氨基糖苷类抗生素致聋的家族性与交叉易感性

对３个家族中氨基糖甙类抗生素中毒性耳聋患者的家族进行调查及分析，发现几种氨基糖甙类药物之间存在家族性和交叉易感性，即在有家族性耳毒性药物致聋的家族成员中，应用任何一种氨基糖甙类抗生素，都比一般人容易发生耳中毒；即使用量不大，也易引起严重后果，特别是年幼者。此种家族性与交叉易感性属常染色体显性遗传。提示临床医生用药前应仔细询问病史，特别是有母系家族耳聋史者应禁用氨基糖甙类全部抗生素，以预防子代耳聋的     

线粒体基因组A1555G突变致非综合征性聋患者的临床表型分析

目的评估线粒体基因组（mitochondrial DNA，mtDNA）A1555G突变致非综合征性聋患者的临床表型及听力学特点。方法对经聚合酶链反应一限制性内切酶酶解法证实携带线粒体基因组A1555G突变的96例母系成员，进行病史调查和纯音听阈测试，并对性别、应用氨基糖甙类抗生素史、发病年龄等与耳聋程度的关系进行统计学分析。结果96例研究对象中耳聋患者与正常个体的性别分布均衡，34例有明确的氨基糖甙类抗生素用药史，67例耳聋患者中33例由氨基糖甙类药物耳毒性引起，26例用药后一周内发生耳聋，7例迟发。10个家系的平均耳聋外显率为68．8％。耳聋患者的临床表型多样，耳聋程度与应用氨基糖甙类药物时的年龄以及发病年龄相关，年龄越小，发生耳聋的程度越重；研究对象中年龄大于60岁的9例均为耳聋患者，但耳聋程度相对较轻。结论mtDNA A1555G突变本身不足以引起临床症状，氨基糖甙类药物和核基因在mtDNA A1555G突变的发病机制上起重要作用。携带mtDNA A1555G突变的成员年龄越小，越易出现听力下降，而且耳聋的程度越重。本组资料对耳毒性药物的风险提供了有价值的信息，从而提高氨基糖甙类药物使用的安全性，最终降低耳聋的发生率。     

含有线粒体DNA1555位突变原因不明的遗传性感音神经性听力损害

在氨基糖甙类抗生素引起的遗传性感音神经性听力损害家系中往往有线粒体 DNA突变 ,通常为 1555位 A→ G突变 ,因此认为线粒体 DNA突变是氨基糖甙类抗生素耳毒性的遗传易感性基础。但是这些家系的有些成员并无氨基糖甙类抗生素应用史却仍有听力损害 ,说明这种突变的作用并不仅仅局限在氨基糖甙类抗生素引起的听力损害。该作者报道一个母性遗传性感音神经性听力损害的家系 ,先证者为一 4 5岁男性 ,自 8岁起逐渐出现进行性听力下降伴间歇性耳鸣 ,无前庭功能障碍。家族中有三代人患有感音神经性耳聋 ,其中他的妹妹从 9岁起使用助听器 ,一个…     

氨基糖甙类抗生素致聋家系线粒体DNA A1555G突变分析

目的 研究线粒体12S rRNA基因A1555G点突变与氨基糖甙类抗生素致聋遗传易感性的关系，为建立相应的基因诊断方法提供依据。方法 收集了五个有明确氨基糖甙类抗生素应用史的耳聋家系共23名成员的外周静脉血标本，从白细胞中提取DNA，PCR扩增线粒体DNA片段，限制性内切酶分析和DNA序列分析检测A1555G点突变。结果 五个家系有母系血缘关系的18份样品均为A1555G点突变阳性，5名配偶为A1555G点突变阴性。结论 线粒体DNA A1555G点突变是氨基糖甙类抗生素致聋遗传易感性最主要的原因，检测A1555G点突变对氨基糖甙类抗生素致聋遗传易感性的预测有重要意义。     

