Serum lipid metabolism characteristics and potential biomarkers in patients with unilateral sudden sensorineural hearing loss.

BACKGROUND: Glycerophospholipids (GPLs) are essential for cell membrane structure and function. Sphingomyelin and its metabolites regulate cell growth, apoptosis, and stress responses. This study aimed to investigate lipid metabolism in patients experiencing sudden sensorineural hearing loss across all frequencies (AF-SSNHL). METHODS: The study included 60 patients diagnosed with unilateral AF-SSNHL, among whom 30 patients had a level of hearing improvement ≥ 15 dB after 6 months of follow-up. A propensity score-matched (2:1) control group was used. Liquid chromatography‒mass spectrometry based untargeted lipidomics analysis combined with multivariate statistics was performed to investigate the lipids change. The "lipidome" R package and weighted gene co-expression network analysis (WGCNA) were utilised to assess the lipids' structural features and the association between lipids and hearing. RESULTS: Lipidomics successfully differentiated the AF-SSNHL group from the control group, identifying 17 risk factors, mainly including phosphatidylcholine (PC), phosphatidylethanolamine (PE), and related metabolites. The ratios of lysophosphatidylcholine/PC, lysophosphatidylethanolamine/PE, and lysodimethylphosphatidylethanolamine/PE were upregulated, while some glycerophospholipid (GPL)-plasmalogens were downregulated in the AF-SSNHL group, indicating abnormal metabolism of GPLs. Trihexosylceramide (d34:1), PE (18:1e_22:5), and sphingomyelin (d40:3) were significantly different between responders and nonresponders, and positively correlated with hearing improvement. Additionally, the results of the WGCNA also suggested that partial GPL-plasmalogens were positively associated with hearing improvement. CONCLUSION: AF-SSNHL patients exhibited abnormally high blood lipids and pronounced GPLs metabolic abnormalities. Sphingolipids and GPL-plasmalogens had an association with the level of hearing improvement. By understanding the lipid changes, clinicians may be able to predict the prognosis of hearing recovery and personalize treatment approaches.

A novel start-loss mutation of the SLC29A3 gene in a consanguineous family with H syndrome: clinical characteristics, in silico analysis and literature review.

BACKGROUND: The SLC29A3 gene, which encodes a nucleoside transporter protein, is primarily located in intracellular membranes. The mutations in this gene can give rise to various clinical manifestations, including H syndrome, dysosteosclerosis, Faisalabad histiocytosis, and pigmented hypertrichosis with insulin-dependent diabetes. The aim of this study is to present two Iranian patients with H syndrome and to describe a novel start-loss mutation in SLC29A3 gene. METHODS: In this study, we employed whole-exome sequencing (WES) as a method to identify genetic variations that contribute to the development of H syndrome in a 16-year-old girl and her 8-year-old brother. These siblings were part of an Iranian family with consanguineous parents. To confirmed the pathogenicity of the identified variant, we utilized in-silico tools and cross-referenced various databases to confirm its novelty. Additionally, we conducted a co-segregation study and verified the presence of the variant in the parents of the affected patients through Sanger sequencing. RESULTS: In our study, we identified a novel start-loss mutation (c.2T > A, p.Met1Lys) in the SLC29A3 gene, which was found in both of two patients. Co-segregation analysis using Sanger sequencing confirmed that this variant was inherited from the parents. To evaluate the potential pathogenicity and novelty of this mutation, we consulted various databases. Additionally, we employed bioinformatics tools to predict the three-dimensional structure of the mutant SLC29A3 protein. These analyses were conducted with the aim of providing valuable insights into the functional implications of the identified mutation on the structure and function of the SLC29A3 protein. CONCLUSION: Our study contributes to the expanding body of evidence supporting the association between mutations in the SLC29A3 gene and H syndrome. The molecular analysis of diseases related to SLC29A3 is crucial in understanding the range of variability and raising awareness of H syndrome, with the ultimate goal of facilitating early diagnosis and appropriate treatment. The discovery of this novel biallelic variant in the probands further underscores the significance of utilizing genetic testing approaches, such as WES, as dependable diagnostic tools for individuals with this particular condition.

