Clinical characteristics and hearing loss etiology of cochlear implantees undergoing surgery in their teens, 20s, and 30s.

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.

Early Postoperative Benefits in Receptive and Expressive Language Development After Cochlear Implantation Under 9 Months of Age in Comparison to Implantation at Later Ages.

OBJECTIVES: The recent expansion of eligibility for cochlear implantation (CI) by the U.S. Food and Drug Administration (FDA) to include infants as young as 9 months has reignited debates concerning the clinically appropriate cut-off age for pediatric CI. Our study compared the early postoperative trajectories of receptive and expressive language development in children who received CI before 9 months of age with those who received it between 9 and 12 months. This study involved a unique pediatric cohort with documented etiology, where the timing of CI was based on objective criteria and efforts were made to minimize the influence of parental socioeconomic status. METHODS: A retrospective review of 98 pediatric implantees recruited at a tertiary referral center was conducted. The timing of CI was based on auditory and language criteria focused on the extent of delay corresponding to the bottom 1st percentile of language development among age-matched controls, with patients categorized into very early (CI at <9 months), early (CI at 9-12 months) and delayed (CI at 12-18 months) CI groups. Postoperative receptive/expressive language development was assessed using the Sequenced Language Scale for Infants receptive and expressive standardized scores and percentiles. RESULTS: Only the very early CI group showed significant improvements in receptive language starting at 3 months post-CI, aligning with normal-hearing peers by 9 months and maintaining this level until age 2 years. During this period (<2 years), all improvements were more pronounced in receptive language than in expressive language. CONCLUSION: CI before 9 months of age significantly improved receptive language development compared to later CI, with improvements sustained at least up to the age of 2. This study supports the consideration of earlier CI, beyond pediatric Food and Drug Administration labeling criteria (>9 months), in children with profound deafness who have a clear deafness etiology and language development delays (<1st percentile).

Comparing pronunciation challenges in South Korean preschoolers with unilateral single-sided deafness due to cochlear nerve deficiency to a norm-referenced standard.

This study aimed to compare the development of pronunciation in South Korean preschoolers with unilateral cochlear nerve deficiency (CND) to that of age-matched preschoolers with normal hearing, a topic that has not been explored previously. In a retrospective analysis, 25 preschoolers with unilateral CND who had undergone a speech evaluation battery, including a pronunciation and vocabulary test, were enrolled. Utilizing the Urimal Test of Articulation and Phonation and customized language ability tests, pronunciation and vocabulary were assessed. The subjects' speech evaluation scores were converted into age-adjusted z-scores using normal controls' data. While vocabulary performance was within normal limits, their average pronunciation z-score was -2.90, significantly lower than both the zero reference point and their vocabulary z-scores. None of the subjects scored above average in pronunciation. Thirteen patients were recommended for articulation therapy, seven were considered as potential candidates for this therapy, and the remaining five were within normal limits. There was no observed correlation between the development of pronunciation and vocabulary. Notably, some subjects' pronunciation scores did not improve, even after serial follow-up during their preschool years. Despite typical vocabulary development, preschoolers with unilateral CND exhibit significant delays in pronunciation. These findings emphasize the necessity for vigilant monitoring of their language development.

TMTC4 is a hair cell-specific human deafness gene.

Transmembrane and tetratricopeptide repeat 4 (Tmtc4) is a deafness gene in mice. Tmtc4-KO mice have rapidly progressive postnatal hearing loss due to overactivation of the unfolded protein response (UPR); however, the cellular basis and human relevance of Tmtc4-associated hearing loss in the cochlea was not heretofore appreciated. We created a hair cell-specific conditional KO mouse that phenocopies the constitutive KO with postnatal onset deafness, demonstrating that Tmtc4 is a hair cell-specific deafness gene. Furthermore, we identified a human family in which Tmtc4 variants segregate with adult-onset progressive hearing loss. Lymphoblastoid cells derived from multiple affected and unaffected family members, as well as human embryonic kidney cells engineered to harbor each of the variants, demonstrated that the human Tmtc4 variants confer hypersensitivity of the UPR toward apoptosis. These findings provide evidence that TMTC4 is a deafness gene in humans and further implicate the UPR in progressive hearing loss.

Health justice and economic segregation in climate risks: Tracing vulnerability and readiness progress.

