常染色体显性遗传性听神经病家系全外显子组测序分析

目的：在多年围绕1个常染色体显性遗传性非综合征型听神经病家系开展系统分子遗传学研究的基础上,进一步探讨该家系耳聋的致病机制,以期发现新的听神经病致病基因和突变位点。方法：对3例耳聋患者和1例配偶进行全外显子组测序,初步筛选出与家系耳聋相关的候选致病基因。采用PCR-Sanger测序法,检测上述候选基因变异是否与家系表型共分离。最后,以50例与研究家系无关的听力正常人为对照,检测候选致病突变在正常群体中的突变频率和SNPs遗传多态性。结果：全外显子测序分析得到41个候选致病基因突变;用PCR-Sanger测序法对核心家系的9名成员和2名家系外听力正常人进行验证,仅发现1个基因突变（ALOX15B 7942797 C>T）与家系耳聋表型共分离。选取50例家系外正常对照的DNA样本对ALOX15B基因进行PCR扩增和序列分析,结果显示有2例听力正常人也检测到该基因的同一变异,提示该变异为SNPs遗传多态性。结论：对核心家系成员的全外显子组测序分析和Sanger测序法验证未发现有意义的突变位点,排除了该家系耳聋由基因编码区突变及Indels致病的可能性。     

常染色体显性遗传性多囊性肾病发病机制的研究进展及治疗前景

多囊性肾脏疾病是肾脏的皮质或(和)髓质出现无数囊肿的一组疾病,是构成终末期肾衰竭的主要病因之一。其临床表现为多发性肾脏囊肿、持续性高血压和泌尿系感染等症状。由于缺乏有效的治疗手段,多数患者发展为终末期肾衰竭而不得不进行肾脏替代治疗或肾移植手术[1]。多囊肾性肾脏     

常染色体显性遗传多囊肾预后因素分析

目的 了解影响常染色体显性遗传多囊肾预后的因素。方法 对１２４例患者进行临床表现、实验室与影像学检查和家族史的分析。结果 １２４例病人终末期肾病（ＥＳＲＤ）占３０．６％，ＥＳＲＤ发生率随年龄增加，男性略高于女性；ＥＳＲＤ组高血压、肉眼血尿、腰痛和肝囊肿较肾功正常组多见，肾肿大较显著；ＥＳＲＤ前期严重并发症有颅内出血、自发肾破裂和糖尿病高渗性昏迷，急性肾功能减退与全身或肾内感染，肾内出血和不合理手术     

常染色体显性遗传性多囊肾病研究的热点问题

常染色体显性遗传多囊肾病（ADPKD）是一种常见的遗传性疾病，发病率约为1／1000－1／400。ADPKD致病基因有2个：PKD1和PKD2,分别于1994年和1996年被克隆。目前研究热点主要集中于致病基因表达产物，即多囊蛋白1和多囊蛋白2的结构功能，亚细胞定位，纤毛在多囊肾病发病中的作用，多囊蛋白与血管异常的关系，用影像学方法评价多囊肾病进展，阻断肾素－血管紧张素系统延缓多囊肾病进展以及其他新的诊疗措施等方面。这些问题的深入研究将有助于阐明ADPKD的分子发病机制，为临床彻底治愈ADPKA奠定基础。     

常染色体显性多囊肾基因PKD1单拷贝区突变

常染色体显性遗传多囊肾病(autosomal dominant polycystic kidney disease,ADPKD)是临床常见的肾脏遗传病之一,目前已发现引起成人ADPKD的基因至少有PKD1和PKD2两种,其中约85%的患者由PKD1基因突变引起。本研究以67例患者PKD1基因单拷贝区的检测为基础,结合PKD1突变检测的所有     

常染色体显性遗传性先天性白内障一家系

<正>先天性白内障在临床上并不少见,但常染色体显性遗传性先天性白内障,近年来报道较少,现将本院眼科门诊调查的一家系报告如下。     

常染色体显性遗传性多囊肾病基因型与临床表型的关系

目的:研究华东地区汉族人常染色体显性遗传性多囊肾病(ADPKD)基因型与临床表现型的关系.方法:利用聚合酶链反应-单链构象多态性分析方法对79例ADPKD患者进行基因诊断,收集经基因诊断确定为2型或1型ADPKD患者的临床资料,以发病年龄、肝囊肿、高血压、尿路感染、尿路结石、血尿等主要临床症状为参数,通过统计学方法研究该病基因型与临床表现型的关系.结果:2型患者的平均发病年龄比1型患者晚9.7岁[(46.09±9.86)岁 vs (36.38±11.35)岁],两者有显著性差异(P<0.05),主要临床症状的出现在两组间无显著性差异.结论:ADPKD2型患者与1型患者临床症状相似,但发病较晚.     

