RESUMEN
Autosomal dominant sensorineural hearing loss (ADSNHL) is a genetically heterogeneous disorder caused by pathogenic variants in various genes, including MYH14. However, the interpretation of pathogenicity for MYH14 variants remains a challenge due to incomplete penetrance and the lack of functional studies and large families. In this study, we performed exome sequencing in six unrelated families with ADSNHL and identified five MYH14 variants, including three novel variants. Two of the novel variants, c.571G > C (p.Asp191His) and c.571G > A (p.Asp191Asn), were classified as likely pathogenic using ACMG and Hearing Loss Expert panel guidelines. In silico modeling demonstrated that these variants, along with p.Gly1794Arg, can alter protein stability and interactions among neighboring molecules. Our findings suggest that MYH14 causative variants may be more contributory and emphasize the importance of considering this gene in patients with nonsyndromic mainly post-lingual severe form of hearing loss. However, further functional studies are needed to confirm the pathogenicity of these variants.
Asunto(s)
Secuenciación del Exoma , Pérdida Auditiva Sensorineural , Cadenas Pesadas de Miosina , Miosina Tipo II , Linaje , Humanos , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/patología , Femenino , Masculino , Cadenas Pesadas de Miosina/genética , Adulto , Mutación/genética , Predisposición Genética a la Enfermedad , Niño , Genes Dominantes , Persona de Mediana Edad , AdolescenteRESUMEN
PURPOSE: Safety and efficacy of SENS-401, a serotonin type 3 (5-HT3) receptor antagonist and calcineurin inhibitor, in patients with acute sudden sensorineural hearing loss (SSNHL). METHODS: Multicentre randomized, double blind, placebo-controlled trial enrolled adult subjects with sudden sensorineural hearing loss (SSNHL) or unilateral/bilateral acute acoustic trauma leading to SSNHL within 96 h of disease onset. Subjects were randomly assigned to one of the three oral dose groups: 29 mg, 43.5 mg or placebo given twice daily for 28 days. The primary endpoint was the change from baseline in Pure Tone Average (PTA) in the affected ear to the end of treatment visit (day 28). Subjects were further followed up 8 weeks after the end of the treatment period (day 84). RESULTS: A total of 115 subjects were randomized. SENS-401 was well tolerated. Although the primary efficacy endpoint was not met at day 28, post-hoc analyses revealed clinically significant and meaningful efficacy outcomes with SENS-401 when compared to placebo in a substantial group of participants diagnosed with idiopathic SSNHL and who had received corticosteroid treatment. Notable improvements were observed in the PTA change from baseline, the complete hearing recovery rate, and the Word Recognition Score (WRS), particularly at day 84. The responder rate consistently favored treated subjects over those who received the placebo. CONCLUSION: While the primary endpoint was not achieved at the end of the treatment period, the study revealed consistently positive efficacy results of clinical relevance in patients with idiopathic SSNHL who received SENS-401, particularly in the 8-weeks follow-up phase after the completion of the treatment.
RESUMEN
Objectives: The aim of this study was to evaluate vestibulo-ocular reflex (VOR) of individuals over 60 years of age who have not been diagnosed with a specific vestibular pathology. Methods: Bilateral six-semicircular canal video head impulse test (vHIT), Dizziness Handicap Inventory and European Evaluation of Vertigo scales were applied to participants. Results: In total, 103 participants were included in the study (75 male, 28 female), and the mean age was 69.35 ± 7.41 years. The mean age of 7th decade group was 64.32±3.12 (59 participants; 38 male, 21 female), and the mean age of 8th decade and older group was 76.11±5.93 (44 participants; 37 male, 7 female). No significant differences were found between the VOR gains of the lateral or vertical semicircular canals between the 7th decade and 8th decade and older groups (p>0.05). In the 8th decade and older group, the presence of right lateral semicircular canal corrective saccade and left posterior semicircular canal corrective saccade showed a positively moderate correlation with VOR gains of the same semicircular canals (r=0.455, p=0.002, and r=0.518, p=0.001, respectively). No significant correlation was found between age and VOR gain in the 7th decade group, however, there was a negatively weak correlation between age and left lateral semicircular canal VOR gain (r=-0.366, p=0.017) in the 8th decade and older group. Conclusion: While assessing the age-related changes in VOR using vHIT, it must be considered that the changes related to aging of the vestibular system begin to emerge in the population over 70 years of age, and corrective saccade findings may be more informative than VOR gains in revealing these changes.
