Introduction: OAE & ABR are screening tests used for newborn screening. The main objective of the study is to determine the incidence of positivity of ABR in newborns detected to have “Refer” in DPOAE in UNHS(Universal Newborn Hearing Screening). Materials & Methods: A prospective observational study was conducted at a tertiary care center over a period of one year from Jan 2020 to July 2021. All neonates will be screened by DPOAE between day 1 to day 28 (first visit). If it is reported ‘Refer’, DPOAE will be repeated either after 6 weeks or on the first immunization day (second visit). If it is again reported as ‘Refer’, the neonate will undergo ABR (third visit). The results were recorded & compiled. The data was analysed statistically using SPSS software (version 20). Results: Out of the 409 neonates, 315 (77.0%) were reported as “Pass” and 94 (23.0%) were reported as “Refer” during DPOAE first visit. The neonates (94) with test result “Refer” in DPOAE 1 (first visit) were considered for DPOAE 2 (second visit) & 77 (83.0%) were reported as “Pass” and 17(17.0%) were reported as “Refer”. The 16 infants who underwent Diagnostic ABR, 6 (37.5%) were reported as “Normal” whereas 10(62.5%) were reported as “Abnormal” group. Conclusion: This study recommends universal screening with OAE & ABR to facilitate early detection of auditory neuropathy and to initiate aural rehabilitation, especially in high-risk groups such as NICU & preterm neonates Keywords: OAE(Otoacoustic emissions), ABR (Auditory Brainstem Response) , UNHS(Universal Newborn Hearing Screening).

This study aims to compare the language and memory skills of cochlear implant (CI) users with and without auditory neuropathy spectrum disorder (ANSD). Cross-sectional, comparative observational study. Tertiary referral center. Twenty-six children with CIs participated in the study. The study group consisted of 11 children diagnosed with ANSD, while the control group included 15 children without ANSD. Language skills were evaluated using the Test of Language Development-Primary: Fourth Edition (TOLD-P:4), and memory abilities were assessed using the Working Memory Scale (WMS). No statistically significant differences were found between the groups in listening [median (range): 64 (55 to 91) vs 76 (55 to 121), P = 0.27], organizing [58 (55 to 88) vs 73 (55 to 94), P = 0.68], speaking [58 (55 to -97) vs 79 (55 to 127), P = 0.16], grammar [65 (55 to 91) vs 82 (55 to 112), P = 0.12], semantics [61 (55 to 97) vs 80 (55 to 115), P = 0.15], and oral language [59 (55 to 88) vs 78 (55 to 115), P = 0.12] index scores. Similarly, verbal memory standard scores did not differ significantly between the groups [median (range): 332 (247 to 571) vs 417 (228 to 808), P = 0.10]. Children with ANSD who use CIs demonstrate language and memory abilities comparable to those of CI users without ANSD. These findings suggest that despite the auditory processing challenges associated with ANSD, cochlear implantation effectively supports the development of language and memory skills.

We report a term infant presenting in early infancy with progressive developmental delay, feeding difficulties, recurrent seizures and failure to thrive. The infant initially exhibited symptoms from early neonatal age, including vomiting, lethargy and seizures, necessitating multiple hospitalisations. Progressive neurological deterioration, hepatomegaly, bilateral nephromegaly, hypothyroidism, gastro-oesophageal reflux disease and auditory neuropathy were noted. MRI showed cerebral atrophy and dilated ventricles. Extensive investigations ruled out infections, metabolic acidosis and structural brain malformations. Whole exome sequencing identified a homozygous missense mutation in the mannosyl-oligosaccharide glucosidase (MOGS) gene (c.2090T>C; p.Leu697Ser), previously reported in MOGS CDG (congenital disorder of glycosylation type IIb). A mannose-based diet led to partial improvement. This case highlights the importance of considering neurometabolic conditions such as CDG in infants with early-onset developmental and epileptic encephalopathy and multisystem involvement. Early diagnosis and supportive multidisciplinary care are vital for improving outcomes and guiding family counselling.

