children with ANSD. However, there are specific prognostic indicators about which clinician needs to be aware before recommending CI for children with ANSD. Our review study identified a set of pre-operative and post-operative indicators that predicted speech and auditory performance and gave some insight into the lesion site in ANSD individuals. This review concludes CI is an effective option for children with ANSD. However, before recommending CI, a detailed assessment is required from different perspectives, which could serve as predictors of postoperative outcomes. This review highlights the need to include more precise tools, such as genetic testing to describe the lesion site to choose the most appropriate management strategy for children with ANSD. Knowledge about the prognostic indicators and the effective assessment protocols would help clinicians for the better candidacy selection.

Impact of Prematurity on Auditory Processing in Children.

Prematurity is one of the most crucial risk factors negatively affecting the maturation of the auditory system. Children born preterm demonstrate high rates of hearing impairments. Auditory processing difficulties in preterm children might be a result of disturbances in the central auditory system development and/or sensory deprivation due to peripheral hearing loss. To investigate auditory processing in preterm children, we utilized a set of psychoacoustic tests to assess temporal processing and speech intelligibility. A total of 241 children aged 6-11 years old (136 born preterm and 105 healthy full-term children forming the control group) were assessed. The preterm children were divided into three groups based on their peripheral hearing status: 74 normal hearing (NH group); 30 children with bilateral permanent sensorineural hearing loss (SNHL group) and 32 children with bilateral auditory neuropathy spectrum disorder (ANSD group). The results showed significantly worse performance in all tests in premature children compared with full-term children. NH and SNHL groups showed significant age-related improvement in speech recognition thresholds in noise that might signify a "bottom-up" auditory processing maturation effect. Overall, all premature children had signs of auditory processing disorders of varying degrees. Analyzing and understanding the auditory processing specificity in preterm children can positively contribute to the more effective implementation of rehabilitation programs.

Duration of Cochlear Microphonics in Click and Toneburst-Evoked Auditory Brainstem Response in Individuals With Auditory Neuropathy Spectrum Disorder and Normal Hearing.

The presence of ringing cochlear microphonics (CM) with an absence of auditory brainstem response (ABR) is an indicator of auditory neuropathy spectrum disorder (ANSD). The duration of CM may vary based on the stimuli used to elicit the response. Generally, ABR is recorded using clicks with very limited use of tonebursts. Thus, this study aims to understand the duration of CM in individuals with ANSD and normal hearing in response to clicks, 500 Hz toneburst, and 4000 Hz toneburst using ABR. Results show that individuals with ANSD have a longer duration of CM than those with normal hearing. The presence of CM was more evident in response to toneburst stimuli than clicks, with 500 Hz being commonly eliciting more CM in both groups. The difference in duration of CM was statistically significant in individuals with ANSD with longer duration obtained for 500 Hz followed by clicks and 4000 Hz toneburst. The duration of the stimuli used plays an important role in revealing the CM while recording ABR. This indicates that the use of toneburst, particularly low frequency such as 500 Hz, will be clinically useful in identifying ANSD especially when otoacoustic emissions are compromised.

The natural history, clinical outcomes, and genotype-phenotype relationship of otoferlin-related hearing loss: a systematic, quantitative literature review.

Congenital hearing loss affects one in 500 newborns. Sequence variations in OTOF, which encodes the calcium-binding protein otoferlin, are responsible for 1-8% of congenital, nonsyndromic hearing loss and are the leading cause of auditory neuropathy spectrum disorders. The natural history of otoferlin-related hearing loss, the relationship between OTOF genotype and hearing loss phenotype, and the outcomes of clinical practices in patients with this genetic disorder are incompletely understood because most analyses have reported on small numbers of cases with homogeneous OTOF genotypes. Here, we present the first systematic, quantitative literature review of otoferlin-related hearing loss, which analyzes patient-specific data from 422 individuals across 61 publications. While most patients display a typical phenotype of severe-to-profound hearing loss with prelingual onset, 10-15% of patients display atypical phenotypes, including mild-to-moderate, progressive, and temperature-sensitive hearing loss. Patients' phenotypic presentations appear to depend on their specific genotypes. For example, non-truncating variants located in and immediately downstream of the C2E calcium-binding domain are more likely to produce atypical phenotypes. Additionally, the prevalence of certain sequence variants and their associated phenotypes varies between populations due to evolutionary founder effects. Our analyses also suggest otoacoustic emissions are less common in older patients and those with two truncating OTOF variants. Critically, our review has implications for the application and limitations of clinical practices, including newborn hearing screenings, hearing aid trials, cochlear implants, and upcoming gene therapy clinical trials. We conclude by discussing the limitations of available research and recommendations for future studies on this genetic cause of hearing loss.

An Umbrella Review of Cochlear Implant Outcomes in Children With Auditory Neuropathy.

