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Objective: To explore the diverse molecular etiologies of postlingual auditory neuropathy spectrum disorder (ANSD) and report on the electrically evoked compound action potential (ECAP) thresholds and the outcome of cochlear implantation (CI)., Methods: Patients with late-onset, progressive hearing loss who went through molecular genetic testing were enrolled. Type of sensorineural hearing loss (SNHL) was classified as flat, reverse-slope, midfrequency, downsloping, or ski slope. We identified postlingual ANSD subjects through diagnostic tracts applied differently depending on the degree of SNHL. For CI recipients, individual ECAP thresholds, postoperative speech perception abilities, and the genetic cause were analyzed., Results: The detection rate of ANSD among patients with postlingual SNHL was 5.1% (15/293 probands). Diverse genetic etiologies were identified in 7 (46.6%) of the 15 postlingual ANSD subjects, the genetic cause being found exclusively in subjects with reverse-slope SNHL. The pattern of intraoperative ECAP responses was also diverse and showed some correlation with the genetic etiology. Despite the diverse molecular etiology and ECAP responses, CI in postlingual ANSD patients, including those with features involving the postsynaptic component, yielded significant improvements in speech understanding., Conclusions: This study proposes a differentiated diagnostic approach that focuses on both poor speech discrimination and reverse-slope hearing loss for the diagnosis of ANSD. Based on the improvement of speech understanding from all cochlear implantees with ANSD as well as the correlation between the genetic etiology and ECAP thresholds, we suggest that CI can significantly benefit ANSD subjects even those with unknown etiologies unless there is overt peripheral neuropathy., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2023, Otology & Neurotology, Inc.)

Purpose: A challenge for patients with ski-slope hearing loss is that hearing aids do not adequately amplify the mid-to-high frequencies necessary for speech perception and conversely, cochlear implant (CI) may damage low-frequency hearing. We aimed to describe the clinical profile of patients with ski-slope hearing loss, with a special focus on aetiology of such hearing loss and audiological course of low-frequency hearing after CI., Methods: We recruited hearing-impaired patients who visited a tertiary referral centre and met the criteria for ski-slope hearing loss patients from 2015 to 2021. Genetic testing was performed in all ski-slope hearing loss patients unless refused. Baseline audiograms of patients who continued to use hearing aids or who finally underwent CIs were reviewed. As for CI patients, outcome and hearing preservation rate were rigorously analysed., Results: Of 46 recruited patients with ski-slope hearing loss, 45 agreed to undergo genetic testing and causative variants were identified in 17 (37.8%) patients. The TMC1, MYO7A, and TMPRSS3 variants were the most common, while LRTOMT was newly identified as a causative gene. Twenty-five patients eventually received CI, while 13 continued to wear the hearing aid and 8 patients did not ever try hearing aids. CI in ski-slope hearing loss led to immediate and sufficient improvement of sentence recognition by as early as 3 months, however, the duration of hearing loss was inversely correlated with the sentence recognition score. The average hearing preservation rate (using the HEARRING classification) after CI was 53.0% (SD 30.0) and 45.6% (SD 31.1) at 1 year. Seventy-nine percent of implantees maintained functional low-frequency hearing (better than 85 dB at 250 and 500 Hz) eligible for electric-acoustic stimulation (EAS). A trend was found that patients with hair cell stereocilia-associated genetic variants may have a slightly better preservation, albeit with no statistical significance., Conclusion: Detection rate of a molecular genetic aetiology of ski-slope hearing loss appears to be lower than other type of hearing loss reported in the literature. Especially with short hearing loss duration, CI in ski-slope hearing loss leads to immediate and sufficient speech improvement, while preserving functional low-frequency hearing eligible for EAS as many as in 79%. A certain genetic aetiology might be associated with a trend towards better low-frequency hearing preservation., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