BackgroundAuditory neuropathy (AN) represents a clinical manifestation of OPA1-related diseases. The diagnostic process of these diseases is challenging owing to the broad spectrum of intermediate phenotypes and diverse inherited patterns. The aim of this study was to comprehensively delineate the feature of OPA1-related patients in a Chinese AN cohort, encompassing the incident rate, inherited pattern, detailed audiological characteristics, and genotype-phenotype correlation.MethodsBetween 2003 and 2020, 452 unrelated probands with a diagnosis of AN were referred to our laboratory for molecular genetic investigation with high-throughput sequencing. Sanger sequencing was performed on the probands and their parents to verify the genetic results. Patients diagnosed as AN by clinical evaluation, auditory brainstem responses, otoacoustic emission and/or cochlear microphonic. Comprehensive auditory evaluations were conducted on OPA1-related patients, and some of them were performed a follow-up study.ResultsWe identified seven probands (1.55%, 7/452) with OPA1 variants in seven unrelated families, demonstrating distinct genetic patterns, including one family with rare autosomal recessive (AR) inheritance, six families with autosomal dominant (AD) inheritance (three were AD de novo). The AN phenotype was observed in all patients prior to the second decade of life, with AN serving as the initial presenting symptom in two patients. Additionally, probands with the rare AR inheritance exhibited a more severe phenotype. A total of eight OPA1 variants were identified, including a novel variant c.2013 + 5G > C. The GTPase domain of OPA1 exclusively harbored missense variants, and 85.71% (6/7) of the patients carried one of missense variants in OPA1. The observed phenotypes exhibited a broad spectrum of manifestations, encompassing vestibular dysfunction and developmental delay, with varying degrees of hearing loss. Among the seven patients, four exhibited severe to profound hearing loss. The annual rates of hearing loss at the frequencies of speech were 2.74 dB/year for one patient, who underwent a 10-year-old follow-up.ConclusionOur results indicated the distinct genetic patterns and variable phenotypic characteristics of OPA1-related AN in the Chinese population. The audiological features of OPA1-related patients were comprehensively described as exhibiting AN. We identified one novel splicing variants that expand the genetic spectrum of OPA1 variants in AN.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13023-025-04040-4.

Abstract Auditory neuropathy spectrum disorder (ANSD) presents unique challenges in audiology, particularly when occurring postlingually. This case study focuses on a 20-year-old male with postlingual ANSD who underwent bilateral cochlear implantation (CI) after experiencing progressive hearing loss. Despite significant advancements in CI technology, outcomes for ANSD patients, particularly in speech perception, remain inconsistent. This study aims to evaluate the effectiveness of CI in improving auditory performance and speech perception in postlingual ANSD patient, addressing a gap in existing research where adult outcomes are less well-documented compared to children. Our methodology includes a detailed analysis of the patient’s auditory and speech outcomes pre- and postimplantation, supplemented by clinical assessments, audiological testing, and rehabilitation progress. The results showed that while the patient experienced improved hearing thresholds, his speech perception remained poor, consistent with neural desynchronization associated with ANSD. In addition, the study highlights the emotional and social benefits of CI, despite the limited improvement in speech understanding. These findings contribute to the field by emphasizing the need for personalized treatment approaches in managing postlingual ANSD, as outcomes vary widely based on individual factors, including neural integrity and the extent of auditory nerve involvement.

Recessive variants in TWNK cause syndromes arising from mitochondrial DNA (mtDNA) depletion. Hearing loss is the most prevalent manifestation in individuals with these disorders. However, the clinical and pathophysiological features have not been fully elucidated. In this study, we collected five cases of hearing loss carrying bi-allelic TWNK variants from three unrelated Chinese families and identified two cases with isolated auditory neuropathy (AN) and three cases segregating with Perrault syndrome, characterized by AN, global developmental delay, and ovarian dysgenesis in females. All patients with cochlear implantation (CI) show poor speech discrimination outcomes, suggesting that the defect involves post-synaptic sites. In the mouse inner ear, Twinkle was immunolocalized to inner phalangeal cells and spiral ganglion neurons. Additionally, the broad expression pattern of Twinkle was observed in the auditory cortex, which to some extent explains the poor rehabilitation outcomes following CI. At the cellular level, Twinkle is localized at the mtDNA membrane, and the p.(Arg609AlaTer6) variant prevents the protein from reaching the mtDNA while the p.(Arg65Trp) variant exhibits a similar localization to the wild type, indicating a second mechanism of action. RT-PCR results indicated that the canonical transcript was abundant in the inner ear, while the shorter transcript was more abundant in the brain. Our findings revealed that bi-allelic TWNK variants lead to AN, which can be either syndromic or non-syndromic, with the molecular pathogenesis involving defects in mtDNA replication at post-synaptic sites. Patients with TWNK-associated conditions are not ideal candidates for CI and gene therapy may offer a solution for hearingrehabilitation.

The impact of transcranial ultrasound on auditory brainstem responses and neuronal activation in the cochlear nucleus.

