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Item Biallelic Loss-of-Function Variants in BICD1 Are Associated with Peripheral Neuropathy and Hearing Loss(MDPI, 2023-05-17) Hirsch, Yoel; Chung, Wendy K.; Novoselov, Sergey; Weimer, Louis H.; Rossor, Alexander; LeDuc, Charles A.; McPartland, Amanda J.; Cabrera, Ernesto; Ekstein, Josef; Scher, Sholem; Nelson, Rick F.; Schiavo, Giampietro; Henderson, Lindsay B.; Booth, Kevin T. A.; Otolaryngology -- Head and Neck Surgery, School of MedicineHearing loss and peripheral neuropathy are two clinical entities that are genetically and phenotypically heterogeneous and sometimes co-occurring. Using exome sequencing and targeted segregation analysis, we investigated the genetic etiology of peripheral neuropathy and hearing loss in a large Ashkenazi Jewish family. Moreover, we assessed the production of the candidate protein via western blotting of lysates from fibroblasts from an affected individual and an unaffected control. Pathogenic variants in known disease genes associated with hearing loss and peripheral neuropathy were excluded. A homozygous frameshift variant in the BICD1 gene, c.1683dup (p.(Arg562Thrfs*18)), was identified in the proband and segregated with hearing loss and peripheral neuropathy in the family. The BIDC1 RNA analysis from patient fibroblasts showed a modest reduction in gene transcripts compared to the controls. In contrast, protein could not be detected in fibroblasts from a homozygous c.1683dup individual, whereas BICD1 was detected in an unaffected individual. Our findings indicate that bi-allelic loss-of-function variants in BICD1 are associated with hearing loss and peripheral neuropathy. Definitive evidence that bi-allelic loss-of-function variants in BICD1 cause peripheral neuropathy and hearing loss will require the identification of other families and individuals with similar variants with the same phenotype.Item Cochlear Implantation in US Military Veterans: A Single Institution Study(Sage, 2023-05-12) Totten, Douglas J.; Saltagi, Abdul; Libich, Karen; Pisoni, David B.; Nelson, Rick F.; Otolaryngology -- Head and Neck Surgery, School of MedicineObjective: Military veterans have high rates of noise-induced hearing loss (NIHL) which is associated with more significant spiral ganglion neuronal loss. This study explores the relationship between NIHL and cochlear implant (CI) outcomes in veterans. Study design: Retrospective case series of veterans who underwent CI between 2019 and 2021. Setting: Veterans Health Administration hospital. Methods: AzBio Sentence Test, Consonant-Nucleus-Consonant (CNC) scores, and Speech, Spatial, and Qualities of Hearing Scale (SSQ) were measured pre- and postoperatively. Linear regression assessed relationships between outcomes and noise exposure history, etiology of hearing loss, duration of hearing loss, and Self-Administered Gerocognitive Exam (SAGE) scores. Results: Fifty-two male veterans were implanted at an average (standard deviation) age of 75.0 (9.2) years without major complications. The average duration of hearing loss was 36.0 (18.4) years. The average time of hearing aid use was 21.2 (15.4) years. Noise exposure was reported in 51.3% of patients. Objectively, AzBio and CNC scores 6 months postoperatively showed significant improvement of 48% and 39%, respectively. Subjectively, average 6-month SSQ scores showed significant improvement by 34 points (p < .0001). Younger age, SAGE score ≥17, and shorter duration of amplification were associated with higher postoperative AzBio scores. Greater improvement in AzBio and CNC scores was associated with lower preoperative scores. Noise exposure was not associated with any difference in CI performance. Conclusion: Despite high levels of noise exposure and advanced age, veterans derive substantial benefits from cochlear implantation. SAGE score ≥17 may be predictive of overall CI outcomes. Noise exposure does not impact CI outcomes.Item Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel(Springer Nature, 2019-11) Shen, Jun; Oza, Andrea M.; Del Castillo, Ignacio; Duzkale, Hatice; Matsunaga, Tatsuo; Pandya, Arti; Kang, Hyunseok P.; Mar-Heyming, Rebecca; Guha, Saurav; Moyer, Krista; Lo, Christine; Kenna, Margaret; Alexander, John J.; Zhang, Yan; Hirsch, Yoel; Luo, Minjie; Cao, Ye; Choy, Kwong Wai; Cheng, Yen-Fu; Avraham, Karen B.; Hu, Xinhua; Garrido, Gema; Moreno-Pelayo, Miguel A.; Greinwald, John; Zhang, Kejian; Zeng, Yukun; Brownstein, Zippora; Basel-Salmon, Lina; Davidov, Bella; Frydman, Moshe; Weiden, Tzvi; Nagan, Narasimhan; Willis, Alecia; Hemphill, Sarah E.; Grant, Andrew R.; Siegert, Rebecca K.; DiStefano, Marina T.; Amr, Sami S.; Rehm, Heidi L.; Abou Tayoun, Ahmad N.; Clin Gen Hearing Loss Working Group; Biostatistics, School of Public HealthPurpose: Pathogenic variants in GJB2 are the most common cause of autosomal recessive sensorineural hearing loss. The classification of c.101T>C/p.Met34Thr and c.109G>A/p.Val37Ile in GJB2 are controversial. Therefore, an expert consensus is required for the