Diabetes mellitus, hearing loss, and therapeutic interventions: A systematic review of insights from preclinical animal models.

OBJECTIVES: The aim of this systematic review article is to evaluate the relationship between diabetes mellitus (DM) and sensorineural hearing loss (SNHL) utilizing preclinical animal models. The review focused on studies assessing SNHL in diabetic animal models, elucidating the mechanisms of DM-associated SNHL, and exploring the response of diabetic animal models to noise overexposure. We also discussed studies investigating the efficacy of potential therapeutic strategies for amelioration of DM-associated SNHL in the animal models. METHODS: A protocol of this systematic review was designed a priori and was registered in the PROSPERO database (registration number: CRD42023439961). We conducted a comprehensive search on PubMed, Science Direct, Web of Science, Scopus, and EMBASE databases. A minimum of three reviewers independently screened, selected, and extracted data. The risk of bias assessment of eligible studies was conducted using the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) tool. RESULTS: Following the screening of 238 studies, twelve original articles were included in this systematic review. The studies revealed that hyperglycemia significantly affects auditory function, with various pathological mechanisms contributing to DM-induced hearing impairment, including cochlear synaptopathy, microangiopathy, neuropathy, oxidative stress, mitochondrial abnormalities, and apoptosis-mediated cell death. Emerging interventions, such as Asiaticoside, Trigonelline, Chlorogenic acid, and Huotanquyu granules, demonstrated efficacy in providing otoprotection for preserving cochlear hair cells and hearing function. CONCLUSIONS: Our systematic review delves into the intricate relationship between DM and hearing impairment in animal models. Future research should focus on targeted therapies to enhance cochlear mitochondrial function, alleviate oxidative stress, and regulate apoptosis. The association between SNHL and social isolation as well as cognitive decline underscores the necessity for innovative therapeutic modalities addressing yet undiscovered mechanisms. Translating findings from animal models to human studies will validate these findings, offering a synergistic approach to effectively manage DM-associated co-morbidities such as hearing impairment.

Toward parametric Bayesian adaptive procedures for multi-frequency categorical loudness scaling.

A series of Bayesian adaptive procedures to estimate loudness growth across a wide frequency range from individual listeners was developed, and these procedures were compared. Simulation experiments were conducted based on multinomial psychometric functions for categorical loudness scaling across ten test frequencies estimated from 61 listeners with normal hearing and 87 listeners with sensorineural hearing loss. Adaptive procedures that optimized the stimulus selection based on the interim estimates of two types of category-boundary models were tested. The first type of model was a phenomenological model of category boundaries adopted from previous research studies, while the other type was a data-driven model derived from a previously collected set of categorical loudness scaling data. An adaptive procedure without Bayesian active learning was also implemented. Results showed that all adaptive procedures provided convergent estimates of the loudness category boundaries and equal-loudness contours between 250 and 8000 Hz. Performing post hoc model fitting, using the data-driven model, on the collected data led to satisfactory accuracies, such that all adaptive procedures tested in the current study, independent of modeling approach and stimulus-selection rules, were able to provide estimates of the equal-loudness-level contours between 20 and 100 phons with root-mean-square errors typically under 6 dB after 100 trials.

What are the neurodevelopmental outcomes of children with asymptomatic congenital cytomegalovirus infection at birth? A systematic literature review.

