Search Results (100)

Objectives: Observational studies have shown that chronic obstructive pulmonary disease (COPD) is associated with an increased risk of hearing impairment. However, causality remains unclear, including with respect to lung function. This study aimed to investigate the associations of lung function and COPD with hearing impairment in the UK Biobank and confirm potential causalities using Mendelian randomization (MR). Methods: Cross-sectional analyses were performed using logistic regression models in a subsample of the UK Biobank. Two-sample MR analyses were performed on summary statistics for forced expiratory volume in one second (FEV1), forced vital capacity (FVC), COPD, and sensorineural hearing loss. Results: FEV1 and FVC were negatively associated with hearing impairment, with odds ratios (95% confidence intervals) of 0.80 (0.77, 0.84) and 0.80 (0.76, 0.83), respectively. COPD was positively associated with hearing impairment, with an odds ratio (95% confidence interval) of 1.10 (1.02, 1.18). In the MR analyses, a negative association was found between FVC and sensorineural hearing loss, with an odds ratio (95% confidence interval) of 0.91 (0.83, 0.99). For FVE1 and COPD, no significant associations were found. Conclusions: The results of this study showed that FVC was causally associated with hearing impairment, suggesting a potential protective effect of FVC on hearing impairment. Full article

Hearing impairments (HIs) are clinically and genetically very heterogeneous. Finding the causative mutations in patients is frequently a challenge. We investigated two brothers affected by a sensorineural, moderate non-syndromic HI. Exome sequencing revealed that they carried the heterozygous c.812C>T (p.Ser271Leu) variant in GATA3. This gene encodes a transcription factor involved in embryonic development, its mutations causing the autosomal dominant HDR (hypoparathyroidism, deafness, and renal disease) syndrome. The variant affects a conserved residue within the proximal zinc-finger motif of GATA3. Sanger sequencing confirmed the presence of the variant in the two brothers, but it showed that surprisingly it was not carried by any of the parents. Segregation studies on 20 fully informative microsatellite markers in the family confirmed that the variant arose de novo. A benign SNP in the mother, close to the position of the variant, allowed us to determine that this was inherited from the father. Gene reporter functional assays supported the pathogenicity of the variant. Clinical reassessment of the two brothers did not disclose any additional abnormality. We conclude that mosaicism for this de novo mutation in the father’s germ line explains the pattern of inheritance in this family and that p.Ser271Leu is causing this unexpected phenotype of non-syndromic HI. Full article

Background/Objectives: The vestibulo-respiratory reflex regulates the tension of the respiratory muscles, which prevents apneas and awakenings during sleep. This study aimed to determine whether functional deficits in the inner ear disturb sleep quality. Methods: We compared sleep parameters in patients with their first episode of acute inner ear deficit (Group A: sudden idiopathic vertigo attack, sudden sensorineural hearing loss), chronic functional inner ear impairment (Group B: chronic peripheral vertigo, permanent hearing loss), and in healthy individuals (Group C). Polygraphy recordings were performed twice, in Group A at the onset of acute otoneurological symptoms and the second time after their withdrawal with an interval of 1 to 13 days, in Group B after 1 to 6 days, and in Group C after 1 to 8 days. Results: In Group A during the symptomatic night, overall and central apnea-hypopnea indices were significantly higher and snoring time was longer. Group A also had higher central apnea-hypopnea index on the first night compared to healthy individuals. In chronic disorders, sleep recordings showed lower autonomic arousal index than in controls or symptomatic nights in Group A. Conclusions: These findings highlight the severity of sleep apnea indicators in Group A. Our results suggest that acute dysfunction of the inner ear substantially impacts central neuronal signaling responsible for regulating normal sleep-related breathing and leads to a deterioration in sleep quality in contrast to individuals with chronic inner ear impairments. It can also be assumed that people with chronic vertigo or hearing loss experience less interrupted sleep than healthy individuals. Full article

