Neurogenetic Disorders with Hearing Loss: Mechanisms, Classifications, and Emerging Insights

Advances in the Hearing Sciences: Current Research and Clinical Applications

Audiologic Management of the Older Patient

Insulin-like growth factor 1 (IGF1) exerts an influence on almost every organ system in the body and plays an important role in growth, development, and metabolism. In the nervous system, IGF1 acts by promoting the development and growth of neurons and glial cells, differentiation of Schwann cells and their migration to axons, neurite outgrowth, and neuronal survival. The lack of IGF1 is associated with several pathological conditions, including severe prenatal growth retardation, postnatal growth failure, microcephaly, mental retardation, and bilateral sensorineural hearing loss. In addition to its physiological effects, based on the findings of in vivo and in vitro experiments and clinical trials, IGF1 is considered to play a potential role in the treatment of various types of neuronal damage. In this review, we discuss the potential use of IGF1 as a therapeutic molecule in the nervous system: (1) auditory system, including hair cells, cochlear ribbon synapses, auditory nerve, and central nervous systems, and (2) other peripheral nervous systems, especially the olfactory system and facial nerve. The role of IGF1 in the progression of age-related sensory deficits, especially hearing loss and olfactory dysfunction, is also discussed. Recent studies on IGF1 demonstrated that exogenous IGF1 can be applied in many fields, thus supporting the continued evaluation of IGF1 as a potential therapeutic molecule. Additional scientific investigations should be conducted to further supplement recent findings.

Objectives/Goals: Hearing loss (HL) can result from environmental and genetic factors. Some genetic variants may be more prevalent in populations living in geographic or cultural isolation. This study explores the genetic variants associated with HL in Puerto Rico and correlates these with auditory and balance disorders to uncover novel variants. Methods/Study Population: After obtaining individual informed consent and assent for a minor when applicable, we will collect clinical audiological data and biological samples (n = 600) from families across Puerto Rico with a history of severe to profound HL. Genomic DNA will be extracted, and exome and mitochondrial genome sequencing will be conducted to identify causal variants in genes associated with HL. The study will assess the prevalence of both novel and reported variants in genes associated with HL and investigate founder variants in the Puerto Rican population. Involvement of genes so far not associated with HL will also be considered when a genetic diagnosis cannot be established. Auditory phenotypes will be correlated with genetic findings, allowing for a comprehensive analysis of genetic contributions to HL in this population. Results/Anticipated Results: This research will advance understanding of the genetic causes of HL in Puerto Rico, leading to more accurate diagnoses, personalized treatment options, and the discovery of novel genes associated with HL. It will also serve as an evidence-based reference to analyze the adequacy of current neonatal hearing screening protocols in PR. Recruitment and sample collection have begun, and we expect our findings to uncover population-specific variants. These results will provide a foundation for further genetic studies aiming at identifying the causes of HL in Puerto Ricans regardless of age of onset. Discussion/Significance of Impact: This study will enhance our understanding of hereditary HL and serve as a basis for developing population-specific diagnostic tools and interventions, particularly in the Puerto Rican population. The research will support future genetic studies and address health disparities in HL in the island.

Objective: To investigate the current situation of occupational exposure to noise among noise workers in an automobile manufacturing enterprise in Tianjin, understand the impact of noise on workers＇ nervous system and hearing, and assess the risk of hearing loss among noise workers. Methods: In May 2021, 3516 workers in an automobile manufacturing enterprise were investigated by using a self-made questionnaire＂Noise Workers Questionnaire＂ and cluster sampling method. The occupational noise hygiene survey and occupational hazards detection were carried out in their workplaces. They were divided into noise exposure group and non-noise exposure group according to whether they were exposed to noise or not. The general characteristics, hearing and nervous system symptoms of the two groups of workers were compared, and the risk of hearing loss was assessed. Results: There were 758 workers in the noise exposure group, aged (26±5) years old, with a working age of 3.0 (2.0, 6.0) years exposed to noise. 2758 workers in the non-noise exposure group, aged (25±6) years old, with a working age of 2.0 (1.0, 4.0) years. There were statistically significant differences in the distribution of workers＇education level, working age and memory loss between the two groups (χ(2)=37.98, 38.70, 5.20, P<0.05). The workers in the noise exposure group showed a decreasing trend of insomnia, dreaminess, sweating and fatigue with the increase of working age (χ(2trend)=6.16, 7.99, P<0.05). The risk classification of binaural high-frequency hearing loss for workers in all noise positions until the age of 50 and 60 was negligible, the risk of occupational noise deafness was low for workers in stamping and welding noise positions until the age of 60. Conclusion: The occupational noise exposed to automobile manufacturing workers may cause certain harm to their nervous and auditory systems. Noise protection measures should be taken to reduce the risk of hearing loss and occupational noise deafness.