Congenital cytomegalovirus (cCMV) is among the most common congenital infections globally. Of 85%-90% cCMV-infected infants without symptoms at birth, 10%-15% develop sequelae, most commonly sensorineural hearing loss (SNHL); their childhood neurodevelopmental outcomes are less well understood. Embase and MEDLINE were searched for publications from 16th September 2016 to 9th February 2024 to identify studies reporting primary data on neurodevelopmental outcomes in children with asymptomatic cCMV (AcCMV), measured using assessment tools or as evaluated by the study investigators, clinicians, educators, or parents. The Newcastle-Ottawa scale was applied to studies to assess risk of bias. Of 28 studies from 18 mostly high-income countries, there were 5-109 children with AcCMV per study and 6/28 had a mean or median age at last follow-up of ≥5 years. Children with AcCMV had better neurodevelopmental outcomes than children with symptomatic cCMV in 16/19 studies. Of 9/28 studies comparing AcCMV with CMV-uninfected children, six reported similar outcomes whilst three reported differences limited to measures of full-scale intelligence and receptive vocabulary among children with AcCMV and SNHL, or more generally in motor impairment. Common limitations of studies for our question were a lack of cCMV-uninfected controls, heterogeneous definitions of AcCMV, lack of focus on neurodevelopment, selection bias and inadequate follow-up. There was little evidence of children with AcCMV having worse neurodevelopmental outcomes than CMV-uninfected children, but this conclusion is limited by study characteristics and quality; findings highlight the need for well-designed and standardised approaches to investigate long-term sequelae.

A novel variant c.902C>A (p. A301D) in KCNQ4 associated with non-syndromic deafness 2A in a Chinese family.

BACKGROUND: Deafness autosomal dominant 2A (DFNA2A) is related to non-syndromic genetic hearing impairment. The KCNQ4 (Potassium Voltage-Gated Channel Subfamily Q Member 4) can lead to DFNA2A. In this study, we report a case of autosomal dominant non-syndromic hearing loss with six family members as caused by a novel variant in the KCNQ4 gene. METHODS: The whole-exome sequencing (WES) and pure tone audiometry were performed on the proband of the family. Sanger sequencing was conducted on family members to determine if the novel variant in the KCNQ4 gene was present. Evolutionary conservation analysis and computational tertiary structure protein prediction of the wild-type KCNQ4 protein and its variant were then performed. In addition, voltage-gated channel activity of the wild-type KCNQ4 protein and its variant were tested using whole-cell patch clamp. RESULTS: It was observed that the proband had inherited autosomal dominant, non-syndromic sensorineural hearing loss as a trait. A novel co-segregating heterozygous missense variant (c.902C>A, p.Ala301Asp) of the KCNQ4 gene was identified in the proband and other five affected family members. This variant was predicted to cause an alanine-to-aspartic acid substitution at position 301 in the KCNQ4 protein. The alanine at position 301 is well conserved across different species. Whole-cell patch clamp showed that there was a significant difference between the WT protein currents and the mutant protein currents in the voltage-gated channel activity. CONCLUSION: In the present study, performing WES in conjunction with Sanger sequencing enhanced the detection of a novel, potentially causative variant (c301 A>G; p.Ala301Asp) in exon 6 of the KCNQ4 gene. Therefore, our findings contributed to the mutation spectrum of the KCNQ4 gene and may be useful in the diagnosis and gene therapy of deafness autosomal dominant 2A.

A systematic review on the contribution of DNA methylation to hearing loss.

BACKGROUND: DNA methylation may have a regulatory role in monogenic sensorineural hearing loss and complex, polygenic phenotypic forms of hearing loss, including age-related hearing impairment or Meniere disease. The purpose of this systematic review is to critically assess the evidence supporting a functional role of DNA methylation in phenotypes associated with hearing loss. RESULTS: The search strategy yielded a total of 661 articles. After quality assessment, 25 records were selected (12 human DNA methylation studies, 5 experimental animal studies and 8 studies reporting mutations in the DNMT1 gene). Although some methylation studies reported significant differences in CpG methylation in diverse gene promoters associated with complex hearing loss phenotypes (ARHI, otosclerosis, MD), only one study included a replication cohort that supported a regulatory role for CpG methylation in the genes TCF25 and POLE in ARHI. Conversely, several studies have independently confirmed pathogenic mutations within exon 21 of the DNMT1 gene, which encodes the DNA (cytosine-5)-methyltransferase 1 enzyme. This methylation enzyme is strongly associated with a rare disease defined by autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). Of note, rare variants in DNMT1 and DNMT3A genes have also been reported in noise-induced hearing loss. CONCLUSIONS: Evidence supporting a functional role for DNA methylation in hearing loss is limited to few genes in complex disorders such as ARHI. Mutations in the DNMT1 gene are associated with ADCA-DN, suggesting the CpG methylation in hearing loss genes deserves further attention in hearing research.