Noise-induced hearing loss (NIHL) is a common type of sensorineural hearing loss caused by exposure to high-intensity noise that leads to irreversible cochlear damage. Despite extensive research on cochlear pathophysiology, the precise mechanisms remain unclear, and no established treatment exists. This is due to the challenges in imaging and the inability to perform biopsies in human patients. Consequently, animal models, particularly mice, have been widely used to study NIHL. Clinically, NIHL presents as either a temporary threshold shift, in which hearing recovers, or a permanent threshold shift, which results in an irreversible loss. Histopathological studies have identified the key features of NIHL, including outer hair cell loss, auditory nerve degeneration, and synaptic impairment. Recent findings suggest that oxidative stress and inflammation are major contributors to NIHL, highlighting the potential for therapeutic interventions, such as antioxidants and anti-inflammatory agents. Given the increasing prevalence of NIHL owing to occupational noise exposure and personal audio device use, addressing this issue is a pressing public health challenge. This review summarizes the clinical features, underlying mechanisms, and emerging treatment strategies for NIHL while identifying current knowledge gaps and future research directions. Full article

Background: Presbycusis, also known as age-related hearing loss (ARHL), is the most frequent sensory disability affecting elderly adults worldwide. ARHL is characterized by bilateral, progressive, sensorineural hearing loss that is more pronounced at a high frequency. Conventional factors associated with ARHL include diabetes, hypertension, and a family history of hearing loss. The severity of hearing impairment varies between individuals. The defined causative molecular pathogenesis for ARHL is unknown, thus the identification of underlying pathogenic mechanisms involved in ARHL is imperative for the development of effective therapeutic approaches. Epigenetics is the study of phenotypic changes caused by the modification of gene expression rather than the alteration of a DNA sequence. While it is hypothesized that ARHL could result from undiscovered epigenetic susceptibility, there is a shortage of information on the role that epigenetic modification plays in ARHL. Here we present an investigation on the involvement of DNA methylation in ARHL. Results: Clinical, audiometric and DNA testing, and high-throughput methylation pattern screening were undertaken for ARHL patients and matched control subjects. Our results demonstrate a strong correlation between patients’ hearing measurements and methylation at CpG sites cg1140494 (ESPN) and cg27224823 (TNFRSF25). We identified 136 differentially methylated CpGs that were shared between a high and low audiometric frequency in the patient’s cohort. CpG cites in hearing loss candidate genes, KCNQ1, TMEM43, GSTM1, TCF25, and GSR, were found to be highly methylated in presbycusis patients as compared to the controls. A methylation polymerase chain reaction (PCR) assay was used to confirm methylation levels at a specific gene locus in ARHL patients and controls. Conclusions: Altered DNA methylation and its impact on gene expression has been implicated in many biological processes. By interrogating the methylation status across the genome of both hearing loss patients and those with normal hearing, our study can help to establish an association between the audiometric patterns and methylation status in ARHL, yielding new avenues for the identification of potential candidate genes for hearing loss. Full article

Background/Objectives: Growth hormone deficiency (GHD) is a rare endocrine disorder characterized by inadequate secretion of growth hormone, which affects growth, cellular processes, and physiological functions. In addition to growth impairment, GHD is associated with a range of otorhinolaryngological (ENT) symptoms, such as sensorineural hearing loss, dizziness, and voice alterations. These symptoms may be underrecognized due to a lack of routine ENT evaluations in GHD management. Methods: This systematic review, conducted in accordance with PRISMA guidelines, assessed the prevalence of ENT symptoms in patients with GHD by analyzing studies from the PubMed, Embase, and Scopus databases. Results: Based on the analysis of eleven studies that met the inclusion criteria, more than half of patients with GHD experience ENT symptoms (61.4%). Symptom variability appeared to correlate with treatment access, age of onset, and the presence of comorbidities. The study underscores the importance of routine ENT assessments as part of the multidisciplinary management of patients with GHD. Conclusions: Early detection and management of ENT symptoms may significantly improve quality of life, reduce social and educational challenges, and support long-term health outcomes. Further research is needed to clarify the role of recombinant human growth hormone therapy in mitigating ENT manifestations in this patient population. Full article