RESUMEN
Hearing loss (HL) is a heterogenous trait with pathogenic variants in more than 200 genes that have been discovered in studies involving small and large HL families. Over one-third of families with hereditary HL remain etiologically undiagnosed after screening for mutations in the recognized genes. Genetic heterogeneity complicates the analysis in multiplex families where variants in more than one gene can be causal in different individuals even in the same sibship. We employed exome or genome sequencing in at least two affected individuals with congenital or prelingual-onset, severe to profound, non-syndromic, bilateral sensorineural HL from four multiplex families. Bioinformatic analysis was performed to identify variants in known and candidate deafness genes. Our results show that in these four families, variants in a single HL gene do not explain HL in all affected family members, and variants in another known or candidate HL gene were detected to clarify HL in the entire family. We also present a variant in TOGARAM2 as a potential cause underlying autosomal recessive non-syndromic HL by showing its presence in a family with HL, its expression in the cochlea and the localization of the protein to cochlear hair cells. Conclusively, analyzing all affected family members separately can serve as a good source for the identification of variants in known and novel candidate genes for HL.
Asunto(s)
Heterogeneidad Genética , Linaje , Adulto , Femenino , Humanos , Masculino , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/patología , Mutación , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismoRESUMEN
INTRODUCTION: There is an ongoing debate about the existence and effects of Helicobacter pylori (Hp) in adenotonsillar tissue. OBJECTIVE: A clinical study was conducted to assess the existence of Hp in the adenoid and/or adenotonsillar tissues, which were surgically excised due to chronic adenotonsillitis. METHODS: Phosphoglucosamine mutase gene for the detection of Hp and cytotoxin-associated gene as virulence gene were examined in 84 adenotonsillar tissues obtained from 64 patients and patients' serum by using polymerase chain reaction. RESULTS: Hp IgG was detected in 57 (89%) patients' serum. A total of seven tissue samples from 64 patients (10.9%) were found positive for Hp DNA, of which five were adenoids and two were tonsil tissues. All polymerase chain reaction positive samples were also positive for the cytotoxin-associated gene, which is a virulence determinant for the organism. CONCLUSION: This study suggests that children are exposed to Hp at an early age of their life in this province. Hp may have a role in the pathogenesis of chronic adenotonsillitis, especially in endemic areas. .
INTRODUÇÃO: Há um debate atual sobre os efeitos da Helicobacter pylori (HpHp) no tecido adenotonsilar. OBJETIVO: Conduzimos um estudo clinico para avaliar a existência de Hp nos tecidos adenoideano e/ou adenotonsilar, os quais foram removidos cirurgicamente em decorrência de adenotonsilite crônica. MÉTODO: No total, 84 amostras de tecido obtidos de 64 pacientes foram analisadas para o gen fosfoglucosamina mutase para a detecção de Hp. Os casos positivos foram a seguir examinados para o gen associado à citotoxina, relacionado à virulência, usando-se o método de Reação de Polimerase em Cadeia (PCR). RESULTADOS: A IgG de Hp foi detectado em 57 (89%) soros de pacientes. Sete amostras de tecido de sessenta e quatro pacientes (10.9%) resultou positivo para o DNA de Hp, das quais cinco eram adenóides e duas eram tecido tonsilar. No PCR todas as amostras foram também positivas para o gen associado à citotoxina, o qual é um determinante de virulência. CONCLUSÃO: Esse estudo sugere que as crianças são expostas ao Hp nos primeiros anos de vida nessa província e que o Hp pode ter um papel na patogênese da adenotonsilite crônica, principalmente em áreas endêmicas. .