Hyperbaric Medicine in Pediatrics - reality of a Portuguese reference center.

OBJECTIVE: To identify and characterize the population of Pediatric patients referred to our hyperbaric oxygen therapy center. METHODS: Retrospective and observational study, including pediatric patients treated with hyperbaric oxygen therapy, from 2006 to 2021, at the hyperbaric medicine reference center in the north of Portugal. Variables of interest were extracted from electronic medical records. RESULTS: Our study included 134 patients. The most frequent reasons for referral were carbon monoxide poisoning (n=59) and sudden sensorineural hearing loss (n=41). In 75 cases (56%), treatment was initiated in an urgent context. Symptom presentation at Emergency Department varied among patients, the most frequent being headache and nausea/vomiting. Concerning carbon monoxide poisoning, the most common sources were water heater, fireplace/brazier, and boiler. Regarding adverse effects, it was identified one case of intoxication by oxygen and four cases of middle ear barotrauma. CONCLUSIONS: The most frequent cause for referral was carbon monoxide poisoning. All patients evolved favorably, with few side effects being reported, emphasizing the safety of this therapy. While most pediatricians may not be aware of the potential benefits arising with hyperbaric oxygen therapy, it is of upmost importance to promote them, so that this technique is increasingly implemented.

[Bibliometric visualization analysis of thiamine-responsive megaloblastic anemia syndrome].

Visual analysis of the current status, research hotspots, evolving trends, and future prospects in the field of thiamine-responsive megaloblastic anemia syndrome (TRMA), providing new insights and directions for subsequent research on the pathogenic mechanisms and prevention strategies of TRMA. Taking the core database of Web of Science as the literature source, selecting TRMA-related literature records published from 1997 to 2023 as the research object, and using R software and Citexs database to conduct visual analysis and discussion of the research content. The results showed that a total of 89 publications related to the topic were published from 1997 to 2023, with an average annual publication volume of 3 papers. Classified by country, it was found that the United States, and Israel among other countries and institutions, published a significant number of papers. Through keyword frequency analysis, high frequencies of keywords such as diabetes, deafness, thiamine-responsive megaloblastic anemia, and mutations in the solute carrier family 19 member 2 (SLC19A2) gene were observed, indicating that to date, these keywords have been the main research directions, highlighting a gradually reached consensus on the mechanism exploration of TRMA. In conclusion, TRMA research focuses on the mechanisms of hot topics such as diabetes, deafness, and thiamine-responsive megaloblastic anemia, and the core gene SLC19A2 research may currently become a new breakthrough point for future molecular studies.

Otology: Hearing Loss.

Hearing loss is the cause of significant morbidity throughout the United States and the world. Because of numerous factors, such as ongoing noise exposure, poorly controlled chronic disease, and an aging population, the burden of hearing loss is expected to continue to increase. Hearing loss commonly is categorized as conductive, sensorineural, or mixed. The type of hearing loss can be determined through a combination of patient history and physical examination, and then confirmed with audiometry and tympanometry. Advanced imaging is not typically necessary, but it may be helpful in specific instances. The presentation of sudden sensorineural hearing loss should prompt urgent referral to an otolaryngologist and audiologist. Management of this condition is selective but may initially include oral corticosteroids. Management for chronic hearing loss involves the use of hearing aids, which can offer a large benefit to users but historically have been expensive and not covered by many insurance plans. Recent US legislation has made hearing aids more accessible and affordable by allowing direct-to-consumer marketing and offering over-the-counter hearing aids without a clinical evaluation.