非综合征型耳聋线粒体基因A1555G突变分析

目的通过分析内蒙古鄂尔多斯市特殊教育学校中非综合征型耳聋患者群体中线粒体基因12S rRNA A1555G突变,以探讨该群体与线粒体突变的关系。方法对鄂尔多斯市特殊教育学校102名非综合征型耳聋患者进行耳聋病因问卷调查、纯音听阈测试、声导抗测试及线粒体A1555G基因突变检测。结果102名非综合征型耳聋患者全部为感音神经性耳聋,54例有明确的氨基糖甙类抗生素用药史,7例（6.9%）存在线粒体基因A1555G位点突变。结论mtDNA 12S rRNA A1555G 在该研究群体中有较高的发生频率,携带有该突变的个体对氨基糖甙类抗生素的耳毒作用有高度易感性。     

与氨基糖甙类抗生素耳毒性相关的线粒体12S rRNA突变的流行病学特征

线粒体DNA（mtDNA）12SrRNA是氨基糖甙类抗生素导致的非综合征型听力损失的一个突变热点区域。在这些突变位点中，位于12SrRNA高度保守的解码区的同质性的A1555G和C1494T突变与耳聋相关，这两个突变导致很多患者的氨基糖甙类抗生素中毒性耳聋。A1555G突变和C1494T突变会在12SrRNA的高度保守的A位形成新的1494C—G1555或1494U—A1555碱基对。这些改变使得12SrRNA在二级结构上与细菌的16srRNA的相应区域的二级结构更加相似．因此．由于C1494T和A1555G突变在12SrRNA形成U—A和G—C配对使得氨基糖甙类抗生素的结合更加容易，这就是为何携带这些突变的人在接触了氨基糖甙类抗生素时会出现或加重耳聋的原因。携带C1494T和A1555G突变的细胞的生化特征是线粒体蛋白质合成的异常并随之引起细胞的呼吸功能异常。而且，当用含高浓度的巴龙霉素或新霉素的DMEM培养基来培养携带这两个突变的细胞系时，可以观察到这些细胞与对照细胞系相比会出现生长缺陷和线粒体内蛋白的翻译异常。这些观察为以下结论提供了直接的遗传和生化方面的证据．即A1555G和C1494T突变是导致氨基糖甙类抗生素诱导的非综合征型耳聋的致病性的mtDNA突变。而且，这些研究数据还为我们进行以下预测提供了有价值的信息和方法：（1）哪些患者有耳毒性风险；（2）提高使用氨基糖甙类抗生素治疗时的安全性；（3）逐渐减少耳聋的发生率。     

线粒体DNA突变与氨基糖甙类抗生素致聋研究进展

线粒体脱氧核糖核酸（mitochondrial deoxyroibose nucleic acid，mtDNA）是唯一存在于核外的遗传物质，具有独特的遗传特性，如严格的母系遗传、具有半自主性、不与组蛋白结合，修复能力低下，容易发生碱基突变。氨基糖甙类抗生素耳聋具有家族聚集的现象，遗传的线粒体突变是氨基糖甙类抗生素致聋（aminoglycoside antibiotics induced deafness，AAID）等非综合征耳聋的原因之一。     

氨基糖甙类抗生素致聋家系线粒体DNA12S和16S rRNA基因突变分析

目的 研究线粒体rRNA基因突变与氨基糖甙类抗生素致聋遗传易感性的关系，为建立相应的基因诊断方法提供依据。方法 收集了五个有明确氨基糖甙类抗生素应用史的耳聋家系共27名成员的外周静脉血标本。从白细胞中提取DNA，PCR扩增线粒体DNA片段。Alw26I限制性内切酶分析和DNA序列分析检测A1555G点突变，并对其中一个家系进行了线粒体DNAl2S和16SrRNA基因的全序列分析。结果家系A．C．D和E的2l份样品均为A1555G点突变阳性，家系B的6份样品为A1555G点突变阴性。家系B线粒体DNAl2S和16SrRNA基因全序列分析显示该家系存在16SrRNA基因第2227位“AA”插入突变。结论 本研究发现了一个A1555G点突变阴性的氨基糖甙类抗生素致聋家系，说明线粒体DNA A1555G点突变不是氨基糖甙类抗生素遗传易感性唯一的分子基础，对氨基糖甙类抗生素致聋遗传易感性的预测仅检测A1555G点突变是不够的。应与mtDNA其它相关突变位点的检测结合起来。     