The objective of this overview of systematic reviews (SRs; umbrella review) was to systematically summarize and critically appraise current evidence of cochlear implant (CI) outcomes in children with auditory neuropathy spectrum disorder (ANSD). This study was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement. The methodological quality and the risk of bias in the included SRs were assessed using A MeaSurement Tool to Assess systematic Reviews 2 checklist and the Risk of Bias in Systematic Reviews tool, respectively. According to eight included SRs, children with ANSD achieve CI outcomes (speech perception performance) similar to their peers with sensorineural hearing loss. In children with postsynaptic ANSD (cochlear nerve deficiency), cochlear nerve hypoplasia is associated with better speech recognition outcomes compared with cochlear nerve aplasia, especially in the absence of additional disabilities. Except for one study, the overall quality of the included SRs was critically low, and except for three studies, evidence of a high risk of bias was identified in other included SRs. Current evidence supports CI benefits for children with ANSD. To improve the quality of evidence, well-designed, prospective studies with appropriate sample sizes, using valid outcome measures, clarifying matching criteria, and taking into account the role of confounding factors are essential.

Language and health-related quality of life outcomes of children early-detected with unilateral and mild bilateral hearing loss.

We aimed to describe the language and health-related quality of life (HRQoL) outcomes of children early-identified with unilateral or mild bilateral permanent hearing loss. This was a cross-sectional community-based study of children with mild bilateral or unilateral permanent hearing loss (including unilateral auditory neuropathy spectrum disorder (ANSD)), drawn from a population-based databank in Victoria, Australia. Enrolment in this databank is independent of early intervention and amplification approaches. Language and caregiver-reported HRQoL outcomes are described by type and degree of loss at three timepoints across child development: at age 2 years (n = 255), 5-7 years (n = 173) and 9-12 years (n = 45). Across all age groups, average language outcomes were poorer than population normative scores by between a half to two thirds of a standard deviation. Children with mild bilateral hearing loss demonstrated poorer average language outcomes than children with unilateral hearing loss, particularly at younger ages. Children with unilateral ANSD showed language outcomes comparable to their peers with unilateral profound hearing loss. Children had poorer HRQoL psychosocial scores compared to physical scores, without obvious patterns of outcomes linked to degree or type of hearing loss. This study demonstrates children with early-identified unilateral or mild bilateral hearing loss have average language and HRQoL outcomes poorer than population normative expectations from an early age. These outcomes are observed at later ages across childhood. These findings provide a contemporary description of language and quality of life outcomes for children identified but not targeted by universal newborn hearing screening and raise questions of how to provide better support for these populations of children and their families.

Aided Performance in Individuals with Late-Onset Auditory Neuropathy Spectrum Disorder (ANSD) - A Pilot Study

Aided Performance in Individuals with Late-Onset Auditory Neuropathy Spectrum Disorder (ANSD) - A Pilot Study

Short-term outcomes of infants with hyperbilirubinemia-associated auditory neuropathy spectrum disorder in neonatal intensive care unit

Hyperbilirubinemia is a high-risk factor for auditory neuropathy spectrum disorder (ANSD) as well as hearing loss in general. This study described the outcomes of hyperbilirubinemia-associated ANSD infants diagnosed in hearing screening in the neonatal intensive care unit (NICU).A total of 578 children with hyperbilirubinemia admitted to the NICU between October 2020 and October 2021 were included in this study. The distortion product otoacoustic emission (DPOAE) and automatic auditory brainstem response (AABR) were combined for hearing screening, and those who failed the DPOAE or/and AABR underwent an auditory brainstem response (ABR) test. Infants with ANSD were followed up for 12 months.Forty infants (40/578, 6.9%) failed the DPOAE or/and AABR tests, of which, 13 (13/578, 2.2%) were diagnosed as ANSD, and 27 (27/578, 4.7%) were diagnosed as having sensorineural hearing loss (SNHL). Of the 13 ANSD infants followed up for 12 months, 7 recovered, 3 improved, 3 did not recover, and 1 was lost, equating to improved or recovered hearing in 75% (9/12) of ANSD infants at 12 months of age. Moreover, the maximum bilirubin in recovered or improved ANSD infants was 408.6 ± 129.0 μmol/L, while the maximum bilirubin in unrecovered ANSD infants was 749.3 ± 323.0 μmol/L. Furthermore, poorly differentiated and absent ABR waveforms were observed in 6 and 14 ears at 1 month, 2 ears were lost, 6 (6/6, 100.0%) and 6 (6/12, 50.0%) ears were recovered or improved at 12 months of age.s: The incidence of hyperbilirubinemia associated-ANSD was 2.2% of infants screened in the NICU. ANSD caused by hyperbilirubinemia may be transient, with most infants improving or recovering hearing by 12 months of age. Infants with poorly differentiated ABR waveforms and low bilirubin concentration are more likely to recover and hearing aids are not recommended in hyperbilirubinemia-associated ANSD below 12 months of age.