Enlarged vestibular aqueduct (EVA) and hearing loss are known to be caused by SLC26A4 mutations, but large phenotypic variability exists among patients with biallelic SLC26A4 mutations. Intrafamilial phenotypic variability was analyzed in multiplex EVA families carrying biallelic SLC26A4 mutations to identify the contribution of SLC26A4 mutations and other genetic or environmental factors influencing the clinical manifestations. Retrospective case series. Eleven multiplex Korean families with EVA and hearing loss that carry biallelic mutations of the SLC26A4 gene were included. Genetic analysis for SLC26A4 and other genes including FOXI1, FOXI1-DBD, and KCNJ10 was performed. The auditory and other phenotypes were compared among siblings with the same SLC26A4 mutations. The difference in the auditory phenotypes was identified between siblings in approximately half of the EVA families. Families with SLC26A4 mutations other than H723R homozygous mutations demonstrated more phenotypic variability, especially in those carrying IVS7-2A>G splice site mutation. Cochlear malformation was a consistent finding among siblings with the same SLC26A4 mutations. No mutation was identified in the FOXI1, FOXI1-DBD, and KCNJ10 genes in the tested families. The possibility of variability concerning auditory phenotype should be considered even within family members carrying the same SLC26A4 mutations when providing genetic counseling to multiplex EVA families. Mutations in the currently known genes associated with EVA other than SLC26A4 were not found to be responsible for the intrafamilial phenotypic variability. Modifier genes or environmental factors other than the currently known genes seem to play a role in the phenotypic expressions of EVA patients.

Hearing loss is the most common sensory-neurological defect in humans. The most common hearing impairment is sensorineural hearing loss (SNHL) caused by the inner ear and related nerves. Diffusion tensor imaging (DTI) is an advanced MRI technique that can provide valuable information about auditory neural pathways and their microstructural changes. The present study was designed to investigate the microstructural changes in auditory pathways-related fiber tracts in children with SNHL. Twenty-two children including 11 subjects with SNHL aged 1-4 years and 11 healthy children were examined as controls. Then, DTI-derived parameters, such as fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AxD), and radial diffusivity (RD), and volume of fiber tracts were extracted from the inferior longitudinal fasciculus, acoustic radiation, and uncinate fasciculus. The results showed an increase in MD, RD, and AxD as well as a decrease in FA, volume, and diameter of auditory-pathway-related fiber tracts. Interestingly, there was an increase in the FA of acoustic radiation. White matter connections in the auditory canal decrease and AR integrity increases due to compensatory effects. These probably reflect atrophy or degradation as well as compensatory cross-modal reorganization in the absence of auditory input and the use of sign language. Diffusion tensor imaging (DTI) plays an important role in preoperative planning.Anatomical knowledge of the auditory tract is essential for lacrimal drainage surgeries, such as cochlear implantation.DTI-based biomarkers for brain changes and allows us to better understand the pathophysiological changes of auditory tract.Microstructural changes in the fiber tracts associated with the auditory pathway can distinguish sensorineural hearing loss (SNHL) from healthy subjects. Sensorineural hearing loss (SNHL) is the most common type and accounts for the majority of all hearing loss. SNHL is a congenital deficit and refers to any cause of hearing loss due to a pathology of the cochlea, auditory nerve, or central nervous system. One of the chief treatment planning is cochlear implant for these patients. So, it is necessary to evaluate the auditory system by imaging devices such as MRI (magnetic resonance imaging) before treatment. Diffusion tensor imaging tractography, or diffusion tensor imaging (DTI) tractography, is an MRI technique that measures the rate of water diffusion between cells to understand and create a map of the body's internal structures; it is most commonly used to provide imaging of the brain. The purpose of the present research was to assess the auditory system and its nerve routs in children before cochlear implant. This study showed that DT imaging is a novel approach for assessment of children with SNHL before and treatment.

Aural Habilitation Update: The Role of Speech Production Skills of Infants and Children With Hearing Loss

Should All Deaf Children Learn Sign Language?

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive multiple congenital malformation and intellectual disability syndrome resulting from variants in DHCR7. Auditory characteristics of persons with SLOS have been described in limited case reports but have not been systematically evaluated. The objective of this study is to describe the auditory phenotype in SLOS. Age- and ability-appropriate hearing evaluations were conducted on 32 patients with SLOS. A subset of 21 had auditory brainstem response testing, from which an auditory neural phenotype is described. Peripheral or retrocochlear auditory dysfunction was observed in at least one ear of 65.6% (21) of the patients in our SLOS cohort. The audiometric phenotype was heterogeneous and included conductive, mixed, and sensorineural hearing loss. The most common presentation was a slight to mild conductive hearing loss, although profound sensorineural hearing loss was also observed. Abnormal auditory brainstem responses indicative of retrocochlear dysfunction were identified in 21.9% of the patients. Many were difficult to test behaviorally and required objective assessment methods to estimate hearing sensitivity. Individuals with SLOS are likely to have hearing loss that may impact communication, including speech and language development. Routine audiologic surveillance should be conducted to ensure prompt management of hearing loss.

