Usami Shin-ichi, Nishio Shin-ya
Professor and Chairman, Department of Otorhinolaryngology Shinshu University School of Medicine Matsumoto, Japan
Assistant Professor, Department of Otorhinolaryngology Shinshu University School of Medicine Matsumoto, Japan
Mitochondrial nonsyndromic hearing loss and deafness is characterized by sensorineural hearing loss (SNHL) of variable onset and severity. Pathogenic variants in can be associated with predisposition to aminoglycoside ototoxicity and/or late-onset SNHL. Hearing loss associated with aminoglycoside ototoxicity is bilateral and severe to profound, occurring within a few days to weeks after administration of any amount (even a single dose) of an aminoglycoside antibiotic such as gentamycin, tobramycin, amikacin, kanamycin, or streptomycin. Pathogenic variants in are usually associated with childhood onset of SNHL that is generally nonsyndromic – although the substitution m.7445A>G has been found in some families who also have palmoplantar keratoderma (scaling, hyperkeratosis, and honeycomb appearance of the skin of the palms, soles, and heels).
DIAGNOSIS/TESTING: The diagnosis of mitochondrial nonsyndromic hearing loss and deafness is established in a proband with hearing loss and identification of a pathogenic variant in or , or one of the eight additional mitochondrial genes known to cause nonsyndromic hearing loss and deafness.
: Appropriate rehabilitation (hearing aids, speech therapy, culturally appropriate language training, cochlear implantation, educational programs for the hearing impaired). Electric acoustic stimulation for individuals with mitochondrial hearing loss with residual hearing in the lower frequencies. Lotions and emollients for mild keratoderma; dermatology referral for severe keratoderma. : Avoidance of aminoglycosides. : Annual audiometric assessment to evaluate stability/progression of hearing loss. Annual physical exam for related clinical findings. : Aminoglycosides and noise exposure, especially in those with normal hearing who have the m.1555A>G or m.1494C>T pathogenic variants. : Molecular genetic testing of at-risk maternal relatives allows for early detection of those who have inherited the mtDNA pathogenic variant and would benefit from avoiding aminoglycosides and appropriate early support and management.
Mitochondrial nonsyndromic hearing loss and deafness is caused by pathogenic variants in mitochondrial DNA (mtDNA) and is transmitted by maternal inheritance. The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have hearing loss. All offspring of females with a mtDNA pathogenic variant are at risk of inheriting the pathogenic variant. Offspring of males with a mtDNA pathogenic variant are not at risk of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the mtDNA pathogenic variant in the family is known. Because of mitotic segregation, the mtDNA pathogenic variant load in amniocytes and chorionic villi is unlikely to correspond to that of other fetal or adult tissues. Furthermore, the presence of the mtDNA pathogenic variant does not predict the age of onset or severity of hearing loss.
线粒体非综合征性听力损失和耳聋的特征是感音神经性听力损失（SNHL），其发病时间和严重程度各不相同。相关基因的致病变异可能与氨基糖苷类耳毒性易感性和/或迟发性SNHL有关。与氨基糖苷类耳毒性相关的听力损失是双侧的，严重至极重度，在给予任何剂量（即使是单剂量）的氨基糖苷类抗生素（如庆大霉素、妥布霉素、阿米卡星、卡那霉素或链霉素）后的几天至几周内发生。相关基因的致病变异通常与儿童期SNHL发病有关，一般为非综合征性——尽管在一些同时患有掌跖角化病（手掌、脚底和脚跟皮肤的鳞屑、角化过度和蜂窝状外观）的家庭中发现了m.7445A>G替代突变。
诊断/检测：线粒体非综合征性听力损失和耳聋的诊断是在患有听力损失的先证者中确定，并且在相关基因或其他八个已知可导致非综合征性听力损失和耳聋的线粒体基因之一中鉴定出致病变异。
适当的康复措施（助听器、言语治疗、适合文化背景的语言训练、人工耳蜗植入、听力受损者的教育项目）。对低频仍有残余听力的线粒体听力损失患者进行电声刺激。轻度角化病使用洗剂和润肤剂；严重角化病转诊皮肤科。避免使用氨基糖苷类药物。每年进行听力测定评估以评估听力损失的稳定性/进展情况。每年进行体格检查以查找相关临床体征。避免使用氨基糖苷类药物和噪声暴露，尤其是对于携带m.1555A>G或m.1494C>T致病变异且听力正常的个体。对有风险的母系亲属进行分子基因检测可早期发现那些遗传了线粒体DNA（mtDNA）致病变异且将受益于避免使用氨基糖苷类药物以及适当的早期支持和管理的个体。
线粒体非综合征性听力损失和耳聋由线粒体DNA（mtDNA）中的致病变异引起，通过母系遗传。先证者的母亲（通常）携带mtDNA致病变异，可能有或没有听力损失。携带mtDNA致病变异的女性的所有后代都有遗传该致病变异的风险。携带mtDNA致病变异的男性的后代没有遗传该致病变异的风险。如果家族中的mtDNA致病变异已知，则对风险增加的妊娠进行产前诊断是可行的。由于有丝分裂分离，羊膜细胞和绒毛膜绒毛中的mtDNA致病变异负荷不太可能与其他胎儿或成人组织的负荷一致。此外，mtDNA致病变异的存在并不能预测听力损失的发病年龄或严重程度。