Climate vulnerability can make urban space unhealthy and accentuate existing health (in)justice and (economic) segregation. Drawing on the vulnerability-readiness nexus and measuring health justice (i.e., health poverty, health distribution, and health access) and economic segregation (through indices), we strive to investigate the plausible pathways of the two constructs at the heat risks. Our work, focusing on metropolitan cities in South Korea, addresses the role of heat vulnerability and readiness nexus regarding health justice and economic segregation through correlational analysis and a time-trend comparative approach between 2011 and 2015 (as five year-long effects). Our results show that potential positive links exist between health poverty as a component of health justice and economic segregation. Moreover, climate readiness, as opposed to vulnerability, plays a crucial role in reducing economic segregation in the context of health justice and heat risks.

Significance of cytomegalovirus tests after three weeks of life in children with hearing loss.

BACKGROUND: To determine the diagnostic role of viral markers for cytomegalovirus (CMV) when tested after the diagnostically critical period (postnatal 3 weeks) in children with sensorineural hearing loss (SNHL). METHODS: A retrospective review of 104 subjects who underwent CMV diagnostic tests after the critical period of 3 postnatal three weeks but before 24 months of age. Infants included had not passed universal newborn hearing screening tests in at least one ear and thus underwent obligatory follow up audiology testing as well as either exome sequencing or magnetic resonance imaging in cases of SNHL. Our cohort was classified into four subgroups depending on the results from audiological and etiologic diagnostic tests (genetic and radiological tests): congenital CMV (cCMV)-related SNHL (Group 1, n = 9), SNHL with another clear etiology (Group 2, n = 34), and SNHL classified as neither Group 1 nor 2 (Group 3, n = 18). We added age-matched, normal-hearing children (Group 4, n = 43) as a control group. CMV related viral metrics were compared among these four groups. RESULTS: CMV PCR positivity, PCR titers, and culture positivity successfully differentiated Group 1 from Groups 2 and 4. Group 3 showed values of these parameters that were significantly different from Groups 2 and 4, while being more similar to those in Group 1, suggesting that a substantial portion of Group 3 truly had cCMV deafness. A hypothetical formula was developed to predict cCMV infections using logistic regression analysis. CONCLUSION: This is the first study to propose the clinical significance of CMV test results obtained after 3 weeks post-birth in children with SNHL and to suggest how we can utilize them.

Hearing loss in neonates and infants.

Hearing in neonates and infants is crucial for their development of language and communication skills. Unless hearing loss is appropriately managed early, it can cause a significant socioeconomic burden considering its detrimental impact on the child's development and its common nature. It is also the most common congenital sensory deficit, with an approximate incidence of 1.5 per 1,000 newborns. Its etiologies are heterogeneous: genetic causes are reportedly involved in up to 80% of cases, while congenital cytomegalovirus infection is the leading environmental factor contributing to congenital hearing loss. The introduction of newborn hearing screening using automated auditory brainstem response and/or automated otoacoustic emission in many developed countries has helped detect and manage hearing loss early. Current auditory rehabilitation options such as cochlear implantation implementing cutting-edge technologies can treat almost all degrees of hearing loss, emphasizing the importance of early hearing detection and intervention. Rapidly developing genetic diagnostic technologies and future cutting-edge treatment options, including gene therapy, will shed light on the future management of hearing loss in neonates and infants.

Auditory Phenotype and Histopathologic Findings of a Mutant Nlrp3 Expression Mouse Model.