[Prognosis of 109 cases of sudden sensorineural hearing loss in children].

Objective:To analyze the factors influencing the prognosis of sudden sensorineural deafness in children, and to provide theoretical basis for clinical prevention and treatment. Methods:The clinical data of 109 children with sudden deafness admitted to our hospital from 2016 to 2023 were retrospectively analyzed. The children were grouped according to eight related factors, including gender, age, climate, duration of hearing loss, concomitant symptoms, degree of hearing loss, sicken ear, and auditory curve. The chi-square test was used for univariate analysis, and logistic regression was employed to identify factors influencing prognosis. Results:After conventional treatment, 56 cases were ineffective（51.40%）, 30 cases were effective（27.5%）, 13 cases were effective（11.9%）, 10 cases were cured（9.2%）, and the total effective rate was 48.6%. Among concomitant symptoms, children with tinnitus had better treatment results（P<0.05）; In the degree of hearing loss, the effective rate of mild hearing loss was the highest（83.3%）, and the effective rate of very severe hearing loss was the lowest（40.0%）. The prognosis of low frequency decline and high frequency decline were better（P<0.05）; There was no significant correlation between gender, age, climate, duration of hearing loss, sicken ear and prognosis（P>0.05）. Conclusion:The auditory curve and the degree of hearing loss are the factors affecting the prognosis of children with sudden deafness. Additionally, children with tinnitus tend to have a better prognosis.

[Advances in vestibular function and rehabilitation of large vestibular aqueduct syndrome].

Large vestibular aqueduct syndrome（LVAS） is a common recessive hereditary hearing loss disease, and some patients may also experience vestibular dysfunction. With the wide application of cochlear implant（CI） and the development of vestibular medicine, the pathophysiological mechanism of LVAS and the influence mechanism of CI on vestibular function are gradually elucidated. Consequently, the evaluation and rehabilitation of vestibular dysfunction function have also become research hotspots. This article reviews studies on vestibular function and related rehabilitation in patients with large vestibular aqueduct syndrome.

Atypical presentations in an RTD patient and report of novel SLC52A3 and SLC52A2 mutations.

INTRODUCTION: Riboflavin Transporter Deficiency (RTD) is a rare neurological disorder characterized by pontobulbar palsy, hearing loss, and motor cranial nerve involvement. SLC52A3 and SLC52A2 mutations are causes of RTD. SLC52A2 mutations are usually found in childhood onset cases. Fifteen Iranian RTD diagnosed patients without SLC52A2 mutations have been previously described. We aimed to identify causative mutations in two childhood cases. METHODS: We recruited patients with diagnosis of BVVL. Comprehensive clinical evaluations were performed on the patients. SLC52A3 and SLC52A2 genes were PCR-amplified and Sanger sequenced. Candidate disease causing variations were screened for segregation with disease status in the respective families and control individuals. RESULTS: A novel homozygous SLC52A3 mutation (p.Met1Val) and a heterozygous SLC52A2 mutation (p.Ala288Val) were both observed in one proband with typical RTD presentations. The aggregate of presentations in the early stages of disease in the second patient that included weakness in the lower extremities, absence of bulbar or hearing defects, prominent sensory polyneuropathy as evidenced in electrodiagnostic studies, and absence of sensory symptoms including sensory ataxia did not prompt immediate RTD diagnosis. Dysarthria and decreased hearing manifested later in the disease course. A novel homozygous SLC52A2 (p.Val314Met) mutation was identified. CONCLUSION: A literature search found recent reports of other atypical RTD presentations. These include MRI findings, speech understanding difficulties accompanied by normal hearing, anemia, and left ventricular non-compaction. Knowledge of unusual presentations lessens the chance of misdiagnosis or delayed RTD diagnosis which, in light of favorable effects of riboflavin supplementation, is of immense importance.