Intracochlear electrocochleography findings in cochlear implant recipients with auditory neuropathy spectrum disorder.

This study aimed to compare intracochlear electrocochleography (ECochG) findings in a group of cochlear implant (CI) recipients with auditory neuropathy spectrum disorder (ANSD) with a group of CI recipients with sensorineural hearing loss (SNHL). Auditory outcome and spectral resolution findings were also compared among CI recipients with and without cochlear microphonic (CM) responses. This single-center, prospective cohort study was undertaken at a tertiary referral center. CM responses by the intracochlear ECochG test were recorded in CI recipients at 0.25-2kHz. Speech, spatial, and hearing quality (SSQ) outcomes and spectral resolution measured with the spectral-temporally modulated ripple test were obtained for each recipient. The study included 62 implanted ears in 46 recipients, of which 59% (n=27) were male and 41% (n=19) were female. Twenty-nine ears with ANSD and 33 ears with SNHL were included. The mean age of the participants was 11 years. The results compared the intracochlear ECochG findings of the ANSD group with those of the SNHL group. Participants were divided into two groups with and without obtainable CM responses. CM responses were obtained in 13 of 29 ears in the ANSD group and 14 of 33 ears in the SNHL group. CM thresholds obtained were better according to behavioral audiometric responses in some frequencies in the ANSD group. No significant difference was found in the auditory outcome and spectral resolution among CI recipients with and without CM responses. Intracochlear ECochG has a limited potential clinical value for monitoring ANSD. CM thresholds obtained using ECochG may not reflect behavioral hearing thresholds.

Impaired AIF-CHCHD4 interaction and mitochondrial calcium overload contribute to auditory neuropathy spectrum disorder in patient-iPSC-derived neurons with AIFM1 variant

Auditory neuropathy spectrum disorder (ANSD) is a hearing impairment caused by dysfunction of inner hair cells, ribbon synapses, spiral ganglion neurons and/or the auditory nerve itself. Approximately 1/7000 newborns have abnormal auditory nerve function, accounting for 10%-14% of cases of permanent hearing loss in children. Although we previously identified the AIFM1 c.1265 G > A variant to be associated with ANSD, the mechanism by which ANSD is associated with AIFM1 is poorly understood. We generated induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells (PBMCs) via nucleofection with episomal plasmids. The patient-specific iPSCs were edited via CRISPR/Cas9 technology to generate gene-corrected isogenic iPSCs. These iPSCs were further differentiated into neurons via neural stem cells (NSCs). The pathogenic mechanism was explored in these neurons. In patient cells (PBMCs, iPSCs, and neurons), the AIFM1 c.1265 G > A variant caused a novel splicing variant (c.1267-1305del), resulting in AIF p.R422Q and p.423-435del proteins, which impaired AIF dimerization. Such impaired AIF dimerization then weakened the interaction between AIF and coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4). On the one hand, the mitochondrial import of ETC complex subunits was inhibited, subsequently leading to an increased ADP/ATP ratio and elevated ROS levels. On the other hand, MICU1-MICU2 heterodimerization was impaired, leading to mCa2+ overload. Calpain was activated by mCa2+ and subsequently cleaved AIF for its translocation into the nucleus, ultimately resulting in caspase-independent apoptosis. Interestingly, correction of the AIFM1 variant significantly restored the structure and function of AIF, further improving the physiological state of patient-specific iPSC-derived neurons. This study demonstrates that the AIFM1 variant is one of the molecular bases of ANSD. Mitochondrial dysfunction, especially mCa2+ overload, plays a prominent role in ANSD associated with AIFM1. Our findings help elucidate the mechanism of ANSD and may lead to the provision of novel therapies.

Diagnóstico precoce de Neuropatia Auditiva em crianças: uma revisão sistemática

Introduction: Auditory Neuropathy Spectrum Disorder (ANSD) is characterized by normal cochlear function and abnormal neural function. Diagnosis must be performed early, so that rehabilitation is adequate and minimizes the negative consequences. Objectives: exhibit the procedures used for the early diagnosis of ANSD in children by developing a protocol, highlighting the importance of conducting studies on the incidence of ANSD and raising awareness among health professionals. Methods: systematic literature review. The electronic databases PubMed and Web of Science were used, applying the boolean operators "AND" and "NOT", with the terms, "Auditory Neuropathy", "diagnosis", "children", "hearing aids" and "cochlear implantation”. Results: 41 studies were analyzed after applying the inclusion/exclusion criteria, dating from 2015-2021. The USA is the country with the highest number of articles published. Discussion: The diagnosis of ANSD is made through otoacoustic emissions, cochlear microphonics and auditory brainstem response. This must be carried out in the first six months of life, and it is necessary to identify the possible etiology. Conclusion: the proposed objectives were achieved, namely the elaboration of the protocol. However it’s necessary to carry out studies on the incidence of ANSD in Portugal, as well as raising awareness among health professionals to this pathology.