interpretation of these two variants. Methods: The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants. Functional, computational, allelic, and segregation data were also obtained. Case-control statistical analyses were performed. Results: The panel reviewed the synthesized information, and classified the p.Met34Thr and p.Val37Ile variants utilizing professional variant interpretation guidelines and professional judgment. We found that p.Met34Thr and p.Val37Ile are significantly overrepresented in hearing loss patients, compared with population controls. Individuals homozygous or compound heterozygous for p.Met34Thr or p.Val37Ile typically manifest mild to moderate hearing loss. Several other types of evidence also support pathogenic roles for these two variants. Conclusion: Resolving controversies in variant classification requires coordinated effort among a panel of international multi-institutional experts to share data, standardize classification guidelines, review evidence, and reach a consensus. We concluded that p.Met34Thr and p.Val37Ile variants in GJB2 are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and incomplete penetrance.Item Exceptional Speech Recognition Outcomes After Cochlear Implantation: Lessons From Two Case Studies(American Speech-Language-Hearing Association, 2022) Herbert, Carolyn J.; Pisoni, David B.; Kronenberger, William G.; Nelson, Rick F.; Otolaryngology -- Head and Neck Surgery, School of MedicinePurpose: Individual differences and variability in outcomes following cochlear implantation (CI) in patients with hearing loss remain significant unresolved clinical problems. Case reports of specific individuals allow for detailed examination of the information processing mechanisms underlying variability in outcomes. Two adults who displayed exceptionally good postoperative CI outcomes shortly after activation were administered a novel battery of auditory, speech recognition, and neurocognitive processing tests. Method: A case study of two adult CI recipients with postlingually acquired hearing loss who displayed excellent postoperative speech recognition scores within 3 months of initial activation. Preoperative City University of New York sentence testing and a postoperative battery of sensitive speech recognition tests were combined with auditory and visual neurocognitive information processing tests to uncover their strengths, weaknesses, and milestones. Results: Preactivation CUNY auditory-only (A) scores were < 5% correct while the auditory + visual (A + V) scores were > 74%. Acoustically with their CIs, both participants' scores on speech recognition, environmental sound identification and speech in noise tests exceeded average CI users scores by 1-2 standard deviations. On nonacoustic visual measures of language and neurocognitive functioning, both participants achieved above average scores compared with normal hearing adults in vocabulary knowledge, rapid phonological coding of visually presented words and nonwords, verbal working memory, and executive functioning. Conclusions: Measures of multisensory (A + V) speech recognition and visual neurocognitive functioning were associated with excellent speech recognition outcomes in two postlingual adult CI recipients. These neurocognitive information processing domains may underlie the exceptional speech recognition performance of these two patients and offer new directions for research explaining variability in postimplant outcomes. Results further suggest that current clinical outcome measures should be expanded beyond the conventional speech recognition measures to include more sensitive robust tests of speech recognition as well as neurocognitive measures of working memory, vocabulary, lexical access, and executive functioning.Item Executive functioning and spoken language skills in young children with hearing aids and cochlear implants: Longitudinal findings(Frontiers Media, 2022-09-23) Jamsek, Izabela A.; Kronenberger, William G.; Pisoni, David B.; Holt, Rachael Frush; Psychiatry, School of MedicineDeaf or hard-of-hearing (DHH) children who use auditory-oral communication display considerable variability in spoken language and executive functioning outcomes. Furthermore, language and executive functioning skills are strongly associated with each other in DHH children, which may be relevant for explaining this variability in outcomes. However, longitudinal investigations of language and executive functioning during the important preschool period of development in DHH children are rare. This study examined the predictive, reciprocal associations between executive functioning and spoken language over a 1-year period in samples of 53 DHH and 59 typically hearing (TH) children between ages 3-8 years at baseline. Participants were assessed on measures of receptive spoken language (vocabulary, sentence comprehension, and following spoken directions) and caregiver-completed executive functioning child behavior checklists during two in-person home visits separated by 1 year. In