Objective: The purpose of this study was to investigate the diagnostic value and clinical significance of cochlear microphonics (CM) combined with otoacoustic emission (OAE) in patients with auditory neuropathy (AN). Methods: The study included patients who were diagnosed with bilateral AN and had CM originating from both sides. The CM amplitude, latency, duration and intensity-amplitude (I/O) function curve were recorded by CM test. According to whether the distortion product otoacoustic emissions (DPOAE) passed through, the patients were divided into three groups: bilateral OAE passed group (OAEPP Group), bilateral OAE failed group (OAERR Group), and unilateral OAE passed through one side failed group (OAEPR Group). OAE was elicited by four or more frequencies of 750-8 000 Hz. The characteristics of CM and its related influencing factors were analyzed, and data were processed and analyzed by SPSS 26.0 software. Results: (1) A total of 256 patients (512 ears) with AN were enrolled, including 161 patients (322 ears) in OAEPP group, 32 patients (64 ears) in OAEPR group and 63 patients (126 ears) in OAERR group. OAE failed in 30.9% of patients with AN. (2) When the stimulation intensity was 100 dB nHL, the CM amplitude of OAE passing ear (OAEP+CMP group) in AN patients aged 3 years was 0.43±0.17μV, which was significantly higher than that of OAE not passing ear (OAER+CMP group) (0.29±0.15) μV (t=4.876，P<0.001). The CM duration of the OAEP+CMP group was (5.18±1.04) ms, which was longer than that of the OAER+CMP group at 4.60±1.12 ms (P=0.005). The I/O function curve of OAEP+CMP group showed a nonlinear trend, while, that of OAER+CMP group showed a linear trend. (3) In the OAEP+CMP group of AN patients, the amplitude of CM was negatively correlated with the onset age, test age, disease course, PTA, and ASSR threshold (P<0.001), with correlation coefficients of r=-0.475, r=-0.519, r=-0.367, r=-0.374, and r=-0.494, respectively. In the OAER+CMP group of AN patients, the amplitude of CM was negatively correlated with the onset age, test age, and ASSR threshold (P<0.05), with correlation coefficients of r=-0.271, r=-0.240, and r=-0.287, respectively. Conclusions: Excluding patients with high-frequency steeply sloping hearing loss, when ABR is absent or abnormal and OAE is absent, CM detection can reduce the rate of missed diagnosis of AN. The analysis of CM amplitude and I/O function curve is helpful to determine the lesion site of AN patients, which is convenient for early diagnosis and effective intervention.

Advances in molecular genetics and the development of new technologies for working with genes determine the beginning of a new era - gene therapy is becoming an important area of medicine, including audiology and otolaryngology. Today, the innovative therapeutic solutions for inner ear disorders have been developed and some gene therapy programs of the inner ear are already undergoing clinical trials. The purpose of our article is to show the current state of the gene therapy in the inner ear research, this most serious and complex area, located at the intersection of science and practice. To learn how to use new opportunities, it is necessary to raise awareness among doctors and patients about hereditary hearing loss. While clinical trial protocols are being improved, it is necessary to develop more reliable clinical diagnostic tools for the early detection of hereditary hearing loss and especially auditory neuropathy spectrum disorders.

Auditory neuropathy spectrum disorder and related auditory features in patients with hearing loss associated with the MT-TS1 m.7471dup variant.

Utility of auditory steady-state response in differentiating pediatric auditory neuropathy spectrum disorders: with normal auditory nerve diameter versus with auditory nerve hypoplasia.

Auditory neuropathy (AN) is a sensorineural hearing loss that impairs speech perception, but its mechanisms and treatments remain limited. Mic60, essential for the mitochondrial contact site and cristae organizing system, is linked to neurological disorders, yet its role in the auditory system remains unclear. We demonstrate that Mic60+/- mice develop progressive hearing loss from 6 months of age, with reduced auditory brainstem response amplitudes despite preserved outer hair cell function, consistent with AN. Mitochondrial abnormalities in spiral ganglion neurons (SGNs) emerge by 3 months, followed by mitochondrial loss and SGN degeneration, indicating progressive auditory neuron dysfunction. In vitro, Mic60 deficiency disrupts mitochondrial respiration, reversible by N-acetylcysteine (NAC). NAC treatment preserves mitochondrial integrity and rescues hearing by enhancing mitophagy. Our findings establish Mic60+/- mice as an AN animal model, highlight the role of Mic60 in the mitochondria of primary auditory neurons, and identify NAC as a potential AN treatment.