常染色体显性遗传颞叶外侧癫痫与LGI 1基因突变

Ottman在1995年首次报道了与10q24相关的一种伴有听觉特征的家族性部分性癫痫,即常染色体显性遗传颞叶外侧癫痫(autosomal dominant lateral temporal epilepsy,ADLTE),后来又命名为合并听觉症状的常染色体显性遗传颞叶癫痫(autosomal dominant partial epilepsy with auditory features,ADPEAF),患者大多表现为有听觉先兆或其他感觉先兆,如视觉症状、嗅觉症状、眩晕等。这些症状都提示这是一种颞叶外侧起源的癫痫。在2002年,Kalachikovl将其定位为10q24上的LGI1(leucine rich,glioma inactivated1)基因,它是迄今发现的第一个不与离子通道相关的癫痫基因[1]。现笔者对ADLTE、LGI1基因突变及两者相关性等方面作一综述。     

两个常染色体显性遗传先天性白内障家系突变热点筛查

[目的]对2个常染色体显性遗传先天性白内障中国家系进行基因突变热点筛查,以了解这两个家系的先天性白内障是否与文献报道的17个突变热点相关.[方法]对两个家系共20名成员(包括患者11人,非患者9人)抽取外周血提取基因组DNA,针对截至2003年1月为止国外文献报道的与常染色体显性遗传先天性白内障发病相关的10个基因上的17个突变热点,包括CRYAA(ARG116CYS),CRYAB(del450A),CRYBA1(EX3-4 DEL),CRYBB2(GLN155TER),CRYGC(THR5PRO,5-BP DUP at NT226),CRYGD(ARG14-CYS,PRO23THR,ARG58HIS,ARG36SER),GJA3(ASN63SER,PRO187LEU),GJA8(GLU48LYS,PRO88SER),BFSP2(ARG287TRP)及MIP(GLU134GLY,THR138ARG),设计引物使PCR扩增片段涵盖上述热点,对扩增产物进行序列分析,检测这11名患者在突变热点上是否有相应的序列改变.[结果]20名被检者的10个基因片段序列与GenBank发表序列相同,在17个突变热点均未发现相应基因突变.[结论]初步排除这个家系的先天性白内障与17个突变热点相关.     

常染色体显性遗传帕金森病家系1例基因缺失序列分析

目的:分析常染色体显性遗传帕金森病家系的基因缺失.方法:根据Parkin基因外显子和内含子DNA序列合成14对引物,以人基因组DNA为模板,巢式PCR扩增,扩增产物纯化后直接测序.通过与正常人相应的DNA序列比较,检测1例常染色体显性遗传帕金森病家系基因缺失位点.结果:该家系检测到染色体6q25.2-q27Parkin基因外显子3中110 bp的缺失,第4和第5外显子检测到部分碱基的变异.结论:Parkin基因外显子3缺失的检出对常染色体显性遗传帕金森病的早期诊断和基因治疗具有指导意义.     

听神经病并发前庭功能障碍34例

目的：了解听神经病（auditory neuropathy，AN）并发前庭功能（vestibular function）障碍的情况，并作一初步分析。方法：随访34例确诊为听神经病的患者，详细了解其临床表现，并行前庭功能检查，描记其眼震电图（electronys-tagmogram，ENG）。结果：34例听神经病患者均无典型眩晕发作史，除3例伴走路不稳、9例伴头晕外亦无明显前庭功能障碍症状；冷热试验诱发性眼震电图反应有以下3种类型；双侧正常26例（76…），左侧半规管麻痹2例（6％），双侧半规管麻痹6例（18％）。结论：听神经病可同时累及前庭神经，但由于前庭神经病变发展缓慢，患者前庭功能障碍可由各种代偿机制弥补，多表现为无症状的前庭功能障碍。     