the sample of DHH children, better executive functioning at baseline (Time 1) was associated with better performance on the higher-order language measures (sentence comprehension and following spoken directions) 1 year later (Time 2). In contrast, none of the Time 1 language measures were associated with better executive functioning in Time 2 in the DHH sample. TH children showed no significant language-executive functioning correlations over the 1-year study period. In regression analyses controlling for Time 1 language scores, Time 1 executive functioning predicted Time 2 language outcomes in the combined DHH and TH samples, and for vocabulary, that association was stronger in the DHH than in the TH sample. In contrast, after controlling for Time 1 executive functioning, none of the regression analyses predicting Time 2 executive functioning from Time 1 language were statistically significant. These results are the first findings to demonstrate that everyday parent-rated executive functioning behaviors predict basic (vocabulary) and higher-order (comprehension, following directions) spoken language development 1 year later in young (3-8 year old) DHH children, even after accounting for initial baseline language skills.Item Family Environmental Dynamics Differentially Influence Spoken Language Development in Children With and Without Hearing Loss(American Speech-Language-Hearing Association, 2022) Holt, Rachael Frush; Kronenberger, William G.; Pisoni, David B.; Psychiatry, School of MedicinePurpose: The aim of this study was to evaluate whether families of children with sensorineural hearing loss (SNHL) are organized similarly to those of typically developing, typically hearing (TH) children and whether the dimensions of family dynamics and environment are related to spoken language development similarly in children with and without SNHL. Method: Primary caregivers of children with SNHL (n = 63) or TH (n = 65) completed the Family Environment Scale-Fourth Edition (FES-4) to assess multiple dimensions of family environment. Children's receptive vocabulary was assessed with the Peabody Picture Vocabulary Test-Fourth Edition, and their receptive language was assessed by an age-appropriate version of the Concepts and Following Directions subtest of the Clinical Evaluation of Language Fundamentals and the Sentence Comprehension subscale of the Comprehensive Assessment of Spoken Language-Second Edition. Principal component analysis was used to examine the dimensional structure of the family environment. Results: Three higher order components were derived from FES-4 subscales for both families of children with SNHL and with TH: Supportive, Controlling, and Conflicted. However, the composition of the factors themselves differed between the two groups. For the TH group, most family environment measures on the FES-4 were not associated with language outcomes. In contrast, for children with SNHL, families who were more supportive, less controlling, and less conflicted had children with better language skills. Conclusions: Three well-accepted dimensions of family dynamics and functioning apply to families of children with SNHL, but their composition differs from those of families with TH children. Family environmental dynamics were much more strongly associated with language outcomes in children with SNHL than in their TH peers. The spoken language development of children with SNHL, in particular, is better in families that provide high levels of support for each other and, in particular, low levels of control, disorganization, and conflict, reflecting the fragile nature of their spoken language development.Item Family-Level Executive Functioning and At-Risk Pediatric Hearing Loss Outcomes(American Speech-Language-Hearing Association, 2021) Blank, Andrew; Frush Holt, Rachael; Pisoni, David B.; Kronenberger, William G.; Otolaryngology -- Head and Neck Surgery, School of MedicinePurpose: Using a new measure of family-level executive functioning (EF; the Family Characteristics Scale [FCS]), we investigated associations between family-level EF, spoken language, and neurocognitive skills in children with hearing loss (HL), compared to children with normal hearing. Method: Parents of children with HL (n = 61) or children with normal hearing (n = 65) completed the FCS-Parent, and clinicians evaluated families using the FCS-Examiner. Children completed an age-appropriate version of the Concepts and Following Directions subtest of the Clinical Evaluation of Language Fundamentals and the Peabody Picture Vocabulary Test–Fourth Edition. Child EF was assessed via the parent report Behavior Rating Inventory of Executive Function. Results: Two higher order components were derived from FCS subscales: Family Inhibition and Family Organization. For both samples, Family Inhibition was positively associated with child inhibition, child shifting, and child language comprehension skills. Family Organization was differentially associated with child inhibition, working memory, and planning/organization