Binaural hearing aid intervention for a patient with nonserviceable hearing loss after surgery for vestibular schwannoma: A case report.

A vestibular schwannoma is a benign tumor; however, the schwannoma itself and interventions can cause sensorineural hearing loss. Most vestibular schwannomas are unilateral tumors that affect hearing only on one side. Attention has focused on improving the quality of life for patients with unilateral hearing loss and therapeutic interventions to address this issue have been emphasized. Herein, we encountered a patient who was a candidate for hearing preservation surgery based on preoperative findings and had nonserviceable hearing after the surgery, according to the Gardner-Robertson classification. Postoperatively, the patient had decreased listening comprehension and ability to localize sound sources. He was fitted with bilateral hearing aids, and his ability to localize sound sources improved. Although the patient had postoperative nonserviceable hearing on the affected side and age-related hearing loss on the unaffected side, hearing aids in both ears were useful for his daily life. Therefore, the patient was able to maintain a binaural hearing effect and the ability to localize the sound source improved. This report emphasizes the importance of hearing preservation with vestibular schwannomas, and the demand for hearing loss rehabilitation as a postoperative complication can increase, even if hearing loss is nonserviceable.

Vestibular evaluation with video head impulse test in pediatric cochlear implant patients.

BACKGROUND: The cochlear implant (CI) is effective for rehabilitating patients with severe to profound sensorineural hearing loss. However, its placement and use have been associated with various complications, such as those affecting the vestibular system. The objective of this study was to compare vestibular function using the video head impulse test (vHIT) in pediatric patients before and after CI placement. METHODS: A descriptive and retrospective study was conducted. The outcomes of 11 pediatric patients of both sexes with a history of profound hearing loss were evaluated. The results of vestibular-ocular reflex (VOR) gain, saccades, asymmetry, Pérez Rey (PR) index, and VOR/saccade ratio for both ears obtained by the vHIT test before and after CI placement were compared. RESULTS: Of the 11 patients evaluated, the VOR gain showed that 81.8% had normal function, 18.2% had hypofunction, and no patients had hyperfunction before implantation. No statistically significant differences were found when compared with post-implant off and post-implant on conditions (p > 0.05). The extracted variables, asymmetry, PR index, and the VOR/saccades ratio also showed no statistically significant differences between the pre- and post-implant conditions, whether off or on. CONCLUSIONS: The vestibular function of pediatric patients did not show significant changes before and after CI placement. The vHIT test is a valuable tool for assessing vestibular function and could be considered a criterion for surgical and rehabilitation decisions in patients undergoing CI placement.

INTRODUCCIÓN: El implante coclear es un dispositivo eficaz para la rehabilitación de pacientes con hipoacusia neurosensorial severa a profunda. Sin embargo, su colocación y uso se ha asociado a diversas complicaciones, entre ellas a nivel del sistema vestibular. El objetivo del presente estudio fue comparar la función vestibular mediante la prueba de videoimpulso cefálico (vHIT) de pacientes pediátricos antes y después de la colocación del implante coclear. MÉTODOS: Se llevó a cabo un estudio descriptivo y retrospectivo. Se evaluaron los resultados de 11 pacientes pediátricos de ambos sexos con antecedente de hipoacusia profunda. Se compararon los resultados de ganancia del VOR, sacadas, asimetría, índice PR así como la relación VOR/sacadas para ambos oídos obtenidos mediante la prueba vHIT antes y después de la colocación del implante coclear. RESULTADOS: De los 11 pacientes evaluados, la ganancia del VOR mostró que el 81.8% tenía normofunción, 18.2% hipofunción y ningún paciente hiperfunción antes del implante. Al compararlo con la ganancia post implante apagado y post implante encendido no se encontraron diferencias estadísticamente significativas (p > 0.05). Las variables sacadas, asimetría, índice PR así como la relación VOR/sacadas tampoco mostraron diferencias estadísticamente significativas entre las condiciones pre y pos implante ya sea apagado o encendido. CONCLUSIONES: La función vestibular de pacientes pediátricos no mostró cambios significativos previo y posterior a la colocación del implante coclear. La prueba vHIT es una herramienta útil que permite evaluar la función vestibular y que podría considerarse como criterio para tomar decisiones quirúrgicas en pacientes que se encuentran en protocolo para implante coclear.