与线粒体12S rRNA 1095 T>C突变相关的遗传性耳聋病因分析

目的探讨线粒体单倍体型、环境因素及核基因背景在1095 T〉C突变携带者耳聋表型中的作用。方法对通过基因筛查在赤峰市特教学校发现的3例携带1095 T〉C突变的耳聋患者进行病史、家系调查、常见耳聋基因检测及线粒体基因组全序列测定。结果3例耳聋患者均表现为重度-极重度感音神经性耳聋，均有聋前氨基糖甙类药物应用史，家族中其他成员听力正常，耳聋外显率低。线粒体全序列分析表明这3例患者的线粒体基因组除都有1095 T〉C突变之外，其线粒体DNA的多态位点还显示独特的多态性。75例中国听力正常对照中发现1例携带该突变。结论1095 T〉C在这些遗传背景不同的、应用过氨基糖甙类抗生素的、有听力损失的家庭中出现及其低外显率强烈提示这个突变是导致听力损失的条件致病因素，可以在携带者接触氨基糖甙类药物后发病，1095 T〉C突变可能与母系遗传氨基糖甙类药物性耳聋有关。     

线粒体基因突变与氨基糖甙类抗生素耳毒性

近年来文献已报道氨基糖甙类抗生素大剂量使用普遍存在对前庭和耳蜗功能的损害，小剂量呈现耳毒易感性的遗传因素［１］，并发现氨基糖甙类抗生素致聋（ａｍｉｎｏｇｌｙｃｏｓｉｄｅａｎｔｉｂｉｏｔｉｃｉｎｄｕｃｅｄｅａｆｎｅｓ，ＡＡＩＤ）家系成员的线粒体ＤＮＡ...     

Factors causing deafness in deaf-mute students

An analysis of 240 deaf-mute students revealed that the main cause of congenital deafness had been heredity (68.5%) which was different from that before 1970s. Of the patients with delayed deafness, 29.8% were hereditary. Altogether, 92 cases (38.3%) had hereditary deafness, among which, 50 cases (46 families) were of autosomal recessive and 42 cases (37 families) autosomal dominant. Thirty-eight cases (41.3%) had their deafness induced by ototoxic antibiotics. A significant familial history of high susceptibility to such antibiotics was available in 26 cases (68.4%). It is suggested that the key of deaf-prevention should be eugenics and the avoidance of ototoxic antibiotic abuse.     

Audiovestibular findings in patients with mitochondrial A1555G mutation

OBJECTIVE: The aims of this study were to explore the prevalence of the A1555G mutation among a group of Japanese patients and to assess the pathophysiology of the hearing impairment associated with the mutation. STUDY DESIGN: Genetic study and retrospective chart review. METHODS: We screened for the mitochondrial DNA A1555G mutation in 138 unrelated Japanese deaf patients, including 63 sporadic cases and 75 familial cases with different patterns of inheritance. When available, patients carrying the mutation received audiovestibular examinations, including speech audiometry, distortion-product otoacoustic emission (DPOAE) testing, electrocochleography (ECochG), and electronystagmography. RESULTS: One of 63 sporadic cases (1.6%) and 6 of 75 familial cases (8.0%) carried the A1555G mutation. Patients with the mutation and a familial history included two with autosomal recessive inheritance and four with maternal inheritance. In addition, two of six patients (33.3%) presenting with aminoglycoside-induced sensorineural hearing loss (SNHL) were associated with the A1555G mutation. All but one of the patients carrying the mutation showed high-frequency SNHL. Distortion-product levels of DPOAE were reduced to the noise levels, suggesting the A1555G mutation caused cochlear deafness. Cochlear microphonics in ECochG showed elevation of the detection thresholds and corresponding audiometric thresholds. The ECochG data implied that patients with high-frequency SNHL had impairment of the cochlear hair cells that was most severe toward the basal turn. The electronystagmographic findings indicated no apparent vestibular dysfunction. CONCLUSIONS: Screening for the A1555G mutation, even in patients with idiopathic bilateral SNHL, likely would be useful for preventing further development and/or acceleration of the deafness.     

