一个2A型肢带型肌营养不良家系CAPN3基因的突变分析

目的对一个2A型肢带型肌营养不良(limb-girdle muscular dystrophy type 2A)家系进行CAPN3基因的致病突变分析。方法收集先证者及家系成员的外周血,提取DNA,应用全外显子测序技术对先证者进行致病基因检测,然后用Sanger测序技术对先证者家系成员进行突变位点的验证。结果全外显子测序发现先证者携带CAPN3基因c. 1194-9A G和c. 1437C T (p. ser479=)的复合杂合突变。Sanger测序验证先证者母亲为CAPN3基因c. 1194-9A G变异携带者。家系中其他患者均存在相同的复合杂合突变,其未发病的姐姐和女儿为CAPN3基因c. 1437C T (p. ser479=)变异携带者,先证者的女婿未检测到上述位点变异。结论 CAPN3基因c. 1194-9A G和c. 1437C T (p. ser479=)的复合杂合突变为该家系的致病原因。     

腓骨肌萎缩症2个家系的临床、电生理和基因学研究

为了研究腓骨肌萎缩症(CMT)的临床、电生理以及基因突变的特点,该研究收集2个家系先证者以及发病亲属的临床资料、电生理资料、全血和DNA,进行家系分析及CMT相关基因检测.结果发现家系1为常染色体显性遗传,患者MLPA检测提示PMP22基因的重复扩增.基因测序未发现患者携带CMT其他相关基因的突变.进一步在患者的3个患病的亲属中发现携带PMP22基因的重复扩增,并且未发现其未患病的叔叔携带该突变.家系2为常染色体隐性遗传,先证者携带SH3TC2基因的c.730C＞T p.Q244X和c.432C＞G p.Y144X两个杂合突变.患者的父母,则分别携带上述两个突变.因此,家系1诊断为CMT1A型,家系2诊断为CMT4C型,临床实践中应注意基因和表型的联系.     

腓骨肌萎缩症1A型的临床、神经电生理和疾病基因突变分析

目的　观察腓骨肌萎缩症 (CMT) 1A型的临床、神经电生理特点和疾病基因的突变分析。方法对一CMT家系中 9个成员进行详尽的临床检查、疾病基因突变分析 ,对先证者进行神经电生理检查和神经肌肉活检。结果　本家系中 5人发病 ,符合常染色体显性遗传模式 ,除 1例患者无临床症状外 ,其余 4例均在2 0岁前起病。临床特点为进行性四肢远端肌无力、肌萎缩 ,末梢型感觉障碍 ,腱反射减弱或消失 ,足部畸形(高弓足 )。神经电生理检查示运动和感觉神经传导速度减慢。基因突变分析发现 17号染色体短臂 11 2区(17p11 2 )包含周围髓鞘蛋白 (PMP) 2 2基因的正向串联重复突变。结论　CMT1A型是CMT最常见类型 ,多于儿童期或青少年期起病 ,表现为进行性四肢远端肌无力、肌萎缩 ,腱反射减弱或消失。神经电生理特点为运动神经传导速度均一性减低 (<38m/s)。 17p 11 2区包含PMP 2 2基因在内的 1 5Mb(偶尔 <1 5Mb)的正向串联重复突变是CMT 1A最主要的突变型。     

夏科-马里-图斯病2A2型一家系的临床病理特点

目的 报道一个早发型夏科-马里-图斯病(CMT)2A2家系,探讨其临床和病理特点.方法 该家系共有5例患者,呈常染色体显性遗传,先证者为36岁女性,6岁开始出现下肢进行性无力,8岁出现双足内翻.家族中另有2例男性和2例女性发病,发病年龄3～7岁,主要表现为缓慢进展的四肢远端肌肉无力、萎缩,伴随四肢远端感觉减退、腱反射减退及关节挛缩.先证者和其儿子的上肢感觉神经、下肢感觉和运动神经诱发电位波幅不能引出.对先证者左侧腓肠神经进行活体组织病理检查.对先证者和其他4例家系患者、3名无症状家系成员行MFN2基因测序.结果 病理检查可见腓肠神经有髓纤维数目重度减少,以大有髓神经纤维减少为主,伴随个别有髓神经纤维再生簇结构以及不典型的洋葱球样结构.电镜下可见轴索中线粒体聚集,未发现线粒体结构异常.5例患者存在MFN2基因R94W突变,无症状家系成员无此突变.结论 我国存在早发型CMT2A2家系,患者周围神经缺乏有髓神经纤维再生改变,提示MFN2基因突变对神经元的损害更大.     