Bidirectional causality between idiopathic sudden sensorineural hearing loss and depression: a Mendelian randomization study.

Idiopathic Sudden Sensorineural Hearing Loss (ISSHL) is a sudden onset, unexplained sensorineural hearing loss. Depression is a common mental disorder and a leading cause of disability. Here, We used a two-sample Mendelian randomization approach using pooled statistics from genome-wide association studies of ISSHL (1491 cases, 196,592 controls) and depression (23,424 cases, 192,220 controls) in European populations. This study investigated the bidirectional relationship between single nucleotide polymorphisms associated with depression and ISSHL using inverse variance weighting.Additional sensitivity analyses, such as Mendelian randomization-Egger (MR-Egger), weighted median estimates, and leave-one-out analysis, were performed to assess the reliability of the findings. Significant causal association between genetic susceptibility to ISSHL and depression in a random-effects IVW approach (OR = 1.037, 95% CI = 1.004-1.072, P = 0.030). In contrast, genetic depression was not risk factors for ISSHL (OR = 1.134, 95% CI = 0.871-1.475, P = 0.350). After validation by different MR methods and the sensitivity analysis, all of the above results are consistent. The evidence we have gathered suggests a causal relationship between ISSHL and depression. The presence of the former induces or further exacerbates the latter, whereas a similar situation does not exist when the latter is an influencing factor.

A novel SALL1 C757T mutation in a Chinese family causes a rare disease --Townes-Brocks syndrome.

BACKGROUND: Townes-Brocks syndrome (TBS) is a rare genetic disorder characterized by imperforate anus, dysplastic ears, thumb malformations, and other abnormalities. Previous studies have revealed that mutations in the SALL1 gene can disrupt normal development, resulting in the characteristic features of Townes-Brocks syndrome. Spalt-like transcription factors (SALLs) are highly conserved proteins that play important roles in various cellular processes, including embryonic development, cell differentiation, and cell survival. Over 400 different variants or mutations have been reported in the SALL1 gene in individuals with TBS. Most of these variants lead to the formation of premature termination codons (PTCs), also known as nonsense mutations. The majority of these PTCs occur in a specific region of the SALL1 gene called the "hotspot region", which is particularly susceptible to mutation. METHODS: In this study, we conducted whole-exome sequencing on a three-generation Chinese family with anorectal malformations. RESULTS: We identified a novel heterozygous mutation (chr16:51175376:c.757 C > T p.Gln253*) in the SALL1 gene. Molecular analysis revealed a heterozygous C to T transition at nucleotide position 757 in exon 2 of the SALL1 (NM_002968) gene. This mutation is predicted to result in the substitution of the Gln253 codon with a premature stop codon (p.Gln253*). The glutamine-rich domain forms a long alpha helix, enabling the mutant protein to interact with the wild-type SALL1 protein. This interaction may result in steric hindrance effects on the wild-type SALL1 protein. CONCLUSIONS: Our findings have expanded the mutation database of the SALL1 gene, which is significant for genetic counseling and clinical surveillance in the affected family. Furthermore, our study enhances the understanding of Townes-Brocks syndrome and has the potential to improve its diagnosis and treatment.

Automated hearing loss type classification based on pure tone audiometry data.