There are still debates about timing and effectiveness of cochlear implants (CI) in pediatric subjects with significant residual hearing who do not belong to traditional indication of CI. In this study, we aimed to investigate the outcomes of CI, specifically on improvement of pronunciation, among hearing-impaired children already with a substantial degree of language skills as evaluated by Categories of Auditory Perception (CAP) scores or sentence score. Our cohort comprised pediatric CI recipients from July 2018 through October 2020. Among them, cases with CAP scores of 5 or 6 preoperatively were defined as "borderline cases". We investigated prevalence and etiologies, and compared speech evaluation data preoperatively and postoperatively at three time points (3, 6 and 9-12 months after implantation). Among 86 pediatric CI recipients, 13 subjects (15.12%) had language development that reached CAP scores of 5 or 6 before implantation. Postoperative speech evaluation data 6 months after implantation revealed significant improvement of pronunciation (Urimal Test of Articulation and Phonation scores: UTAP), Infant-Toddler Meaningful Auditory Integration Scale (IT-MAIS) and word perception scores, but not of CAP and sentence perception scores. Notably, the significant improvement of pronunciation based on UTAP scores outstripped that of other speech parameters and this continued steadily up to one-year postoperatively. The result of the study serves as evidence for what to expect from cochlear implantation in hearing-impaired children who have already achieved a substantial degree of language development in terms of CAP scores or sentence perception scores, preoperatively., Competing Interests: The authors have declared that no competing interests exist.

The cortical auditory evoked potential (CAEP)-based P1 component acts as a biomarker for cochlear implantation (CI) outcomes in children with auditory neuropathy spectrum disorder (ANSD). To date, early intervention primarily before the age of two years and six months of CI usage is necessary and sufficient to achieve age-appropriate cortical maturation and good prognosis. However, varying degrees of neural dyssynchrony, resulting from the etiological heterogeneity of ANSD, may preclude uniform application of this hypothesis to ensure auditory cortical maturation. Thus, a focused evaluation of those carrying OTOF variants, which may be the salient molecular etiology of prelingual ANSD, would circumvent the issue of heterogeneity. Here, we sought to provide a much better understanding of the brain perspectives (i.e., P1 maturation) in OTOF-associated ANSD subjects and set the stage for an optimal strategy to enhance language development. We conducted a preliminary study comprising 10 subjects diagnosed with OTOF-related ANSD who underwent CI by a single surgeon and subsequently underwent measurements of the P1 component. We observed that DFNB9 subjects who received CI after 2 years of age exhibited "absent" or "anomalous" P1 components that correspond to delayed language development. However, timely implantation, as early as 12 months of age per se, might be insufficient to achieve age-appropriate cortical maturation of DFNB9 in cases with six to seven months of device use. This suggests the importance of sustained rehabilitation in DFNB9 than in other etiologies. Indeed, an additional follow-up study showed that a reduction in P1 latency was linked to an improvement in auditory performance. Collectively, our results suggest that central auditory maturation and successful outcome of CI in DFNB9 may have more demanding requirements, that is, earlier implantation and more sustained rehabilitation. We believe that the current study opens a new path toward genome-based neuroimaging in the field of hearing research., Competing Interests: None to declare.

A new slim modiolar electrode (CI532/632) has been reported to ensure better modiolar proximity than conventional electrodes. Better modiolar proximity has been proposed to yield better electrode discrimination capability and potentially better speech outcomes, necessitating its efficient measurement. Currently, intracochlear positional index (ICPI), the most reliable indicator for evaluating modiolar proximity, has been measured exclusively through 'metal artifact-less' cone beam CT. However, popular use of this index is precluded due to lack of cone beam CT in many institutions. Thus, eyes are now on elucidation of easy-to-measure indicators of modiolar proximity derived from conventional CT, which is accessible in all centers. We observed that enhanced tomographic resolution significantly reduces partial volume artifacts, providing better visualization of modiolus-electrode distance. Aided by ultra-high kernel specification with high-resolution index, we developed a novel and easy-to-measure, conventional CT-specific indicator, "modified ICPI", for evaluation of modiolar proximity. Further, we showed that it closely correlates with the previously proposed parameter of modiolar proximity, the spiral diameter, measured from post-insertion radiograph, reiterating the value of X-ray-based spiral diameter. Through this study, we have taken a step toward the stage of immediate visual feedback regarding modiolar proximity and changes in insertion technique intraoperatively, ensuring optimal modiolar proximity.