Objective:This study evaluated interpeak latency (IPL) and its inter-trial variability (VIL) of the electrically evoked compound action potential (eCAP) as potential alternatives to the phase-locking value (PLV) for quantifying cochlear nerve (CN) synchrony in cochlear implant (CI) users.Design:The IPL was assessed in postlingually deafened adults and three pediatric populations: children with auditory neuropathy spectrum disorder, cochlear nerve deficiency, and typical sensorineural hearing loss. VIL was evaluated only in adults. Their associations with temporal resolution and speech perception outcomes were evaluated. Frequency analysis was conducted to understand the impacts of eCAP recording noise on IPL, VIL, and PLV. Simulations of inter-trial jitter in the eCAP were performed to quantify how the IPL, VIL, and PLV metrics varied with increased temporal jitter.Results:eCAP traces recorded in all patient groups showed a multi-peak issue affecting the accuracy of IPL and VIL assessments. Temporal resolution and speech perception outcomes were significantly correlated with VIL but not with IPL metrics. The PLV was impacted less by recording noise than either the IPL or the VIL. Simulation results revealed that the IPL was less sensitive to the amount of inter-trial jitter in the eCAP than were the VIL and the PLV.Conclusions:The IPL is not a reliable indicator of CN synchrony. The VIL is indicative of neural synchrony in the CN but is affected more by the eCAP recording noise than the PLV. The PLV is therefore the preferred measure for quantifying neural synchrony in the CN in CI users.

Topographical Mapping of Cortical Responses to Speech Stimuli in Auditory Neuropathy Spectrum Disorder: Insights from 64-Channel EEG Recordings

Objective: The aim of this study is to analyze the clinical characteristics and genetic variants of a late-onset auditory neuropathy pedigree caused by maternally inherited- mitochondrial mutation. Methods: A male proband who presented with bilateral sensorineural hearing loss at Henan Children's Hospital in September 2023 was chosen, along with his family members (4 generations, 20 individuals) as the study subjects. Data from this pedigree were collected, organized, and analyzed for clinical genetic characteristics. Medical histories were obtained from family members, pedigree charts were drawn, audiological, imaging, and physical examinations were conducted. Pathogenic genes and mutations were screened using high-throughput sequencing. Sanger sequencing was employed for variant confirmation and segregation validation in the family. Results: In this family, a total of 12 members (10 members collected) had sensorineural hearing loss, characterized by late-onset hearing impairment with an onset age ranging from 9 to 30 years. The patients exhibited poor speech recognition rates, and audiometric examinations are consistent with auditory neuropathy. There was no history of ototoxic drug use. High-throughput sequencing identified the variant NC_012920.1:m.7471dup in the mitochondrial MT-TS1 gene as the pathogenic variant. Sanger sequencing results confirmed that the pathogenic gene mutation site perfectly co-segregated with the auditory neuropathy phenotype in this family. According to the classification criteria and guidelines for genetic variations by the American College of Medical Genetics and Genomics, the variant was classified as a pathogenic mutation. Conclusion: The mitochondrial MT-TS1 gene mutation m.7471dup is considered to be the pathogenic cause in this late-onset auditory neuropathy pedigree.

This study considered the impact of spectral and temporal smearing on vowel and consonant discrimination in school-age children and adults with normal hearing (NH). The overall purpose of this work was to test the hypothesis that degraded spectral cues preferentially impact vowel discrimination, while reduced access to temporal cues preferentially affects consonant discrimination. This work is a first step toward understanding how the effects of poor spectral and temporal resolution may affect phonological awareness and speech perception in children with cochlear hearing loss (C-HL) and auditory neuropathy (AN). Participants were 10 young adults and 18 school-age children with NH. Speech perception testing included vowel and consonant minimal pair discrimination for stimuli that were either unprocessed, spectrally smeared, or temporally smeared. All participants completed psychophysical estimates of spectral, temporal, and intensity resolution as well as standardized assessments of phonological awareness and receptive vocabulary. Psychophysical estimates of spectral, temporal, and intensity resolution for unprocessed stimuli were consistent with previous literature, including improvement in thresholds as a function of child age. As predicted for both age groups, spectral smearing had greater effects on vowel discrimination, while temporal smearing had greater effects on consonant discrimination with minimal pairs differentiated by either presence/absence of a stop consonant or voicing. All participants demonstrated normal, age-adjusted, phonological awareness, and receptive vocabulary skills. For both children and adults, degraded spectral and temporal cues differentially affected access to vowel and consonant information. These results suggest the need for further investigations evaluating the effects of long-term reductions in access to spectral and temporal cues in children with hearing loss. This topic is particularly relevant to hearing losses such as C-HL and AN, which are primarily characterized by reduced perception of spectral and temporal acoustic cues, respectively. https://doi.org/10.23641/asha.29660819.