一个常染色体显性视网膜色素变性家系表型分析和RHO基因突变检测

目的分析一常染色体显性视网膜色素变性(autosomal dominant retinitis pigmentosa,adRP)家系的临床表型,确定该家系与视紫红质(rhodopsin,RHO)基因的关系。方法依据RP诊断标准及患者临床表型,确定一连续4代发病的adRP家系遗传的特点;采集家系中13位成员外周血8-10ml,提取基因组DNA;聚合酶链反应(polymerase chain reaction,PCR)扩增RHO基因的第1-5外显子基因片段,产物纯化后直接测序;测序结果与美国国立生物技术信息中心(National Center forBiotechnology Information,NCBI)数据库上公布的核酸标准序列进行比对分析。结果该家系临床特点为所有患者均于10岁左右出现夜盲,1例22岁出现视野损害,2例40岁左右出现视野损害,并且于50岁左右双眼相继发生急性闭角型青光眼和并发性白内障。该家系5例患者在RHO基因外显子、上下游非编码序列以及内含子及外显子拼接部中均未发现碱基改变。结论本研究家系患者存在遗传异质性和表型异质性,RHO基因不是该家系的致病基因。     

Neurophysiological characteristics in infants and young children with auditory neuropathy

Objective: To analyze neurophysiological characteristics in infants and young children with auditory neuropathy (AN) and explore their clinical significance. Methods: Audiological measurements(acoustic immittance, EOAEs, ABR, CM, MLR and ERPs) and peripheral neurological tests were conducted and evaluated in 13 infants and young children with AN. Six of them received highresolution temporal bone CT scans and/or cerebral MRI examinations. Results: All of the children showed type ““A““ tympanograms with abseatation of stapedial reflexes. EOAEs were normal in 12 of 13 subjects. In one child who had a history of anoxia during the birth, the EOAEs were not elicited. Click-evoked ABRs were absent in 12 of 13 subjects when maximum output of the instrument was reached. The CM potentials were presented bilaterally in all individuals, which were independent of the EOAEs and ABR. Of eight cases tested, all had clear MLR and six showed normal ERPs(P300 and MMN). Peripheral neurological tests and radiological findings were within the normal ranges. Conclusion: The diagnosis of AN in infants and young children should focus on analyzing their neurophysiological characteristics,especially on CM,MLR and ERPs. Combined use of EOAEs, ABR and CM was recommended for hearing screening on newborns with high risk factors.     

一遗传性听神经病家系的听力学表型特征

目的:探讨一个遗传性听神经病家系的听力学特征.方法:对23名家系成员(直系亲属21人,配偶2人)进行病史采集、体格检查及系统的听力学检测,包括纯音测听、声导抗、听性脑干反应(auditory brainstem response,ABR)、耳蜗微音器电位(cochlear microphonics,CMs)及诱发性耳声发射(evoked otoacoustic emissions,EOAEs).对其中2名患者进行纯音听力随访.结果:7名家系成员符合听神经病诊断.其中6人于9岁前发病,1～2年内快速发展为重度聋;纯音测听为双耳对称的重度～极重度感音神经性听力损失,高频下降型曲线;镫骨肌反射及ABR引不出,而CMs、EOAEs正常或基本正常.1例无听力障碍主诉,言语识别率正常;纯音测听显示双耳对称的轻度高频感音神经性听力损失,镫骨肌反射及ABR引出,EOAEs及CMs正常.2例患者纯音测听随访显示听力损失进行性加重.所有患者无耳聋外表现.结论:该听神经病家系的听力学表型特征是:非综合征型、双侧对称性、高频下降为主的感音神经性听力损失,患者可表现为早年发病并快速进展的重度～极重度耳聋,或成年后发病并缓慢进展的轻度听力下降.     