The Universal Neonatal Hearing Screening (UNHS) program is crucial for the early detection and treatment of hearing impairment in newborns. Poland has successfully implemented a nationwide UNHS program, adhering to international standards. Research indicates that hearing loss affects approximately 2–4 per 1000 infants, with sensorineural hearing loss being the most prevalent. Major risk factors include genetic alterations, craniofacial anomalies, prematurity, hyperbilirubinemia, and congenital infections such as cytomegalovirus. Despite the program’s success, challenges related to limited parental awareness and disparities in access highlight the need for continuous improvement in screening and follow-up procedures. Additionally, gene therapy is emerging as a promising treatment for hearing loss. While still experimental, gene therapy could become a key complementary treatment option in the future, offering new hope for those with hearing impairments. Full article

Age-related hearing loss (ARHL) is a highly prevalent, burdensome sensorineural hearing loss closely associated with impaired autophagic influx. Our previous studies revealed that neuritin, a neurotrophic factor primarily expressed in the central nervous system, could alleviate drug-induced damages in hair cells (HCs) and spiral ganglion neurons. However, its effects on ARHL and whether these effects are closely related to autophagy remain unclear. Using the Nrn1 knock-in mice and cultured cochlear basilar membrane (CBM) of the neonatal mouse, we show that neuritin could restore aging-associated hearing loss and alleviate senescence-associated damage in the cochlea. Overexpression of neuritin in support cells (SCs) alleviates the loss of cochlear HCs and nerve fibers, reducing the damage to spiral ganglion neurons and the shifts in ABR’s high-frequency threshold. Furthermore, conditional overexpression of neuritin in SCs improves autophagic influx by upregulating the expression of microtubule-associated protein 1 light chain 3 type B (LCB3) protein and downregulating the expression of p21 protein. In cultured neonatal mouse CBM, neuritin administration significantly inhibits D-galactose-induced HC loss, cellular apoptosis, and ROS production and promotes autophagic influx. These effects were weakened when the autophagy inhibitor 3-MA was added. In summary, our results confirm the therapeutic potential of neuritin treatment for ARHL. Full article

The BCS1L gene encodes a mitochondrial chaperone which inserts the Fe₂S₂ iron–sulfur Rieske protein into the nascent electron transfer complex III. Variants in the BCS1L gene are associated with a spectrum of mitochondrial disorders, ranging from mild to severe phenotypes. Björnstad syndrome, a milder condition, is characterized by sensorineural hearing loss (SNHL) and pili torti. More severe disorders include Complex III Deficiency, which leads to neuromuscular and metabolic dysfunctions with multi-systemic issues and Growth Retardation, Aminoaciduria, Cholestasis, Iron Overload, and Lactic Acidosis syndrome (GRACILE). The severity of these conditions varies depending on the specific BCS1L mutation and its impact on mitochondrial function. This study describes a 27-month-old child with SNHL, proximal renal tubular acidosis, woolly hypopigmented hair, developmental delay, and metabolic alterations. Genetic analysis revealed a homozygous BCS1L variant (c.38A>G, p.Asn13Ser), previously reported in a patient with a more severe phenotype that, however, was not functionally characterized. In this work, functional studies in a yeast model and patient-derived fibroblasts demonstrated that the variant impairs mitochondrial respiration, complex III activity (CIII), and also alters mitochondrial morphology in affected fibroblasts. Interestingly, we unveil a new possible mechanism of pathogenicity for BCS1L mutant protein. Since the interaction between BCS1L and CIII is increased, this suggests the formation of a BCS1L-containing nonfunctional preCIII unable to load RISP protein and complete CIII assembly. These findings support the pathogenicity of the BCS1L c.38A>G variant, suggesting altered interaction between the mutant BCS1L and CIII. Full article

Background: Body motion significantly contributes to understanding communicative and social interactions, especially when auditory information is impaired. The visual skills of people with hearing loss are often enhanced and compensate for some of the missing auditory information. In the present study, we investigated the recognition of social interactions by observing body motion in people with post-lingual sensorineural hearing loss (SNHL). Methods: In total, 38 participants with post-lingual SNHL and 38 matched normally hearing individuals (NHIs) were presented with point-light stimuli of two agents who were either engaged in a communicative interaction or acting independently. They were asked to classify the actions as communicative vs. independent and to select the correct action description. Results: No significant differences were found between the participants with SNHL and the NHIs when classifying the actions. However, the participants with SNHL showed significantly lower performance compared with the NHIs in the description task due to a higher tendency to misinterpret communicative stimuli. In addition, acquired SNHL was associated with a significantly higher number of errors, with a tendency to over-interpret independent stimuli as communicative and to misinterpret communicative actions. Conclusions: The findings of this study suggest a misinterpretation of visual understanding of social interactions in individuals with SNHL and over-interpretation of communicative intentions in SNHL acquired later in life. Full article