Purpose: This study aimed to investigate the etiology of hearing loss, including genetic variants, in individuals who underwent cochlear implantation (CI) in their teens to thirties. It also sought to analyze post-CI speech performance and identify prognostic factors affecting CI outcomes in this age group. Methods: We conducted a retrospective review of 421 cochlear implant patients at Seoul National University Bundang Hospital, focusing on 63 subjects aged 10–39 years who underwent their first CI by a single surgeon between July 2018 and June 2022. The study included audiologic evaluation, molecular genetic testing, and analysis of speech performance post-CI. Statistical analyses were performed using SPSS 25 and GraphPad Prism 7. Results: Among 63 participants (M:F, 24:39), nine underwent CI in their teens, 24 in their 20 s, and 30 in their 30 s. Most of them (40, 63.5%) had postlingual deafness. The study found that 65.2% (40/63) of subjects received a genetic diagnosis, with DFNB4 being the most common etiology (37.5%, 15/40). Post-CI speech evaluation showed an average sentence score of 80% across all subjects. Factors such as the onset of hearing loss, duration of deafness (DoD), and preoperative Speech Intelligibility Rating (SIR) significantly influenced CI outcomes. Notably, longer DoD was associated with poorer CI outcomes, but this did not affect individuals with postlingual hearing loss as much. Conclusion: The study concludes that in individuals aged 10–39 undergoing CI, the onset of hearing loss and preoperative SIR are critical predictors of postoperative outcomes. CI is recommended for those with postlingual hearing loss in this age group, irrespective of the DoD. The study highlights the importance of genetic factors especially DFNB4 in hearing loss etiology and underscores the value of the relatively easy-to-evaluate factor, preoperative SIR in predicting CI outcomes. [ABSTRACT FROM AUTHOR]

Objectives Gradually progressive sensorineural hearing loss (SNHL) is a prevalent sensory defect. It is generally untreatable, making rehabilitation by hearing aid or cochlear implantation the only option. However, SNHL as one of the symptoms of the hereditary autoinflammatory systemic disease cryopyrin-associated periodic syndrome, or as the only symptom of the cochlea-specific form (DFNA34), was suggested to respond to IL-1 antagonist (anakinra) therapy, which ameliorates NLRP3 variants-induced over-secretion of IL-1β. We analysed genotypic and phenotypic spectrum of cryopyrin-associated periodic syndrome or DFNA34, specifically focusing on the responsiveness of SNHL to anakinra. Methods Seventeen families diagnosed with either cryopyrin-associated periodic syndrome or DFNA34 were recruited. Genotyping and phenotyping including audiogram, MRI findings, and in vitro IL-1β assay were performed. Results Our cohort had an etiologic homogeneity of 94.1% to NLRP3 variants and a high de novo occurrence (84.6%). We identified the second DNFA34 pedigree worldwide with a novel NLRP3 variant supported by in vitro analysis. Significant improvement of hearing status against the natural course, showing response to anakinra, was identified in three probands, one of whom used to have severe SNHL. Hearing threshold worse than 60 dB at the start of anakinra and cochlear enhancement on brain MRI seemed to be related with poor audiologic prognosis and responsiveness to anakinra therapy despite stabilized systemic symptoms and inflammatory markers. Conclusion We propose a constellation of biomarkers comprising NLRP3 genotypes, hearing status at diagnosis, and cochlear radiological findings as prognostic factors of hearing status after anakinra treatment and possibly as sensitive parameters for treatment dosage adjustment. [ABSTRACT FROM AUTHOR]

Recent advances in molecular genetic testing (MGT) have improved identification of genetic aetiology of candidates for cochlear implantation (CI). However, whether genetic information increases CI outcome predictability in post-lingual deafness remains unclear. Therefore, we evaluated the outcomes of CI with respect to genetic aetiology and clinical predictors by comparing the data of study subjects; those with an identified genetic aetiology (GD group), and those without identifiable variants (GUD group). First, we identified the genetic aetiology in 21 of 40 subjects and also observed genetic etiologic heterogeneity. The GD group demonstrated significantly greater improvement in speech perception scores over a 1-year period than did the GUD group. Further, inverse correlation between deafness duration and the 1-year improvement in speech perception scores was tighter in the GD group than in the GUD group. The weak correlation between deafness duration and CI outcomes in the GUD group might suggest the pathophysiology underlying GUD already significantly involves the cortex, leading to lesser sensitivity to further cortex issues such as deafness duration. Under our MGT protocol, the correlation between deafness duration and CI outcomes were found to rely on the presence of identifiable genetic aetiology, strongly advocating early CI in individual with proven genetic aetiologies. [ABSTRACT FROM AUTHOR]