A novel high-throughput analysis approach: immune response-related genes are upregulated in age-related hearing loss Yolande Tra1, Robert D Frisina2, Mary D&#39;Souza31MD Poison Center, School of Pharmacy, University of Maryland, Baltimore, MD, 2Department of Chemical and Biomedical Engineering, College of Engineering, University of South Florida, Tampa FL, 3Department of Surgery, and the Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, NY, USABackground: Presbycusis is defined as the hearing loss that occurs with aging. Genes that are responsible for this clinical condition have still not been identified. The present study explores gene discovery for age-related hearing loss using the CBA/CaJ mouse model of age-related hearing loss.Methods and results: In the present investigation, in addition to a gene-based analysis, a molecular pathway analysis was performed to evaluate differences in gene expression in 15 aged mice with age-related hearing loss, and 25 young to middle-aged mice with normal hearing. Using three different statistical approaches, the gene-based analysis revealed four common probe sets, ie, Ctss (Cathespin), Csnk (casein kappa), Mpeg1 (macrophage-expressed gene 1), and Clecsf12 (C-type calcium-dependent carbohydrate recognition domain lectin, superfamily member 12) that are significantly upregulated with age and hearing loss in the mouse cochlea (inner ear). Relative real-time polymerase chain reaction was used for quantitative, sensitivity analysis of gene transcription changes and confirmed the gene microarray results. Three strategies for pathway analysis were consistent with these gene expression discoveries, and revealed a common immune response pathway. More specifically, the analysis suggests that B cell-mediated humoral immune function plays an important role in the underlying etiology of presbycusis, similar to certain other neurodegenerative diseases. Other top pathways from this analysis included those involving dendritic antigen-presenting cells, carbohydrate binding, G-protein coupled receptor binding, and epithelial-to-mesenchymal transition pathways.Conclusion: Combining microarray gene discovery, polymerase chain reaction, and multiple pathway analyses revealed insights into immune system involvement in the progression of age-related hearing loss.Keywords: high-throughput gene analysis, gene microarray, presbycusis, bioinformatics, biostatistics, auditory system

Teens at Risk: Audiologists Respond

Hereditary hearing loss is characterized by remarkable phenotypic heterogeneity. Patients with the same pathogenic mutations may exhibit various hearing loss phenotypes. In the Chinese population, the c.235delC mutation is the most common pathogenic mutation of GJB2 and is closely related to hereditary recessive hearing loss. Here, we investigated the hearing phenotypes of patients with hearing loss associated with the homozygous c.235delC mutation, paying special attention to asymmetric interaural hearing loss. A total of 244 patients with the GJB2 c.235delC homozygous mutation encountered from 2007 to 2015 were enrolled. The severity of hearing loss was scaled with the American Speech-Language-Hearing Association (ASHA). Auditory phenotypes were analyzed, and three types of interaural asymmetry were defined based on audiograms: Type A (asymmetry of hearing loss severity), Type B (asymmetry of audiogram shape), and Type C (Type A plus Type B). Of the 488 ears (244 cases) examined, 71.93% (351) presented with profound hearing loss, 14.34% (70) with severe hearing loss, and 9.43% (46) with moderate to severe hearing loss. The most common audiogram shapes were descending (31.15%) and flat (24.18%). A total of 156 (63.93%) of the 244 patients exhibited asymmetric interaural hearing loss in terms of severity and/or audiogram shape. Type A was evident in 14 of these cases, Type B in 106, and Type C in 36. In addition, 211 of 312 ears (67.63%) in the interaural hearing asymmetry group showed profound hearing loss, and 59 (18.91%) exhibited severe hearing loss, with the most common audiogram shapes being flat (27.88%) and descending (22.12%). By contrast, in the interaural hearing symmetry group, profound hearing loss was observed in 140 ears (79.55%), and the most common audiograms were descending (46.59%) and residual (21.59%). Hearing loss associated with the GJB2 c.235delC homozygous mutation shows diverse phenotypes, and a considerable proportion of patients show bilateral hearing loss asymmetry.

Hearing impairment, the most prevalent sensory deficit, affects more than 466 million people worldwide (WHO). We presently lack causative treatment for the most common form, sensorineural hearing impairment; hearing aids and cochlear implants (CI) remain the only means of hearing restoration. We engaged with CI users to learn about their expectations and their willingness to collaborate with health care professionals on establishing novel therapies. We summarize upcoming CI innovations, gene therapies, and regenerative approaches and evaluate the chances for clinical translation of these novel strategies. We conclude that there remains an unmet medical need for improving hearing restoration and that we are likely to witness the clinical translation of gene therapy and major CI innovations within this decade.

The auditory system is highly sensitive to bilirubin toxicity. Damage to the auditory nervous system includes auditory neuropathy or auditory dyssynchrony and auditory processing problems which may occur with or without deafness, hearing loss. Auditory dysfunction may occur in children with or without other signs of classical kernicterus. Bilirubin selectively damages the brainstem auditory nuclei, and may also damage the auditory nerve and spiral ganglion containing cell bodies of primary auditory neurons. The inner ear, thalamic and cortical auditory pathways appear to be spared. Noninvasive auditory neurophysiological tests such as the auditory brainstem response (ABR) or brainstem auditory response (BAER) play an important role in the early detection of bilirubin-induced auditory and central nervous system dysfunction in the neonate.