基于高通量测序的一个非综合征型耳聋家系遗传性分析

目的采用高通量测序方法对一个非综合征型耳聋(non-syndromic hearing loss,NSHL)家系进行基因测序,探讨该家系的分子遗传学机制。方法调查该耳聋家系成员的病史并进行相应检查,抽取外周血并提取DNA,用高通量测序方法对129个已知的与综合征型耳聋及非综合征型耳聋相关的基因进行测序,经计算机分析系统进行碱基读取,获得DNA序列。结果该非综合征型耳聋家系中3例患者均携带GJB3c.375CT杂合突变、KCNQ4c.777TC杂合突变、ILDR1c.1545TG纯合突变、GJB2c.1277CT、c.1152GA及c.1067GT纯合突变、线粒体DNA m.1121TC突变,Ⅱ6携带ILDR1c.1545TG杂合突变、GJB2c.1277CT、c.1152GA及c.1067GT纯合突变,Ⅰ3携带GJB2c.1277CT纯合突变,Ⅱ3、Ⅱ7、Ⅱ11均携带GJB2c.1277CT杂合突变。结论该非综合征型耳聋家系的致病基因可能为线粒体DNA m.1121TC突变,也可能为GJB2与GJB3双基因致聋。     

腓骨肌萎缩症伴神经性耳聋一家系临床和分子遗传学分析

目的探讨一个X连锁腓骨肌萎缩症(CMTX)伴常染色体隐性遗传的神经性耳聋家系的临床特点并研究其分子遗传学病因。方法对9名家系成员进行详细的临床检查，先证者进行了神经肌电图、听觉诱发电位和神经活检，3名耳聋患者进行电测听检查。运用聚合酶链反应一单链构象多态性分析技术(PCR-SSCP)结合直接测序法进行间隙连接蛋白32(eonnexin32)的突变分析，直接测序法进行间隙连接蛋白26(connexin26)的突变分析。结果家系中3名腓骨肌萎缩症患者为X连锁显性遗传，3名神经性耳聋患者为常染色体隐性遗传，其中1名患者同时出现腓骨肌萎缩症和神经性耳聋的临床症状。CMTX由connexin32错义突变C223T(Arg75Trp)引起。耳聋症状与connexin32点突变无共分离现象，对connexin26直接测序亦未发现突变，耳聋的致病基因有待进一步探讨。结论该家系腓骨肌萎缩症和耳聋分别由不同基因突变引起，这种在一个家系中同时出现两种不同遗传方式，不同致病基因的遗传病罕有报道。     

家族性低钾型周期性麻痹基因型和表型分析

研究背景分析一中国汉族家族性低钾型周期性麻痹家系的致病基因和相关临床资料。方法采用DNA序列技术对先证者(Ⅲ3)进行CACNA1S、SCN4A、KCNE3全基因组筛查,针对检测到的变异进一步检测家系中其他患者和无症状家系成员是否存在相同基因突变,经对临床资料分析以确定相关基因突变是否为致病性突变基因。结果先证者(Ⅲ3)及家系中其他患者(Ⅱ1、Ⅲ4、Ⅳ3)均检测到CACNA1S基因IVS25-194C/T突变,而无症状家系成员(Ⅲ1)未检测到该突变;该家系成员(除Ⅰ1)均检测到SCN4A基因IVS18-130G/A突变,该位点位于内含子区域且有症状和无症状家系成员同时出现;先证者(Ⅲ3)和无症状家系成员(Ⅲ1)同时检测到SCN4A基因外显子12区域c.1984GA突变,系错义突变(V662I),但家系中其他患者(Ⅱ1、Ⅲ4、Ⅳ3)均未发现该位点突变。结论结合临床资料和生物信息学预测,推测CACNA1S、SCN4A、KCNE3基因突变均非该家系致病性突变基因。但该家系资料丰富了我国原发性低钾型周期性麻痹家系的临床和基因数据库。除KCNE3、CACNA1S和SCN4A基因外,中国低钾型周期性麻痹家系可能存在新的致病基因突变,尚待进一步研究。     

以双耳聋为首发症状的基底动脉部分闭塞一例

临床资料 患者,男,53岁,职员.因"双耳听力丧失伴头晕10 d"于2009年9月30日入院.患者10 d前于工作时无明显诱因出现头晕、耳鸣,数小时后双耳听力丧失,无恶心,无肢体活动障碍,就诊于耳鼻喉科,纯音测听示双侧感音神经性耳聋,收入我科.     