Autosomal dominant coralliform cataract related to a missense mutation of the γD-crystallin gene

Background Congenital cataract is a sight-threatening disease that affects about 1 -6 cases per 10 000 live births and causes 10% -30% of all blindness in children. About 25% of all cases are due to genetic defects. We identified autosomal dominant congenital coralliform cataracts-related genetic defect in a four-generation Chinese family.Methods Complete ophthalmological examinations were performed prior to lens extraction. Lens samples were then studied by electron microscopy. Genomic DNA from family members were examined using whole-genomic linkage analysis, with two-point logarithm of odds (LOD) scores calculated using the Linkage program package (version 5. 1 ). Mutation analysis of candidate genes was performed by direct sequencing. Finally, a three-dimensional protein model was predicted using Swiss-Model (version 2.0).Results Eleven of the 23 examined individuals had congenital cataracts. Ultrastructure studies revealed crystal deposits in the lens, and granules extensively dispersed in transformed lens fiber cells. The maximum two-point LOD score, 3. 5 at θ = 0. 1, was obtained for the marker D2S,325.Mutation analysis of the γ-crystallin (CRYG) gene cluster identified a mutation (P23T) in exon 2 of γD-crystallin (CRYGD). Protein structure modeling demonstrated that the P23T mutation caused a subtle change on the surface of the γD protein.Conclusions The results suggest that the coralliform cataract phenotype is due to a mutated CRYGD gene, and that this sequence change is identical to one reported by Santhiya to be related to another distinct clinical condition, lamellar cataract. This study provides evidence that this same genetic defect may be associated with a different phenotype. This is the first report identifying the genetic defect associated with an autosomal dominant congenital coralliform cataract.     

Huntington舞蹈病一家系4例遗传分析

目的对Huntington舞蹈病一家系4例进行遗传学分析,为家系成员提供遗传咨询并为后续Huntington舞蹈病发病机制及实验治疗研究提供依据。方法对患者家系进行家系调查和分析,观察患者症状,对患者进行医院常规检查及实验室遗传学分析。结果通过基因诊断,家系中有7人携带Huntington舞蹈病基因。其中2人表现为Huntington舞蹈病典型不自主震颤;2人具有高度区域选择性的脑萎缩和神经元脱失;3人表型正常,未到发病年龄,表现为延迟显性。结论 Huntington舞蹈病是一种以神经系统退行性改变为主要特征的常染色体显性遗传病,发病年龄通常在32～50岁。其遗传学基础是由于基因的动态突变———IT15基因5′端编码区(CAG)n三核苷酸的异常扩增引起的,呈现典型的延迟显性和遗传印记现象。     

Application of intraoperative round window electrocochleography for screening the patients with auditory neuropathy

Background Most patients with auditory neuropathy （AN） could receive good even the best effects after cochlear implantation. How to diagnose AN objectively and accurately is very important. In this study, we screened the patients with AN according to the presence or absence of compound action potential （CAP） of intraoperative round window electrocochleography （RW ECochG）. Methods Intraoperative RW ECochG was performed on 32 patients with profound sensorineural deafness, who had normal cochlea during cochlear implantation surgery under general anesthesia in the standard operating room. The cochlear microphonic （CM） and CAP of RW ECochG was observed and recorded. Results The presence of CM but the absence of CAP of RW ECochG occurred in 12 among the 32 patients. They were suspected to suffer from AN. The rest patients who had CM and CAP of RW ECochG were thought not to suffer from AN. Conclusion Application of intraoperative RW ECochG during the cochlear implantation surgery may objectively and accurately screen the patients with AN, and can give a meaningful clue for implanted device working.     

婴幼儿听神经病的听力学特点

目的 通过分析7例(14耳)听神经病患儿的听力测试结果,探讨婴幼儿听神经病听力学特点.方法 对5例(10耳)瞬态耳声发射(Transient evoked Otoacoustic Emission TEOAE)筛查通过但对声音反应差患儿和2例(4耳)听觉脑干诱发电位(Auditory brain stem response ABR)筛查40dB nHL未通过患儿行声导抗、畸变产物耳声发射(distortion product otoacoustic e-mission DPOAE)、ABR、听觉稳态诱发电位(auditory steady state response ASSR)检查,记录并分析结果.结果 所有患儿声导抗均呈A型,镫骨肌反射未引出;DPOAE正常;14耳ABR均未见分化的Ⅱ波及以后波形,仅1例1耳于90dB nHL见分化的Ⅰ波;听觉稳态诱发电位0.5～4kHz听闽介于65～90dBHL,表现为中至重度听力损失,与ABR听阅严重不符.结论 耳声发射正常伴异常的听觉稳态和听觉脑干诱发电位及其反应闽之间的严重不一致性,是听神经病较为显著的听力学特点,可应用于婴幼儿听神经病的早期诊断.