This study aims to explore the presence of contralateral suppression of otoacoustic emissions (CS-OAEs) in unilateral cochlear implant (CI) users with auditory neuropathy spectrum disorder (ANSD). We enrolled three unilateral CI users with bilateral ANSD and stable otoacoustic emissions in the nonimplanted ear, exhibiting diverse postsynaptic ANSD backgrounds including cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndrome, Optic Atrophy Plus Syndrome, and Spinocerebellar Ataxia. Measurements of transient-evoked otoacoustic emissions (TEOAEs) were conducted both with and without contralateral electrical stimulation (CES) across five frequency bands. CES was delivered via a CI using a direct audio input cable connected to a computer. In order to elicit a response, broad-band noise is applied and presented at a comfortable level. Minor amplitude reductions (between 0.2 and 0.6 dB SPL) were observed in TEOAEs with CES across different frequencies for each subject. Despite these changes, there was no prominent suppression effect observed, which emphasizes the differences in CS-OAE responses among individuals with postsynaptic ANSD. The absence of significant CS-OAE suppression suggests that direct electrical stimulation through CES may not consistently engage the efferent auditory system in patients with postsynaptic ANSD characteristics. It is essential to broaden the study population to encompass a more diverse range of ANSD presentations in order to confirm the effectiveness of CES in stimulating efferent pathways.

Transmembrane protein 43 (TMEM43 or LUMA) encodes a highly conserved protein found in the nuclear and endoplasmic reticulum membranes of many cell types and the intercalated discs and adherens junctions of cardiac myocytes. TMEM43 is involved in facilitating intra/extracellular signal transduction to the nucleus via the linker of the nucleoskeleton and cytoskeleton complex. Genetic mutations may result in reduced TMEM43 expression and altered TMEM43 protein cellular localization, resulting in impaired cell polarization, intracellular force transmission, and cell-cell connections. The p.S358L mutation causes arrhythmogenic right ventricular cardiomyopathy type-5 and is associated with increased absorption of lipids, fatty acids, and cholesterol in the mouse small intestine, which may promote fibro-fatty replacement of cardiac myocytes. Mutations (p.E85K and p.I91V) have been identified in patients with Emery-Dreifuss Muscular Dystrophy-related myopathies. Other mutations also lead to auditory neuropathy spectrum disorder-associated hearing loss and have a negative association with cancer progression and tumor cell survival. This review explores the pathogenesis of TMEM43 mutation-associated diseases in humans, highlighting animal and in vitro studies that describe the molecular details of disease processes and clinical, histologic, and molecular manifestations. Additionally, we discuss TMEM43 expression-related conditions and how each disease may progress to severe and life-threatening states.

From cochlear microphonics to cortical silence: Audiological progression in auditory neuropathy spectrum disorder

BackgroundA novel in-frame insertion variant in the B-Cell Receptor-Associated Protein 31 (BCAP31) gene, which encodes a crucial ER membrane protein involved in the quality control and transport of transmembrane proteins, as well as in ER-mitochondria apoptotic signaling, was determined in a family demonstrating X-linked, recessive, nonsyndromic auditory neuropathy spectrum disorder (ANSD).MethodsExome sequencing analysiswas followed by bioinformatics analysis to identify the cause of hearing loss in a family whose pedigree indicated an X-linked recessive mode of inheritance. Immunohistochemistry was performed to locate Bcap31 in the mouse cochlea. Mitochondrial function was evaluated by measuring intracellular ATP, ROS and mitochondrial membrane potential in control and patient-derived lymphoblastoid cells (LCLs) before and after the administration of mitochondria isolated from human umbilical cord mesenchymal stem cells (UC-MSCs).ResultsANSD observed in our study is characterized by initial inner hair cell damage, followed by accelerated degeneration of cochlear outer hair cells. Functional studies of patient-derived LCLs revealed mitochondrial dysfunction, evidenced by increased ROS, reduced ATP levels, and decreased mitochondrial membrane potential compared with normal LCLs. Further, these cells demonstrated heightened sensitivity to cisplatin-induced apoptosis, as indicated by the increased proapoptotic gene expression. Notably, the administration of mitochondria isolated from umbilical cord mesenchymal stem cells significantly restored mitochondrial dysfunction and alleviated cisplatin-induced cytotoxicity in the patient-derived cells.ConclusionsThese results indicate BCAP31 dysfunction as a potential cause of transient ANSD, progressing to sensorineural hearing loss through mitochondrial impairment. Furthermore, they highlighted the therapeutic potential of allogenic mitochondrial transplantation as a novel strategy for treating hearing loss with an underlying component of mitochondrial dysfunction. This study contributes to the understanding of BCAP31’s role in auditory neuropathy and mitochondrial health.Graphical