The promontory test and electrocochleography in deafness caused by mumps

Contradictory histological findings in patients with deafness following mumps led us to conduct electrophysiological investigations. Promontory testing (PT) and measurement of cochlear microphonics (CM) enabled us to distinguish between neural and sensory deafness. On the basis of a careful history and serological tests in 19 cases of unilateral deafness we found that the hearing loss was probably caused by mumps. In all patients except one auditory sensations could be obtained by electric stimulation of the acoustic nerve whereas no CM were detectable even with strong stimuli of 100 dB tonepips. In view of the electrophysiological findings, doubt is cast on the neural genesis of deafness following mumps as assumed by Lehnhardt (1962).     

先天性非综合征型耳聋相关基因检测及热点突变分析

目的应用耳聋基因芯片对先天性非综合征型感音神经性聋患儿及有明确遗传史病例的家族成员进行常见耳聋相关基因检测,分析不同的可能已知相关因素引起的先天性聋患儿基因突变的热点位点,探讨突变基因位点与耳聋病因的相关性,并对热点突变基因的家系遗传规律进行初步分析。方法先天性非综合征型感音神经性聋儿童109例,通过CT检查及问卷调查寻找其可能的发病原因。对所有病例均采集血液样本,提取DNA,并以26例健康儿童作为对照组,应用耳聋基因芯片进行常见耳聋相关基因检测,分析突变位点及突变频率与耳聋病因的相关性。同时,对有明确遗传史的5个家族的相关成员进行相应检测,并绘制家系图,对热点突变基因可能的遗传方式进行初步探讨。结果 109例耳聋儿童的外周血样本中,GJB2和SLC26A4基因突变均有较高的检出率,所有病例均未检测到GJB3基因突变。线粒体均质突变检出3例,均有明确的氨基甙类抗生素用药史;实验组基因突变检出率明显高于对照组(P<0.001),有明确遗传病史组突变检出率明显高于无遗传病史组(P<0.001),有前庭导水管扩大组突变检出率明显高于无前庭导水管扩大组(P<0.001);SLC26A4基因突变主要集中于SLC26A42168A>G和SLC26A4IVS7-2A>G位点,与有无遗传病史和有无前庭导水管扩大均有显著相关性(P<0.01),GJB2基因突变主要集中于GJB2235delC和GJB2299delAT位点,本组病例显示其突变率与有无遗传病史无显著相关性(P>0.05);对4个大前庭导水管综合征家系和1个遗传性耳聋家系的分析显示,5个家系的遗传方式均符合常染色体隐性遗传规律。结论先天性非综合征型耳聋患者耳聋相关基因突变率明显高于正常人群,GJB2、SLC26A4基因突变均有较高检出率。本组病例显示GJB2基因突变与家族遗传史无明显相关性,而SLC26A4基因主要在大前庭导水管综合征患者中被检出,并表现出明显的家族遗传性,其遗传方式符合常染色体隐性遗传规律;线粒体均质突变多集中于12SrRNA1555A>G位点,主要在药物中毒性耳聋患儿中被检出。     

Genetic disposition to deafness in maternal rubella: fact or myth?