Objective: The pathogenesis of hearing loss in autoinflammatory disorders due to activation of the inflammasome remains incompletely understood. Previously no animals expressing mutant Nlrp3 (NOD-, LRR- and pyrin domain-containing protein 3) survived to an age when hearing evaluation was possible due to embryonic lethality. We aimed to establish a novel mouse model that manifests quantifiable hearing loss with other syndromic features due to alteration of Nlrp3 and investigate the audiologic and histopathologic phenotype in the cochlea to clarify how the genetic alterations of NLRP3 could induce autoinflammatory hearing loss. Methods: To induce inner ear expression of the mutant Nlrp3, Nlrp3 D301NneoR mice were bred with Gfi1 Cre knock-in mice for conditional mutant Nlrp3 activation in the cochlea and hematopoietic cells. Hearing thresholds were measured. Hematoxylin-eosin sections of the cochlea, brain, kidney, and liver were examined under light microscopy. Immunohistochemical analyses using polyclonal anti-NLRP3 antibodies on cochlear whole-mount preparations and frozen sections were performed. Results: We, for the first time in the literature, established a mouse model that manifests quantifiable hearing loss due to Nlrp3 alteration. ABR recordings of Nlrp3 D301NneoR/+; Gfi1 Cre/+ mice, albeit with limited life expectancy, exhibited severe to profound hearing loss at postnatal day 20 (P20). There was overall overexpression of mutant Nlrp3, and mutant Nlrp3 expression was noted in the spiral prominence, the outer sulcus region (Claudius cells and outer sulcus cells), the organ of Corti, the inner sulcus, and the spiral ganglion neurons in the cochlea. The hematoxylin-eosin sections of Nlrp3 D301NneoR/+; Gfi1 Cre/+ mice cochleae at P12 exhibited a disorganized organ of Corti between the outer hair cells/supporting Deiters' cells and basilar membrane compared with the normal phenotype mice, leading to a collapsed Nuel's space. This morphologic feature gradually returned to normal by P15. Varying degrees of inflammation with lymphocytic infiltrations were observed in the brain, kidney, and liver. Conclusion: We report the first mutant Nlrp3 overexpression mouse model (Nlrp3 D301NneoR/+; Gfi1 Cre/+) that shows obvious overexpression of Nlrp3 in the cochlea, a transient developmental lag of the cochlea, and severe to profound hearing loss. We expect that this mouse line, which models human autoinflammatory hearing loss, could provide a valuable tool to elucidate the underlying pathogenic mechanism of inflammasome activation-mediated hearing loss.

Improving genetic diagnosis by disease-specific, ACMG/AMP variant interpretation guidelines for hearing loss.

The 2018 Hearing Loss Expert Panel (HL-EP)-specific guidelines specified from the universal 2015 ACMG/AMP guidelines are proposed to be used in genetic HL, which prompted this study. A genetic HL cohort comprising 135 unrelated probands with available exome sequencing data was established. Overall, 169 variants were prioritized as candidates and interpreted using the 2015 ACMG/AMP and 2018 HL-EP guidelines. Changes in rule application and variant classification between the guidelines were compared. The concordance rate of variant classification of each variant between the guidelines was 71.60%, with significant difference. The proportion of pathogenic variants increased from 13.02% (2015) to 29.59% (2018). Variant classifications of autosomal recessive (AR) variants that previously belonged to VUS or likely pathogenic in the 2015 guidelines were changed toward pathogenic in the 2018 guidelines more frequently than those of autosomal dominant variants (29.17% vs. 6.38%, P = 0.005). Stratification of the PM3 and PP1 rules in the 2018 guidelines led to more substantial escalation than that in the 2015 guidelines. We compared the disease-specific guidelines (2018) with the universal guidelines (2015) using real-world data. Owing to the sophistication of case-level data, the HL-specific guidelines have more explicitly classified AR variants toward "likely pathogenic" or "pathogenic", serving as potential references for other recessive genetic diseases.

Full etiologic spectrum of pediatric severe to profound hearing loss of consecutive 119 cases.

Determining the etiology of severe-to-profound sensorineural hearing loss (SP-SNHL) in pediatric subjects is particularly important in aiding the decision for auditory rehabilitation. We aimed to update the etiologic spectrum of pediatric SP-SNHL by combining internal auditory canal (IAC)-MRI with comprehensive and state-of-the-art genetic testings. From May 2013 to September 2020, 119 cochlear implantees under the age of 15 years with SP-SNHL were all prospectively recruited. They were subjected to genetic tests, including exome sequencing, and IAC-MRI for etiologic diagnosis. Strict interpretation of results were made based on ACMG/AMP guidelines and by an experienced neuroradiologist. The etiology was determined in of 65.5% (78/119) of our cohort. If only one of the two tests was done, the etiologic diagnostic rate would be reduced by at least 21.8%. Notably, cochlear nerve deficiency (n = 20) detected by IAC-MRI topped the etiology list of our cohort, followed by DFNB4 (n = 18), DFNB1 (n = 10), DFNB9 (n = 10) and periventricular leukomalacia associated with congenital CMV infection (n = 8). Simultaneous application of state-of-the-art genetic tests and IAC-MRI is essential for etiologic diagnosis, and if lesions of the auditory nerve or central nerve system are carefully examined on an MRI, we can identify the cause of deafness in more than 65% of pediatric SP-SNHL cases.