结节性硬化症TSC2基因5238-5255 del 18 bp及2713 C>T基因突变分析

目的检测并分析2例中国汉族结节性硬化症(tuberous sclerosis complex,TSC)患者TSC2基因突变特点。方法采用直接测序法对31个家系的34例TSC患者及其父母33名进行TSC1基因和TSC2基因全长编码外显子基因检测。测序后发现第25家系先证者为TSC2基因外显子40的框内移码突变5238-5255 del 18 bp,第11家系先证者为TSC2基因外显子23错义突变Arg905Trp。进一步采用变性凝胶电泳及内切酶技术在患者与120名正常对照中检测这两种突变。结果第25家系先证者外显子40出现5238-5255d el CATCAAGCGGCTCCGCCA突变,导致6个氨基酸缺失的框内移码突变(1746-1751del His-Ile-Lys-Arg-Leu-Gly),第11家系先证者外显子23出现2713 C>T(Arg905Trp)错义突变,2713位碱基由胞嘧啶(C)改变为胸腺嘧啶(T),导致第905位氨基酸精氨酸被色氨酸替代。120名正常对照未检测到这两种突变。结论TSC2基因5238-5255 del 18 bp及2713 C>T突变为两种致病性突变。     

缝隙连接蛋白B1基因I20T新突变导致伴有短暂性脑白质损害的X连锁Charcot-Marie-Tooth病1型

目的 报道1个伴有短暂性脑白质损害的X连锁Charcot-Marie-Tooth病1型(CMT1x)家系的临床、影像学和基因改变特点.方法 先证者为14岁男孩,出现短暂发作性言语不能和轻度肢体麻木无力2年5个月.其母亲存在弓形足.对先证者进行头颅MRI、神经电生理检查和腓肠神经活体组织检查;对先证者及其父母,50名女性无周围神经病及脑病对照者进行缝隙连接蛋白B1(GJB1)基因检测.结果 先证者周围神经的运动神经动作电位波幅显著下降,传导速度轻度减慢.听觉和体感诱发电位潜伏期明显延长.MRI显示胼胝体和大脑后部白质对称性异常信号,6个月后病变显著减轻.病理检查提示慢性轴索性周围神经病,电镜检查还可见有髓神经纤维的髓鞘施兰切迹加宽.先证者及其母亲GJB1基因存在I20T突变,其父和50名女性对照者无此突变.结论 伴短暂性脑白质损害的CMT1X可能与GJB1基因I20T新突变有关,其大脑白质的MR1改变具有可逆性.     

GJB1基因突变致腓骨肌萎缩症一家系

分析X-连锁腓骨肌萎缩症1型（X-linked Charcot-Marie-Tooth disease type 1, CMT1X）一家系的临床表现、电生理与突变基因特点。该家系为两代4人,共有2例CMT1X患者。先证者12岁起病,先证者母亲40岁起病,两者均表现为进行性肢体无力、萎缩,行走不稳。神经电生理检查均提示：四肢多发感觉运动神经损害（轴索损害为主并脱髓鞘）;多发肌肉呈神经源性损害。突变基因分析,先证者存在缝隙连接蛋白B1(gap junction protein Bata-1,GJB1)基因c.283 G>T(p.V95L)半合子突变,先证者母亲存在GJB1基因c.283 G>T(p.V95L),杂合突变。CMT1X是第二常见的腓骨肌萎缩症（Charcot-Marie-Tooth disease, CMT）类型,由GJB1基因突变引起,临床表现为进行性发展的周围神经病可合并中枢神经系统损害,基因检测有助诊断。     

TTR Val50Leu突变导致家族性淀粉样多发性神经病的临床和电生理研究

目的分析TTR Val50Leu突变导致家族性淀粉样多发性神经病的临床和电生理特点。方法对一个由TTR Val50Leu突变导致的家族性淀粉样多发性神经病家系进行报道,先证者以足部疼痛为首发症状,2年内逐渐向小腿及上肢进展,并出现自主神经症状。通过对先证者及其家系中相关者进行临床表现、电生理检查及基因检测,分析该病的临床和电生理特点。结果先证者的外祖父、母亲、舅舅、弟弟(其外祖父、母亲、舅舅已故)与其具有相似症状。先证者电生理检查上肢正中神经感觉传导受累,运动正常,尺神经的感觉传导及运动传导均正常,但尺神经F波异常,下肢胫神经和腓总神经的感觉传导及运动传导均未见肯定波形,腓肠神经受累,交感皮肤反应未引出。其弟弟上肢正中神经及尺神经改变同先证者,下肢胫神经运动波幅下降,腓总神经运动正常,交感皮肤反应四肢波幅降低,余同先证者。其女儿上述电生理检查未见异常。基因检测发现三者均在TTR基因exon2存在c.148GT突变,TTR蛋白存在Val50Leu突变。结论 TTR Val50Leu突变导致的家族性淀粉样多发性神经病家系属早发型,以足部疼痛为首发症状,进展迅速,自主神经症状出现较早。电生理符合多发性神经病表现,早期可伴有交感皮肤反应波幅降低。     