Eleven parental pairs, each having a child deaf from maternal rubella, were evaluated with a battery of specialized audiologic tests. The tests which included measurement of Békésy hearing threshold and the stapedial reflex threshold at 0.5, 1.0, and 2.0 kHz were used to test the theory that these parents have a predisposition to elevated reflex thresholds, Békésy hearing threshold dips, and a history of familial deafness. The present study failed to find any history of familial deafness or Békésy dips. Elevated reflex thresholds were noted in seven couples. This proportion was shown to be significant (p less than 0.03). The relevance of these findings in light of current clinical practice is discussed. A comparison of pure tone hearing levels of the children of parents with and without elevated reflex thresholds, failed to show a significant difference.     

Auditory midbrain implant: a combined approach for vestibular schwannoma surgery and device implantation.

HYPOTHESIS: The lateral suboccipital approach is a well-established route for safe removal of vestibular schwannomas in neurofibromatosis Type 2 (NF2) patients. The goal of this study was to assess if this approach can be extended to a lateral supracerebellar infratentorial approach to enable insertion of an auditory midbrain implant (AMI) penetrating array along the tonotopic gradient of the inferior colliculus central nucleus (ICC). BACKGROUND: The AMI is a new auditory prosthesis designed for penetrating stimulation of the ICC in patients with neural deafness. The initial candidates are NF2 patients who, because of the growth and/or surgical removal of bilateral acoustic neuromas, develop neural deafness and are unable to benefit from cochlear implants. The ideal surgical approach in NF2 patients must first enable safe removal of vestibular schwannomas and then provide sufficient exposure of the midbrain for AMI implantation. METHODS: This study was performed on formalin-fixed and fresh cadaver specimens. Computed tomography scan and magnetic resonance imaging were used to study the heads of the specimens and for surgical navigation. RESULTS: The lateral suboccipital craniotomy enabled sufficient exposure of the cerebellopontine angle and internal auditory canal for tumor removal. It could then be extended to a lateral supracerebellar infratentorial approach that provided good exposure of the dorsolateral aspect of the tentorial hiatus and mesencephalon for implantation of the AMI along the tonotopic gradient of the ICC. This approach did not endanger the trochlear nerve or any major midline venous structures in the quadrigeminal cistern. CONCLUSION: This modified lateral suboccipital approach ensures safe removal of large vestibular schwannomas and provides sufficient exposure of the inferior colliculus for ideal AMI implantation.     

The auditory midbrain implant: a new auditory prosthesis for neural deafness-concept and device description.

The auditory midbrain implant (AMI) is a new central auditory prosthesis designed for penetrating stimulation of the human inferior colliculus. The major group of candidates for the AMI consists of neurofibromatosis type 2 (NF2) patients who develop neural deafness because of growth and/or surgical removal of bilateral acoustic neuromas. Because of the absence of a viable auditory nerve, these patients cannot benefit from cochlear implants. An alternative solution has been the auditory brainstem implant (ABI), which stimulates the cochlear nucleus. However, speech perception performance in NF2 ABI patients has been limited. The fact that the ABI is able to produce high levels of speech perception in nontumor patients (with inaccessible cochleae or posttraumatic damage to the cochlear nerve) suggests that limitations in ABI performance in NF2 patients may be associated with cochlear nucleus damage caused by the tumors or the tumor removal process. Thus, stimulation of the auditory midbrain proximal to the damaged cochlear nucleus may be a better alternative for hearing restoration in NF2 patients. We propose the central nucleus of the inferior colliculus (ICC) as the potential site. A penetrating electrode array aligned along the well-defined tonotopic gradient of the ICC should selectively activate different frequency regions, which is an important elementfor supporting good speech understanding. The goal of this article is to present the ICC as an alternative site for an auditory implant for NF2 patients and to describe the design of the first human prototype AMI. Practical considerations for implementation of the AMI will also be discussed.     