Evaluation of users' level of satisfaction for an artificial intelligence-based diagnostic program in pediatric rare genetic diseases.

The artificial intelligence (AI)-based genetic diagnostic program has been applied to genome sequencing to facilitate the diagnostic process. The objective of the current study was to evaluate the experience and level of satisfaction of participants using an AI-based diagnostic program for rare pediatric genetic diseases. The patients with neurodevelopmental disorders or hearing impairments, their guardians, and their physicians from 16 tertiary general hospitals were enrolled. The study period was from April 2020 to March 2021. A survey was designed to assess their experience and level of satisfaction. A total of 30 physicians and 243 patients and guardians (199 neurodevelopmental disorders and 44 hearing impairments) completed the survey. DNA samples of the subjects were collected through buccal swabs or blood collection: 211 subjects (86.8%) through buccal swab and 29 subjects (11.9%) through blood collection. Average turnaround time for result receipt was 57.54 ± 32.42 days. For the sampling method, 193 patients and guardians (81.1%) and 28 physicians (93.3%) preferred buccal swab. The level of satisfaction of the 2 groups participating in the AI-based diagnostic program was 8.31 ± 1.71 out of 10 in the patient and guardian group and 8.42 ± 1.23 in the physician group. Clinicians, patients, and guardians are satisfied with the AI-based diagnostic program in general. With an increase in AI-based precision medicine solutions, the evaluation of the user's satisfaction with appropriate provision will help improve personal health care.

Efficacy of cochlear implants in children with borderline hearing who have already achieved significant language development with hearing aids.

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.

Gray matter volume reduction in the emotional brain networks in adults with anosmia.

Loss of olfaction, or anosmia, frequently accompanies emotional dysfunctions, partly due to the overlapping brain regions between the olfactory and emotional processing centers. Here, we investigated whether anosmia was associated with gray matter volume alterations at a network level, and whether these alterations were related to the olfactory-specific quality of life (QOL) and depressive symptoms. Structural brain magnetic resonance imaging was acquired in 22 individuals with postinfectious or idiopathic anosmia (the anosmia group) and 30 age- and sex-matched controls (the control group). Using independent component analysis on the gray matter volumes, we identified 10 morphometric networks. The gray matter volumes of these networks were compared between the two groups. Olfactory-specific QOL and depressive symptoms were assessed by self-report questionnaires and clinician-administered interviews, respectively. The anosmia group showed lower gray matter volumes in the hippocampus-amygdala and the precuneus networks, relative to the control group. Lower gray matter volumes in the hippocampus-amygdala network were also linearly associated with lower olfactory-specific QOL and higher depressive symptom scores. These findings suggest a close relationship between anosmia and gray matter volume alterations in the emotional brain networks, albeit without determined causal relations.

Late-onset hearing loss case associated with a heterozygous truncating variant of DIAPH1.

Diaphanous-related formin 1 (DIAPH1) is a formin homology F-actin elongating protein encoded by DIAPH1. Homozygous recessive variants resulting in the loss of DIAPH1 function cause seizures, cortical blindness, and microcephaly syndrome (SCBMS), but hearing loss has not been reported. In contrast, dominant variants of human DIAPH1 are associated with DFNA1 non-syndromic sensorineural hearing loss. The deafness phenotype is due partly to abnormal F-actin elongation activity caused by disruption of the DIAPH1 autoinhibitory mechanism. We report an elderly female heterozygous for the c.3145C>T: p.R1049X variant who showed late-onset sensorineural hearing loss in her fifth decade. p.R1049X lacks F-actin elongation activity because this variant truncates one-third of the FH2 domain, which is vital for DIAPH1 dimerization and processive F-actin elongation activity. Concordantly, no increase of F-actin or processive F-actin elongation activity was observed after overexpression of p.R1049X DIAPH1 in HeLa cells or by single-molecule microscopy using Xenopus XTC cells. However, overexpression of the p.R1049X variant impairs formation of cell-cell junctions and mitosis. We speculate that late-onset hearing loss is a long-term consequence of heterozygosity for the recessive p.R1049X variant, a phenotype that may have been overlooked among carriers of other recessive alleles of DIAPH1.

Rising of LOXHD1 as a signature causative gene of down-sloping hearing loss in people in their teens and 20s.