Background: While auditory neuropathy spectrum disorder (ANSD) is a heterogeneous disorder and its management quite varies depending upon the etiology, even including self-resolution, OTOF is an important molecular etiology of prelingual ANSD and has emerged as an attractive target for implementation of precision medicine in terms of timing and prognosis prediction of auditory rehabilitation. However, to date, the literature is lacking in the genotype-phenotype relationship of this gene as well as efficient molecular testing strategy in the clinic in many populations and to make things more complicated in Koreans, the most prevalent variant p.Arg1939Gln among Korean ANSD children frequently evaded detection by next generation sequencing (NGS), resulting in delayed genetic diagnosis and late cochlear implantation (CI). The aims of this study are to document the mutational and phenotypic spectrum of OTOF-related ANSD (DFNB9) in the Korean population, further establishing genotype-phenotype correlation and proposing a set of the most commonly found OTOF variants to be screened first.Methods: Genetic diagnosis through the NGS-based sequencing was made on patients with ANSD in two tertiary hospitals. Genotype and phenotypes of eleven DFNB9 patients were reviewed. For data analysis, Mann-Whitney test and Fisher's exact test were applied.Results: This study disclosed four prevalent variants in Koreans: p.Arg1939Gln with an allele frequency of 40.9%, p.Glu841Lys (13.6%), p.Leu1011Pro and p.Arg1856Trp (9.1%). Three novel variants (c.4227 + 5G > C, p.Gly1845Glu, and p.Pro1931Thr) were identified. Interestingly, a significant association of p.Arg1939Gln with worse ASSR thresholds was observed despite consistently no ABR response. Ten of 11 DFNB9 patients received CI for auditory rehabilitation, showing favorable outcomes with more rapid improvement on early-CI group (age at CI ≤ 18 mo.) than late-CI group.Conclusions: This study included the largest Korean DFNB9 cohort to date and proposed a set of the most frequent four OTOF variants, allowing the potential prioritization of exons during Sanger sequencing. Further, a significant association of p.Arg1939Gln homozygotes with poor residual hearing was observed. We may have to suspect p.Arg1939Gln homozygosity in cases of poor auditory thresholds in ANSD children with putative negative OTOF variants solely screened by NGS. Reciprocal feedback between bench and clinics regarding DFNB9 would complement each other. [ABSTRACT FROM AUTHOR]

• TMPRSS3 , a type II transmembrane serine protease, is involved in various biological processes including the development and maintenance of the inner ear. • Through three-dimensional modeling and structural analysis, TMPRSS3 variants compromise protein stability by altering intramolecular interactions, and each mutant differently interacts with the serine protease active site. • Most cochlear implantation (CI) recipients with TMPRSS3 variants have favorable outcomes; age at CI was significantly correlated with speech performance outcomes, whereas genotype was not correlated with these outcomes. TMPRSS3 , a type II transmembrane serine protease, is involved in various biological processes including the development and maintenance of the inner ear. Biallelic variants in TMPRSS3 typically result in altered protease activity, causing autosomal recessive non-syndromic hearing loss (ARNSHL). Structural modeling has been conducted to predict the pathogenicity of TMPRSS3 variants and to gain a better understanding of their prognostic correlation. The mutant-driven changes in TMPRSS3 had substantial impacts on neighboring residues, and the pathogenicity of variants was predicted based on their distance from the active site. However, a more in-depth analysis of other factors, such as intramolecular interactions and protein stability, which affect proteolytic activities is yet to be conducted for TMPRSS3 variants. Among 620 probands who provided genomic DNA for molecular genetic testing, eight families with biallelic TMPRSS3 variants that were segregated in a trans configuration were included. Seven different mutant alleles, either homozygous or compound heterozygous, contributed to TMPRSS3 -associated ARNSHL, expanding the genotypic spectrum of disease-causing TMPRSS3 variants. Through three-dimensional modeling and structural analysis, TMPRSS3 variants compromise protein stability by altering intramolecular interactions, and each mutant differently interacts with the serine protease active site. Furthermore, the changes in intramolecular interactions leading to regional instability correlate with the results of functional assay and residual hearing function, but overall stability predictions do not. Our findings also build on previous evidence indicating that most recipients with TMPRSS3 variants have favorable cochlear implantation (CI) outcomes. We found that age at CI was significantly correlated with speech performance outcomes; genotype was not correlated with these outcomes. Collectively, the results of this study contribute to a more structural understanding of the underlying mechanisms of ARNSHL caused by TMPRSS3 variants. [ABSTRACT FROM AUTHOR]