云南省10个非综合征性聋家系mtDNA 12S rRNA A1555G突变流行病学调查及分析

目的:探讨云南省10个非综合征性感音神经性聋家系的mtDNA 12SrRNA A1555G突变筛查、流行状况、遗传规律及对于特定药物干预预防的意义。方法:对10个家系以现场问卷方式调查母系家族耳聋的发病情况并绘制出详细的母系家系图,然后对自愿参与检测的母系成员采外周静脉血提取DNA,PCR扩增目的片段、限制性酶切检测A1555G突变阳性个体。结果:10个家系中参与采血者共96例,其中听力正常36例,感音神经性聋患者60例;经过筛查,4例无A1555G位点突变,92例(95.8%)有A1555G位点突变,其中7例为异质性表现,85例为均质性突变;73例有明确氨基苷类抗生素用药史,其余抗生素用药史不明确。结论:云南省药物性聋患者的比例较大,并且mtDNA 12SrRNA A1555G突变率高,对该地区进行mtDNA 12SrRNA A1555G突变筛查及药物干预预防宣教有重要意义。     

Audiological performance in cochlear implanted patients deafened by meningitis depending on duration of deafness

The objective of our study was to evaluate audiological outcome in cochlear implanted children deafened by meningitis and its correlation with duration of deafness from meningitis in a retrospective clinical study at an academic tertiary referral center. Sixty patients profoundly deafened by meningitis were evaluated. Two groups of children depending on duration of deafness—group 1 defined by duration of deafness less than 6 months and group 2 defined by duration of deafness over 6 months were evaluated. The control group A (duration of deafness <6 months) and group B (duration of deafness >6 months) with similar demographics data and a non-meningitis-related cause of deafness were evaluated. Patient history, cochlear implantation and audiological findings (MAIS, MUSS and open set tests questionnaire) were investigated. Standardized diagnostic and therapeutic procedure was performed in all patients. Our results showed better auditory performance and language control in children implanted within 6 months after meningitis. Over the period of 36 months group 2 was able to catch up with the group 1 in the MUSS and MAIS tests. However, the results of the common phrases test remain significantly better in group 1 over this time period (P = 0.0188). In case of meningitis, audiological and radiological assessment should be performed within 4 weeks after the onset of disease. We see a clear indication for immediate implantation in patients with profound SNHL caused by meningitis. The aim should be bilateral implantation in this population to achieve the best possible performance by implantation before obliteration occurs. Premeningetic auditory experience is an important advantage which should be used. Frequent bilateral and sometimes late obliteration should be taken into consideration in the decision-making process as well.     

A mutation in Wolfram syndrome type 1 gene in a Japanese family with autosomal dominant low-frequency sensorineural hearing loss

CONCLUSION: Our findings suggest that Wolfram syndrome type 1 gene (WFS1) mutation is an important cause of autosomal dominant low-frequency sensorineural hearing loss (LFSNHL) in Japan. OBJECTIVE: DFNA6/14 is caused by a heterozygous mutation of WFS1 and is a common cause of autosomal dominant LFSNHL among populations in both Europe and the US. The purpose of this study was to investigate WFS1 mutations among Japanese patients whose phenotypes were consistent with those of DFNA6/14. MATERIAL AND METHODS: Using audiometry and genetic analysis, we searched for WFS1 mutations in three unrelated Japanese patients with LFSNHL and a familial history of autosomal dominant hearing loss. RESULTS: One patient carried a heterozygous G2700A mutation at codon 844 in exon 8, resulting in substitution of a threonine for an alanine (A844T). Genetic analysis of the available members of the patient's family showed that the A844T mutation segregated with LFSNHL, but was not detected in any of 140 control chromosomes. It thus appears likely that the A844T mutation is causative for hearing loss in this group. Speech audiometry, self-recording audiometry and auditory brainstem responses showed the patient to have cochlear deafness without retrocochlear dysfunction. No mutation was found in the other two patients.