BACKGROUND: Down-sloping sensorineural hearing loss (SNHL) in people in their teens and 20s hampers efficient learning and communication and in-depth social interactions. Nonetheless, its aetiology remains largely unclear, with the exception of some potential causative genes, none of which stands out especially in people in their teens and 20s. Here, we examined the role and genotype-phenotype correlation of lipoxygenase homology domain 1 (LOXHD1) in down-sloping SNHL through a cohort study. METHODS: Based on the Seoul National University Bundang Hospital (SNUBH) genetic deafness cohort, in which the patients show varying degrees of deafness and different onset ages (n=1055), we have established the 'SNUBH Teenager-Young Adult Down-sloping SNHL' cohort (10-35 years old) (n=47), all of whom underwent exome sequencing. Three-dimensional molecular modelling, minigene splicing assay and short tandem repeat marker genotyping were performed, and medical records were reviewed. RESULTS: LOXHD1 accounted for 33.3% of all genetically diagnosed cases of down-sloping SNHL (n=18) and 12.8% of cases in the whole down-sloping SNHL cohort (n=47) of young adults. We identified a potential common founder allele, as well as an interesting genotype-phenotype correlation. We also showed that transcript 6 is necessary and probably sufficient for normal hearing. CONCLUSIONS: LOXHD1 exceeds other genes in its contribution to down-sloping SNHL in young adults, rising as a signature causative gene, and shows a potential but interesting genotype-phenotype correlation.

Human deafness-associated variants alter the dynamics of key molecules in hair cell stereocilia F-actin cores.

Stereocilia protrude up to 100 µm from the apical surface of vertebrate inner ear hair cells and are packed with cross-linked filamentous actin (F-actin). They function as mechanical switches to convert sound vibration into electrochemical neuronal signals transmitted to the brain. Several genes encode molecular components of stereocilia including actin monomers, actin regulatory and bundling proteins, motor proteins and the proteins of the mechanotransduction complex. A stereocilium F-actin core is a dynamic system, which is continuously being remodeled while maintaining an outwardly stable architecture under the regulation of F-actin barbed-end cappers, severing proteins and crosslinkers. The F-actin cores of stereocilia also provide a pathway for motor proteins to transport cargos including components of tip-link densities, scaffolding proteins and actin regulatory proteins. Deficiencies and mutations of stereocilia components that disturb this "dynamic equilibrium" in stereocilia can induce morphological changes and disrupt mechanotransduction causing sensorineural hearing loss, best studied in mouse and zebrafish models. Currently, at least 23 genes, associated with human syndromic and nonsyndromic hearing loss, encode proteins involved in the development and maintenance of stereocilia F-actin cores. However, it is challenging to predict how variants associated with sensorineural hearing loss segregating in families affect protein function. Here, we review the functions of several molecular components of stereocilia F-actin cores and provide new data from our experimental approach to directly evaluate the pathogenicity and functional impact of reported and novel variants of DIAPH1 in autosomal-dominant DFNA1 hearing loss using single-molecule fluorescence microscopy.

Powerful use of automated prioritization of candidate variants in genetic hearing loss with extreme etiologic heterogeneity.

Variant prioritization of exome sequencing (ES) data for molecular diagnosis of sensorineural hearing loss (SNHL) with extreme etiologic heterogeneity poses a significant challenge. This study used an automated variant prioritization system ("EVIDENCE") to analyze SNHL patient data and assess its diagnostic accuracy. We performed ES of 263 probands manifesting mild to moderate or higher degrees of SNHL. Candidate variants were classified according to the 2015 American College of Medical Genetics guidelines, and we compared the accuracy, call rates, and efficiency of variant prioritizations performed manually by humans or using EVIDENCE. In our in silico panel, 21 synthetic cases were successfully analyzed by EVIDENCE. In our cohort, the ES diagnostic yield for SNHL by manual analysis was 50.19% (132/263) and 50.95% (134/263) by EVIDENCE. EVIDENCE processed ES data 24-fold faster than humans, and the concordant call rate between humans and EVIDENCE was 97.72% (257/263). Additionally, EVIDENCE outperformed human accuracy, especially at discovering causative variants of rare syndromic deafness, whereas flexible interpretations that required predefined specific genotype-phenotype correlations were possible only by manual prioritization. The automated variant prioritization system remarkably facilitated the molecular diagnosis of hearing loss with high accuracy and efficiency, fostering the popularization of molecular genetic diagnosis of SNHL.