skills across the samples. Additionally, Family Inhibition was associated with child planning and organization skills for children with HL. Conclusions: Results support the FCS as a measure of family-level EF. Family-level inhibition related to better child inhibition, flexibility/shifting, and language comprehension across both samples and to better planning and organization skills in children with HL. As children with HL experienced greater difficulties in EF, families demonstrated greater organization, possibly as a compensatory measure. Results suggest that inhibition and organization at a family level may be important targets for the development of novel interventions to promote EF and language outcomes for children with HL.Item Genetic and pharmacologic alterations of claudin9 levels suffice to induce functional and mature inner hair cells(bioRxiv, 2023-10-10) Chen, Yingying; Lee, Jeong Han; Li, Jin; Park, Seojin; Perez Flores, Maria C.; Peguero, Braulio; Kersigo, Jennifer; Kang, Mincheol; Choi, Jinsil; Levine, Lauren; Gratton, Michael Anne; Fritzsch, Bernd; Yamoah, Ebenezer N.; Pharmacology and Toxicology, School of MedicineHearing loss is the most common form of sensory deficit. It occurs predominantly due to hair cell (HC) loss. Mammalian HCs are terminally differentiated by birth, making HC loss incurable. Here, we show the pharmacogenetic downregulation of Cldn9, a tight junction protein, generates robust supernumerary inner HCs (IHCs) in mice. The putative ectopic IHCs have functional and synaptic features akin to typical IHCs and were surprisingly and remarkably preserved for at least fifteen months >50% of the mouse's life cycle. In vivo, Cldn9 knockdown using shRNA on postnatal days (P) P1-7 yielded analogous functional putative ectopic IHCs that were equally durably conserved. The findings suggest that Cldn9 levels coordinate embryonic and postnatal HC differentiation, making it a viable target for altering IHC development pre- and post-terminal differentiation.Item GRXCR2 Regulates Taperin Localization Critical for Stereocilia Morphology and Hearing(Elsevier, 2018-10-30) Liu, Chang; Luo, Na; Tung, Chun-Yu; Perrin, Benjamin J.; Zhao, Bo; Otolaryngology -- Head and Neck Surgery, School of MedicineMutations in human GRXCR2, which encodes a protein of undetermined function, cause hearing loss by unknown mechanisms. We found that mouse GRXCR2 localizes to the base of the stereocilia, which are actin-based mechanosensing organelles in cochlear hair cells that convert sound-induced vibrations into electrical signals. The stereocilia base also contains taperin, another protein of unknown function required for human hearing. We show that taperin and GRXCR2 form a complex and that taperin is diffused throughout the stereocilia length in Grxcr2-deficient hair cells. Stereocilia lacking GRXCR2 are longer than normal and disorganized due to the mislocalization of taperin, which could modulate the actin cytoskeleton in stereocilia. Remarkably, reducing taperin expression levels could rescue the morphological defects of stereocilia and restore the hearing of Grxcr2-deficient mice. Thus, our findings suggest that GRXCR2 is critical for the morphogenesis of stereocilia and auditory perception by restricting taperin to the stereocilia base.Item Home Literacy Experiences and Shared Reading Practices: Preschoolers With Hearing Loss(Oxford University Press, 2023) DesJardin, Jean L.; Stika, Carren J.; Eisenberg, Laurie S.; Johnson, Karen C.; Hammes Ganguly, Dianne; Henning, Shirley C.; Otolaryngology -- Head and Neck Surgery, School of MedicineHome literacy experiences and observed parent and child behaviors during shared book reading were investigated in preschool-age children with hearing loss and with typical hearing to examine the relationships between those factors and children's language skills. The methods involved parent-reported home literacy experiences and videotaped parent-child dyads during shared book reading. Children's language skills were tested using the Preschool Language Scale-4. The results indicated significant differences between groups for home literacy experiences and observed parent and child behaviors. Parents of children with hearing loss were found to read more frequently to their children than parents of children with typical hearing, yet scored lower for literacy strategies and teaching techniques compared to parents of children with typical hearing. Children with hearing loss scored lower in interactive reading behaviors compared to children with typical hearing. For children with hearing loss, frequency of book reading and child interactive reading behaviors were strong predictive factors for children's language skills. These results suggest that families of children with hearing loss would benefit from professional support as they read storybooks to their children. Similarly, children with hearing loss should be encouraged to be more interactive during shared book reading.
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