Autosomal dominant non-syndromic hearing loss (ADNSHL) is a genetically heterogenic condition. The transformation/transcription domain associated protein (TRRAP) gene has been recently associated with ADNSHL, and only four variants of the gene have so far been reported in this disease. Here, we report on a Hungarian ADNSHL family in which the affected individuals exhibited sensorineural hearing loss with similar clinical symptoms, including initial impaired high frequencies that subsequently affected speech and lower frequencies. Whole exome sequencing and screening of the shared genetic variants of the affected individuals was performed. Our results revealed a novel heterozygous missense variant (NM_001244580.2, c.5360A>G, p.Lys1787Arg) in the TRRAP gene. This variant is completely co-segregated with hearing impairment. It is present in a heterozygous form in the affected mother and daughter but not carried by any unaffected family members. This study highlights the importance of elucidating the germline genetic background of ADNSHL, which may help to predict individual risk and the risk of family members. This will improve prevention, screening, and therapeutic measures for each patient and hearing loss-prone families. Full article

Background: Alport syndrome (AS) is a clinically and genetically heterogeneous glomerulopathy resulting from pathogenic variants in COL4A3, COL4A4, and COL4A5. Genetic diagnosis is increasingly being conducted using next-generation sequencing (NGS). Methods: Within eight years, we examined a group of 247 Polish individuals and found in total 138 unrelated probands suspected with AS based on clinical course, laboratory findings, and/or family history, as well as the total of 109 family members. We applied a targeted NGS panel to identify the genetic spectrum of AS. Known and novel variants were revealed, and detailed evaluation was performed according to ACMG/AMP guidelines to classify them as pathogenic/likely pathogenic/VUS changes. Identified genotypes were compared with clinical manifestations: hematuria, proteinuria, chronic kidney disease, sensorineural hearing impairment, ocular abnormalities, and hypertension. Results: The molecular background was established in 109/138 probands. Overall, 79 different COL4A3-COL4A5 changes (56 known and 23 novel) were revealed. About 97% were SNVs, and only two COL4A5 CNVs were identified. In total, 11 recurrent COL4A3-COL4A5 variants were observed, including the most frequent COL4A5:p.Gly624Asp, accounting for 31% of X-linked AS. Conclusions: The use of NGS panel has shown considerable promise in the field of AS, increasing diagnostic rate to 79% and reducing time to diagnosis. The phenotype-driven gene panel, specific for genetic diseases in the pediatric population, is an affordable alternative to WGS and WES, offering comparable diagnostic efficacy and supporting its implementation as a first-line genetic test in rare diseases, including AS. Based on the obtained genotype–phenotype correlation, we assessed that NGS allows us to avoid invasive renal biopsy in AS diagnosis. It provides AS confirmation/exclusion, atypical AS identification, symptomatic/asymptomatic monoallelic COL4A3-COL4A5 carrier (especially COL4A5 females) determination, and inheritance pattern establishment. AS diagnosis confirmation enables clinical course prediction and is crucial for the early introduction of renoprotective treatment with renin–angiotensin–aldosterone system blockade, aimed at slowing the disease progression and estimating the risk in family members, which is important for genetic counselling. Full article

