Azaiez Hela, Thorpe Ryan K, Odell Amanda M, Smith Richard JH
Molecular Otolaryngology Research Laboratories, Department of Otolaryngology – Head & Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, Iowa
Genetic Counselor, Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology – Head & Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, Iowa
-related hearing loss is an auditory synaptopathy that results from defective synaptic transmission from normally functioning cochlear inner hair cells (IHCs) to the auditory nerve. Thus, newborn hearing screening (NBHS) that relies on otoacoustic emission (OAE) testing, which primarily assesses function of outer hair cells (OHCs), is usually normal, whereas hearing tests that rely on auditory brain stem response (ABR) testing are abnormal given the failure of signal transmission from IHCs to the auditory nerve. All individuals with -related hearing loss have severely impaired speech discrimination. The two phenotypes comprising -related hearing loss are typical -related hearing loss and atypical -related hearing loss. Typical -related hearing loss is characterized by congenital or prelingual, typically severe-to-profound bilateral hearing loss (70 to ≥90 dB) associated with normal OAEs and abnormal ABRs. With age, OAEs decrease or disappear in 20%-80% of individuals. Atypical -related hearing loss is characterized by either temperature-sensitive -related hearing loss or progressive -related hearing loss. Temperature-sensitive -related hearing loss is characterized by hearing that ranges from normal hearing to moderate hearing loss (0-55 dB) at baseline body temperature and declines to bilateral hearing loss ranging from severe (71-90 dB) to profound (>90 dB) with an elevation of body temperature (approximately 0.5 °C or more). The increased hearing loss resolves typically within hours of baseline body temperature returning to normal. Progressive -related hearing loss ranges from mild to moderate at onset, and over the course of a few months or years could progress to profound. Rate of hearing loss progression is variable.
DIAGNOSIS/TESTING: The diagnosis of -related hearing loss is established in a proband with suggestive findings and biallelic pathogenic variants in identified by molecular genetic testing.
There is no cure for -related hearing loss. Early auditory intervention is critical to the development of speech and language. Habilitation options are tailored to the degree and frequency of hearing loss. While hearing aids may be trialed in persons with mild-to-severe hearing loss, these are unlikely to be beneficial due to auditory synaptopathy being the underlying cause. In contrast, cochlear implants may provide clinical benefit because they bypass the dysfunctional synapse and stimulate the auditory nerve directly. Educational and early intervention programs designed for individuals with hearing loss should start as early as possible. For individuals with atypical temperature-sensitive -related hearing loss, prevent febrile episodes and avoid exercise and/or ambient conditions that would cause body temperature to rise. Treat febrile episodes as quickly as possible. : To monitor the individual's response to supportive care and the emergence of new manifestations, the primary focus should be routine audiometric follow up. The frequency of follow up should be individualized and is likely to vary over time. For individuals with temperature-sensitive -related hearing loss, prevent fevers and other activities/ambient conditions that would cause body temperature to rise. It is appropriate to clarify the genetic status of apparently asymptomatic sibs of a proband shortly after birth by molecular genetic testing for the pathogenic variants found in the proband so that appropriate early support and management can be provided to the child and family.
-related hearing loss is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an pathogenic variant, each sib of an affected individual has at conception a 25% chance of having -related hearing loss, a 50% chance of being a carrier and not having -related hearing loss, and a 25% chance of not being a carrier and not having -related hearing loss. Once the pathogenic variants have been identified in a family member with -related hearing loss, prenatal and preimplantation genetic testing for -related hearing loss are possible.
[疾病名称]相关听力损失是一种听觉突触病，由正常功能的耳蜗内毛细胞（IHC）向听神经的突触传递缺陷引起。因此，依赖耳声发射（OAE）测试的新生儿听力筛查（NBHS）通常是正常的，因为OAE主要评估外毛细胞（OHC）的功能，而依赖听觉脑干反应（ABR）测试的听力测试则是异常的，因为信号无法从IHC传递到听神经。所有患有[疾病名称]相关听力损失的个体都有严重受损的言语辨别能力。构成[疾病名称]相关听力损失的两种表型是典型的[疾病名称]相关听力损失和非典型的[疾病名称]相关听力损失。典型的[疾病名称]相关听力损失的特征是先天性或语前性，通常为重度至极重度双侧听力损失（70至≥90dB），伴有正常的OAE和异常的ABR。随着年龄增长，20%-80%的个体OAE会降低或消失。非典型的[疾病名称]相关听力损失的特征是温度敏感性[疾病名称]相关听力损失或进行性[疾病名称]相关听力损失。温度敏感性[疾病名称]相关听力损失的特征是在基线体温时听力范围从正常听力到中度听力损失（0-55dB），随着体温升高（约0.5°C或更高），听力下降至双侧听力损失，范围从重度（71-90dB）至极重度（>90dB）。听力损失增加通常在基线体温恢复正常后的数小时内缓解。进行性[疾病名称]相关听力损失起病时为轻度至中度，在几个月或几年的过程中可能进展为重度。听力损失进展速度因人而异。
诊断/检测：通过分子遗传学检测在[疾病名称]中发现具有提示性发现和双等位基因致病变异的先证者，即可确立[疾病名称]相关听力损失的诊断。
[疾病名称]相关听力损失无法治愈。早期听觉干预对言语和语言发展至关重要。康复方案需根据听力损失的程度和频率进行调整。虽然轻度至重度听力损失的患者可试用助听器，但由于潜在病因是听觉突触病，这些助听器可能无益。相比之下，人工耳蜗可能会带来临床益处，因为它们绕过功能失调的突触，直接刺激听神经。为听力损失患者设计的教育和早期干预项目应尽早开始。对于非典型温度敏感性[疾病名称]相关听力损失的个体，应预防发热发作，避免运动和/或环境条件导致体温升高。尽快治疗发热发作。：为监测个体对支持性护理的反应和新症状的出现，主要重点应是定期进行听力测试随访。随访频率应个体化，且可能随时间变化。对于温度敏感性[疾病名称]相关听力损失的个体，预防发热和其他会导致体温升高的活动/环境条件。在出生后不久，通过对先证者中发现的[疾病名称]致病变异进行分子遗传学检测，明确明显无症状的同胞的基因状态，以便为儿童和家庭提供适当的早期支持和管理，这是合适的。
[疾病名称]相关听力损失以常染色体隐性方式遗传。如果已知父母双方均为[疾病名称]致病变异的杂合子，受影响个体的每个同胞在受孕时有25%的几率患有[疾病名称]相关听力损失，50%的几率成为携带者但不患有[疾病名称]相关听力损失，25%的几率既不是携带者也不患有[疾病名称]相关听力损失。一旦在患有[疾病名称]相关听力损失的家庭成员中确定了致病变异，就可以进行[疾病名称]相关听力损失的产前和植入前基因检测。