Hearing problems are commonly diagnosed with the use of tonal audiometry, which measures a patient's hearing threshold in both air and bone conduction at various frequencies. Results of audiometry tests, usually represented graphically in the form of an audiogram, need to be interpreted by a professional audiologist in order to determine the exact type of hearing loss and administer proper treatment. However, the small number of professionals in the field can severely delay proper diagnosis. The presented work proposes a neural network solution for classification of tonal audiometry data. The solution, based on the Bidirectional Long Short-Term Memory architecture, has been devised and evaluated for classifying audiometry results into four classes, representing normal hearing, conductive hearing loss, mixed hearing loss, and sensorineural hearing loss. The network was trained using 15,046 test results analysed and categorised by professional audiologists. The proposed model achieves 99.33% classification accuracy on datasets outside of training. In clinical application, the model allows general practitioners to independently classify tonal audiometry results for patient referral. In addition, the proposed solution provides audiologists and otolaryngologists with access to an AI decision support system that has the potential to reduce their burden, improve diagnostic accuracy, and minimise human error.

Fatal Presentation of Susac Syndrome in a Congenitally Deaf Patient With a Cochlear Implant.

OBJECTIVE: To report a fatal case of Susac syndrome in a congenitally deaf patient with a cochlear implant and a history of migraines, emphasizing the diagnostic challenges in patients with preexisting conditions. PATIENT: A 33-year-old male with congenital hearing loss, a cochlear implant, and chronic migraines who presented with mild subacute auditory disturbance and headaches that later progressed to severe encephalopathy. INTERVENTION: Explantation of a non-magnetic resonance imaging (MRI) compatible cochlear implant followed by MRI, fundoscopy, and the administration of immunosuppressive medications. MAIN OUTCOME MEASURES: Diagnosis was confirmed by characteristic MRI appearance and the presence of a hemi-retinal artery occlusion. RESULTS: After weeks of immunosuppressive treatment, the patient died of a global cerebral ischemic event of unknown origin. CONCLUSIONS: For patients with preexisting sensorineural hearing loss and cochlear implants, Susac syndrome poses a diagnostic challenge. Auditory disturbances in the absence of cochlear implant failure should prompt further evaluation for visual disturbances and encephalopathy. MRI and fundoscopy should be performed to detect other features of the disease.

Increased risk of hearing loss associated with MT-RNR1 gene mutations: a real-world investigation among Han Taiwanese Population.

BACKGROUND: Previous studies have implicated inherited mutations in mitochondrial DNA (mtDNA) in sensorineural hearing loss (SNHL). However, the definitive association between mitochondrial 12S rRNA (MT-RNR1) variants and hearing loss in the population has not been well established, particularly in Asia. The objective of this retrospective cohort study was to assess the association between MT-RNR1 variants and the risk of SNHL in patients in Taiwan. METHODS: The cohort included 306,068 participants from Taiwan between January 2003 and December 2020. Participants were classified based on genetic variants, particularly mitochondrial mutations (rs267606618, rs267606619, rs267606617). MT-RNR1 variant cases were matched 1:10 with non-mutant patients by age, gender, and visit year, excluding those with pre-existing hearing loss. The primary endpoint was SNHL, identified using specific ICD-TM codes with a 90% positive predictive value. Medication exposure history was determined via self-report or electronic medical records in the hospital. Cox proportional hazard regression models were used to assess the association between MT-RNR1 variants and hearing loss, adjusting for various covariates. Kaplan-Meier survival curves and log-rank tests compared hearing loss incidence between groups. RESULTS: The mean age of the mtDNA variants group is 32.4 years, with a standard deviation of 19.2 years. The incidence density of hearing loss for the mutation group was 36.42 per 10,000 person-years (95% Confidence Interval [CI], 27.21-47.73), which was higher than the 23.77per 10,000 person-years (95% CI, 21.32-26.42) in the wild-type group (p = 0.0036). Additionally, diabetes mellitus was associated with an increased risk of developing SNHL in individuals with MT-RNR1 variants (adjusted hazard ratio = 1.76 [95% CI, 1.00-3.09], p < 0.05). CONCLUSION: This study highlights the increased risk of hearing loss in patients carrying MT-RNR1 variants, particularly those with diabetes mellitus. Future research that integrates genetic and clinical data is crucial for developing more precise interventions to monitor and treat hearing loss in this vulnerable population.