Background: Sensorineural hearing loss (SNHL) is a major contributor to hearing impairment, yet effective therapeutic options remain elusive. Mendelian randomization (MR) has proven valuable for drug repurposing and identifying new therapeutic targets. This study aims to pinpoint novel treatment targets for SNHL, exploring their pathophysiological roles and potential adverse effects. Methods: This research utilized the UKB-PPP database to access cis-protein quantitative trait locus (cis-pQTL) data, with SNHL data sourced from the FinnGen database as the endpoint for the MR causal analysis of drug targets. Colocalization analysis was employed to determine whether SNHL risk and protein expression share common SNPs. A phenotype-wide association analysis was conducted to assess the potential side effects of these targets. Drug prediction and molecular docking were subsequently used to evaluate the therapeutic potential of the identified targets. Results: Four drug target proteins significantly associated with sensorineural hearing loss (SNHL) were determined by Mendelian randomization (MR) analysis and co-localization analysis. These drug targets include LATS1, TEF, LMNB2, and OGFR and were shown to have fewer potential side effects when acting on these target proteins by phenotype-wide association analysis. Genes associated with sensorineural hearing loss are primarily implicated in the Hippo signaling pathway, cell–cell adhesion, and various binding regulatory activities and are involved in the regulation of cell proliferation and apoptosis. Next, drugs for the treatment of SNHL were screened by the DsigDB database and molecular docking, and the top 10 drugs were selected based on p-value. Among them, atrazine CTD 00005450 was identified as the most likely therapeutic target, followed by ampyrone HL60 DOWN and genistein CTD 00007324. In addition, LMNB2, LATS1, and OGFR could be intervened in by multiple drugs; however, fewer drugs intervened in TEF. Conclusion: This study has successfully identified four promising drug targets for SNHL, which are likely to be effective in clinical trials with minimal side effects. These findings could significantly streamline drug development for SNHL, potentially reducing the costs and time associated with pharmaceutical research and development. Full article

Background/Objectives: Hearing loss is one of the most common sensorineural impairments, and approximately 60% of early-onset cases are due to genetic variations. The otogelin-like protein, encoded by the OTOGL gene, is a component of the acellular membranes of the inner ear, such as the tectorial membrane, and is thought to play an important role in cochlear amplification. OTOGL gene variants are a rare cause of hearing loss such as DFNB84B, a mild-to-moderate sensorineural hearing loss presenting in early childhood with autosomal recessive inheritance. In this study, we aim to enhance our comprehension of the phenotypes of hearing loss caused by OTOGL variants. Methods: A total of 7056 Japanese patients with hearing loss were recruited, and based on massively parallel DNA sequencing on 158 target genes, we selected patients with biallelic OTOGL variants. Results: Ten affected individuals with OTOGL gene variants were detected, the largest group of patients yet to be reported, and eight of the eleven variants were novel. Our results showed that variations in this gene led to mild-to-moderate non-progressive hearing loss, and the accompanying symptoms, mainly vestibular symptoms, were speculated to present in adulthood. Conclusions: Determination of the phenotypes of genes causative of hearing loss is expected to greatly benefit patients with hearing loss as it can assist in predicting outcomes and lead to appropriate intervention, which, in OTOGL-associated hearing loss cases, is based around the fact that the patients need not be concerned with deterioration in hearing, but require careful follow-up for vestibular symptoms. Full article

Background/Objectives: A heterozygous mutation in the WFS1 gene is responsible for autosomal dominant non-syndromic hearing loss (DFNA6/14/38) and Wolfram-like syndrome, which is characterized by bilateral sensorineural hearing loss with optic atrophy and/or diabetes mellitus. However, detailed clinical features for the patients with the heterozygous p.A684V variant remain unknown. Methods: We report the clinical details of 14 cases with a heterozygous p.A684V variant in the WFS1 gene identified from target resequencing analysis of 63 previously reported deafness genes by next-generation sequencing of 15,684 hearing loss patients (mean age 27.5 ± 23.1 years old, 6574 male, 8612 female and 498 for whom information was unavailable). Results: Among the 14 patients from 13 families with the p.A684V variant, nine were sporadic cases. In addition, we confirmed de novo occurrence of this variant in seven families. This result strongly supports the notion that this variant was located on a mutational hotspot. When comparing previously reported cases of autosomal dominant WFS1 gene-associated hearing loss, most of the patients in this study showed severe-to-profound bilateral sensorineural hearing loss (genotype–phenotype correlation). Two patients had optic atrophy, while the others did not have any other complications. Conclusions: The identified heterozygous p.A684V variant appears to be a hotspot mutation and likely to cause severe-to-profound hearing loss in early childhood. Cochlear implantation is considered favorable in cases of hearing impairment due to this variant. Full article