目的:探讨家族性温敏性听神经病(TSAN)的临床特点及遗传病因,这是一种非常罕见的听觉神经病(AN)亚型,由于核心体温升高而导致听力阈值升高,并评估TSAN家族的基因型-表型相关性。方法:一个非血缘关系的中国家庭的六个成员,包括四个兄弟姐妹抱怨发烧时沟通困难,参加了这项研究。在发热和发热发作期间,对四个兄弟姐妹的临床和听力学特征进行了全面评估,并使用下一代测序(NGS)技术探索了听力损失(HL)的遗传病因。他们的父母,没有因体温变化而引起HL波动的投诉,只注册了遗传学部分。结果:患者高热发作期间的听力学测试符合AN的经典诊断标准,包括轻度HL,不良的言语歧视,保留的耳蜗微音(CM),和缺乏听觉脑干反应(ABR)。重要的是,与以前报道的TSAN病例中观察到的模式不同,我们患者的ABRs和心电图(ECochG)信号在无脑期间改善至正常.遗传分析确定了OTOF基因的复合杂合变体(编码otoflin蛋白),包括一个以前报道的致病变异,c.5098G>C(p。Glu1700Gln),和一个新颖的变体,c.4882C>A(p。Pro1628Thr)。鉴定的变体均不影响与耳铁蛋白的主要功能相关的C2结构域。这两个变体都忠实地与系谱中的TSAN分离,表明OTOF是该家族常染色体隐性性状分离的致病基因。结论:ABRs缺失(或明显异常)的CM的存在是诊断AN的可靠标准。由TSAN中功能失调的神经递质释放引起的表型的严重程度可能反映了改变耳铁蛋白C2结构域的变体。本研究的观察结果丰富了目前对TSAN表型和基因型的认识,为进一步研究其发病机制奠定了基础。
Objective: To investigate the clinical course and genetic etiology of familial temperature-sensitive auditory neuropathy (TSAN), which is a very rare subtype of auditory neuropathy (AN) that involves an elevation of hearing thresholds due to an increase in the core body temperature, and to evaluate the genotype-phenotype correlations in a family with TSAN. Methods: Six members of a non-consanguineous Chinese family, including four siblings complaining of communication difficulties when febrile, were enrolled in this study. The clinical and audiological profiles of the four siblings were fully evaluated during both febrile and afebrile episodes, and the genetic etiology of hearing loss (HL) was explored using next-generation sequencing (NGS) technology. Their parents, who had no complaints of fluctuating HL due to body temperature variation, were enrolled for the genetics portion only. Results: Audiological tests during the patients\' febrile episodes met the classical diagnostic criteria for AN, including mild HL, poor speech discrimination, preserved cochlear microphonics (CMs), and absent auditory brainstem responses (ABRs). Importantly, unlike the pattern observed in previously reported cases of TSAN, the ABRs and electrocochleography (ECochG) signals of our patients improved to normal during afebrile periods. Genetic analysis identified a compound heterozygous variant of the
OTOF gene (which encodes the otoferlin protein), including one previously reported pathogenic variant, c.5098G > C (p.Glu1700Gln), and one novel variant, c.4882C > A (p.Pro1628Thr). Neither of the identified variants affected the C2 domains related to the main function of otoferlin. Both variants faithfully cosegregated with TSAN within the pedigree, suggesting that
OTOF is the causative gene of the autosomal recessive trait segregation in this family. Conclusion: The presence of CMs with absent (or markedly abnormal) ABRs is a reliable criterion for diagnosing AN. The severity of the phenotype caused by dysfunctional neurotransmitter release in TSAN may reflect variants that alter the C2 domains of otoferlin. The observations from this study enrich the current understanding of the phenotype and genotype of TSAN and may lay a foundation for further research on its pathogenesis.