小脑蚓部肿瘤致双耳听力丧失1例报告

1　临床资料患者 ,女 ,2 2岁。反复呕吐 1月 ,头痛和双耳听力下降半月于 2 0 0 0年 6月13日入院。头痛呈阵发性加剧 ,听力障碍进行性加重 ,以后仅能用文字交流 ,伴步态不稳 ,无眩晕 ,耳鸣及意识障碍。既往无外耳道流脓史。查体 :神志清楚 ,双侧视神经乳头轻度水肿 ,双耳听力完全丧失 ,右下肢轻瘫试验阳性 ,双侧指鼻及跟膝胫试验均不准确。辅助检查 :电测听纯音刺激 12 0ｄＢ于 5 0 0Ｈｚ、1ｋＨｚ和 2ｋＨｚ均无反应 ,提示双耳听力丧失。脑干听觉诱发电位示双侧Ⅰ波潜伏期及波幅正常 ,Ⅲ及Ⅴ波潜伏期明显延长 ,波幅明显减低 ,提示中枢性损害…     

河南地区两个腓骨肌萎缩症家系PMP22基因突变研究

目的分析在河南地区两个腓骨肌萎缩症(CMT)家系的临床表现及PMP22基因重复突变的特点。方法收集两家系中21名成员的临床资料,并应用等位基因特异性PCR-双酶切方法检测17p11.2-1 PMP22基因重复(即1760 bp片段)序列的情况,同时选择50名健康人做为对照。结果两家系中共14名成员经等位基因特异性PCR-双酶切方法检测出PMP22基因大片重复(即1760 bp片段)序列;家系一患病者有3名(Ⅱ5、Ⅱ7、Ⅲ11),无临床症状但基因检测结果示PMP22基因重复突变为携带者有6名(Ⅱ9、Ⅲ6、Ⅲ8、Ⅲ10、Ⅳ1、Ⅳ2);家系二患病者有4名(Ⅱ3、Ⅱ9、Ⅱ11、Ⅲ7),携带者只有Ⅲ5。两家系中余7人及健康对照50人均未检测出上述重复突变。结论 PCR-双酶切法检测PMP22特异性基因重复序列在早期诊断CMT有重要价值。     

听神经病在纯音听阈测听和声导抗检查中的特征性表现

目的 探讨听神经病在纯音听阈测听及声导抗检查中的临床听力学特点及诊断要点.方法 回顾性分析中山大学附属第三医院耳鼻喉科收治的17例(32耳)听神经病确诊患者在纯音听阈测听、声导抗检查中的听力学特点.结果 17例患者中15例为双侧发病,呈左右对称性听力曲线;26耳以轻至中度低频感音性聋为主(听力图上升型);病程<5年的听力损失主要为轻度、中度听力障碍(17/32耳),病程>5年的听力损失主要为重度、极重度听力障碍.16例(31耳)声导抗为"A"型鼓室图,15例(30耳)同侧及交叉镫骨肌声反射均未引出,2例(2耳)镫骨肌声反射阈值升高.结论 听神经病在纯音听阔测听及声导抗检查中主要表现为:(1)为双侧对称性、渐进性听力下降;(2)早期为低频上升型听力图,后期为全频听力下降;(3)呈"A"型鼓室图,镫骨肌声反射阈值升高或引不出;(4)患耳无响度重振现象.     

听神经病在纯音听阈测听和声导抗检查中的特征性表现

目的 探讨听神经病在纯音听阈测听及声导抗检查中的临床听力学特点及诊断要点.方法 回顾性分析中山大学附属第三医院耳鼻喉科收治的17例(32耳)听神经病确诊患者在纯音听阈测听、声导抗检查中的听力学特点.结果 17例患者中15例为双侧发病,呈左右对称性听力曲线;26耳以轻至中度低频感音性聋为主(听力图上升型);病程<5年的听力损失主要为轻度、中度听力障碍(17/32耳),病程>5年的听力损失主要为重度、极重度听力障碍.16例(31耳)声导抗为"A"型鼓室图,15例(30耳)同侧及交叉镫骨肌声反射均未引出,2例(2耳)镫骨肌声反射阈值升高.结论 听神经病在纯音听阔测听及声导抗检查中主要表现为:(1)为双侧对称性、渐进性听力下降;(2)早期为低频上升型听力图,后期为全频听力下降;(3)呈"A"型鼓室图,镫骨肌声反射阈值升高或引不出;(4)患耳无响度重振现象.     

听神经病在纯音听阈测听和声导抗检查中的特征性表现

目的 探讨听神经病在纯音听阈测听及声导抗检查中的临床听力学特点及诊断要点.方法 回顾性分析中山大学附属第三医院耳鼻喉科收治的17例(32耳)听神经病确诊患者在纯音听阈测听、声导抗检查中的听力学特点.结果 17例患者中15例为双侧发病,呈左右对称性听力曲线;26耳以轻至中度低频感音性聋为主(听力图上升型);病程<5年的听力损失主要为轻度、中度听力障碍(17/32耳),病程>5年的听力损失主要为重度、极重度听力障碍.16例(31耳)声导抗为"A"型鼓室图,15例(30耳)同侧及交叉镫骨肌声反射均未引出,2例(2耳)镫骨肌声反射阈值升高.结论 听神经病在纯音听阔测听及声导抗检查中主要表现为:(1)为双侧对称性、渐进性听力下降;(2)早期为低频上升型听力图,后期为全频听力下降;(3)呈"A"型鼓室图,镫骨肌声反射阈值升高或引不出;(4)患耳无响度重振现象.     

脊髓小脑共济失调1型的临床表现与基因诊断

目的 为一个表现为行走不稳、言语含糊和视力下降的家系的数名患者明确基因诊断,探讨其临床特点.方法 完成家系调查和神经科体检,部分成员行头部MRI和视觉、听觉诱发电位;开展SCA3、SCA1及SCA7突变基因CAG重复数目检测.结果 该家系呈常染色体显性遗传,5例成员有异常临床表现,头部MRI示小脑、脑干萎缩明显;VEP示潜伏期延迟和波幅下降,BAEP示Ⅴ波波幅下降,Ⅰ～Ⅴ、Ⅲ～Ⅴ、IPL、ILD延迟.家系成员SCA3及SCA7突变基因CAG检测均在正常范围,对照组SCA1目的 片段CAG重复数目为19～37,3例患者异常等位基因CAG重复数分别为54、60、68,诊断为SCA1患者;1例患者等位基因CAG重复数目分别为29和40,后者介于正常与异常扩展范围之间,但该患者有临床表现,且有一个患病儿子,确诊为SCA1患者.结论 SCA1患者的临床表现具有异质性,CAG重复数目检测可以为基因诊断提供依据.     

A neurosurgeon in Iraq: A personal perspective

The practice of neurosurgery in a war zone provides enormous challenges and risks for the individual surgeon working in such an austere and hostile environment, but also provides a unique opportunity to treat a high volume of severe penetrating and blast injuries to the head, neck and the spine. The purpose of this article is to present the author's personal experiences and perspective as a military neurosurgeon working in the US Airforce Hospital in Balad (the 332nd Expeditionary Medical Group) Iraq in for 3 months in 2004. Strategies for managing the mass casualties, and the severe penetrating craniofacial trauma are presented and the reasons for the low mortality of troops injured in Iraq are discussed.     

A study in failure

Failure can be both chastening and instructive, but not while it is rendered undiscussable by its taboo status which itself is unwittingly supported by dilemmas of careers and jobs, by vagaries of funding, and not least, by ideological investments. The impetus for this study derives from a recently completed demonstration project which had been designed to evaluate the impact on child development of group counseling of young, first-pregnancy mothers. The project was directed toward improving the social-emotional-cognitive interaction between mother and child. Its larger aim was to demonstrate the effectiveness of a preventive mental health component of a comprehensive health program for children. A complementary objective was the training of public health clinic nurses to become group counselors with a view toward enlarging their roles, skills, and services at public health pre-natal and well-baby clinics.Demographically matched experimental (N = 94) and control (N = 89) groups were drawn from first-pregnancy patients at public prenatal clinics. Both groups were visited and interviewed every two weeks at home by trained interviewers who administered a complex, time-staggered set of test-retest instruments. Extensive demographic and psychosocial information was collected, including data about child-rearing practices. Mothers in the experimental group were to attend (prenatally and postnatally) 20 weekly counseling meetings conducted by public well-baby clinic nurses who had been assigned by their clinic staff to participate in the project and who received intensive training by three mental health clinicians (two child psychiatrists and a clinical psychologist).It was expected that after 20 group-counseling sessions the experimental and control groups of paired mothers/infants could be compared on a number of mental health and developmental measures based on a battery of informal, openended interviews as well as established test instruments.The clientele was prototypically black, teen-age, unmarried, and of lower socioeconomic status; the very “problem” group presumably in need of, and to whom, such programs are addressed.     

A role for endothelin receptor type A in migraine without aura susceptibility? A study in Portuguese patients

Background and purpose: Migraine is a common neurological disabling disorder, and anomalies of vascular function have been implied in its pathophysiology. Several findings point to a possible role of the endothelin receptor type A (EDNRA) in migraine. We aim to assess the involvement of endothelin receptor type A (EDNRA) in migraine susceptibility in a sample of Portuguese migraineurs. Methods: Three tagging SNPs (rs702757, rs5333 and rs5335) were analysed in 188 cases – 111 without aura (MO) and 77 with aura (MA) – and 287 controls. A multivariable logistic regression was performed, including the three SNPs, adjusted for gender. Allelic and haplotypic frequencies were compared between cases and controls. Significant or promising results were confirmed by a multifactor dimensionality reduction analysis (MDR). Results: We found a nominal association for the rs702757 T‐allele [odds ratio (OR) = 1.44, 95% confidence intervals (CI): 1.05–1.99] and for the TT‐genotype (OR = 2.34, 95% CI: 1.12–4.90) for MO, that do not remain significant after multiple test correction. A trend towards an increased risk for MA regarding the C‐allele of rs5333 was also found. However, an additional MDR analysis was performed, and highly significant results were found for the two SNPs. The T‐C‐G haplotype (rs702757‐rs5333‐rs5335) was found to be significantly overrepresented in the MO subgroup, even after permutation was performed. Conclusions: Our results show additional findings for a role of EDNRA as a susceptibility factor for MO, although we cannot exclude the involvement of this gene in MA susceptibility in our population. Our study also emphasizes the need for replication of association findings in different populations.     

Targeting adenosine A2A receptors in Parkinson's disease

The adenosine A2A receptor has emerged as an attractive non-dopaminergic target in the pursuit of improved therapy for Parkinson's disease (PD), based in part on its unique CNS distribution. It is highly enriched in striatopallidal neurons and can form functional heteromeric complexes with other G-protein-coupled receptors, including dopamine D2, metabotropic glutamate mGlu5 and adenosine A1 receptors. Blockade of the adenosine A2A receptor in striatopallidal neurons reduces postsynaptic effects of dopamine depletion, and in turn lessens the motor deficits of PD. A2A antagonists might partially improve not only the symptoms of PD but also its course, by slowing the underlying neurodegeneration and reducing the maladaptive neuroplasticity that complicates standard 'dopamine replacement' treatments. Thus, we review here a prime example of translational neuroscience, through which antagonism of A2A receptors has now entered the arena of clinical trials with realistic prospects for advancing PD therapeutics.