应用全外显子测序筛查常染色体隐性遗传痉挛性共济失调家系(附1例报告及文献复习)

目的报道常染色体隐性遗传痉挛性共济失调(ARSACS)家系1病例,对亚裔人群ARSACS的临床特征和基因变异进行分析。方法回顾ARSACS患者临床资料,采用全外显子测序方法对收治的ARSACS家系1病例进行基因检测。结合文献报道的16个亚裔ARSACS家系资料进行对比分析。结果 ARSACS病例典型临床表现为小脑共济失调合并痉挛及周围神经病变。先证者携带SACS基因上纯合无义突变(c. 11374C T,p. R3792X),未患病的父母携带该位点的单杂合突变。先证者姐姐通过一代测序验证亦携带上述纯合突变。先证者及先证者姐姐儿童时期有着同样的症状:剪刀步态和宽基步态、眼震、手足畸形,肌电图及神经传导速度提示感觉运动性周围神经病、头颅MRI显示小脑萎缩。先证者姐姐尚有双侧肺大泡。结论 ARSACS的基因突变类型及位点各异,由编码sacsin蛋白的SACS基因突变引起的神经退行性疾病,ARSACS在亚洲人群中罕见,无特定的高频突变。诊断主要依靠临床症状体征及辅助检查如肌电图等,不典型患者,基因筛查至关重要。     

一个特殊伴2型糖尿病的腓骨肌萎缩症家系基因突变检测

目的探讨合并2型糖尿病的腓骨肌萎缩症(CMT)一家系临床特点及可能的分子生物学发生机制。方法对40名家系成员进行详细家系调查、临床及辅助检查,并运用实时荧光PCR、普通PCR及基因测序等方法检测周围神经髓鞘蛋白22(peripheral myelin protein 22,PMP22)和髓鞘糖蛋白零(myelin protein zero,MPZ)基因有无突变。结果家系成员中5例经临床诊断为腓骨肌萎缩症1型(CMT1),其中4例伴2型糖尿病。该家系成员未发现PMP22基因大片段扩增突变及点突变;仅发现1例MPZ基因5820位点A→G多态性现象。结论 PMP22和MPZ基因突变不是本组合并2型糖尿病CMT家系的致病基因,需要进一步研究以明确该家系基因遗传规律。     

全面性癫(癎)伴热性惊厥附加症一家系的临床特点及SCN2A基因分析

目的 报告一个全面性癫(癎)伴热性惊厥附加症(generlized epilepsy with febrile seizures plus,GEFS+)家系,并探讨其临床及基因特点.方法 对该家系进行全面的调查,对其临床资料进行回顾性分析;采集该家系38名成员的静脉血并抽提其基因组DNA,采用PCR-DNA直接测序和P...     

Further evidence that neurofilament light chain gene mutations can cause Charcot-Marie-Tooth disease type 2E

A missense mutation in the neurofilament light chain gene (NEFL, NF-L) at chromosome 8p21 was recently reported in a single Charcot-Marie-Tooth type 2 family (CMT2). This new CMT2 variant is designated CMT2E. The NEFL gene mutation showed co-segregation with the disease phenotype and is thus most likely the disease-causing mutation. However, the possibility that it is a closely linked rare polymorphism can not be ruled out with certainty. We observed a novel NEFL missense mutation in a second CMT family, providing supporting evidence that CMT2E is caused by NEFL gene mutations.     

X连锁腓骨肌萎缩症Cx32基因的突变、临床和电生理特点

目的 分析X连锁腓骨肌萎缩症（CMTX）患者Cx32基凶的突变及其临床表现和电生理特点、方法应用多聚酶链反应一单链构象多态性分析结合DNA直接测序的方法,对24例无周围髓鞘蛋白（PMP）22基因大片段重复突变,家系中无男传男的腓骨肌萎缩症（CMT）先证者进行Cx32基因的突变分析;对先证者及其家系内患者进行临床和电生理检查。结果 在6个X连锁遗传家系和1例散发患者中发现了7个不同的Cx32基因突变,其中4个家系临床分型为CMTI型,2个家系为CMT中间型,散发病例为CMT1型检测到有Cx32基因突变的家系成员共38例,其巾男性20例,全部为CMTX患者;女性18例,其中6例为CMTX患者,12例为无临床症状的携带者;26例患者均为周围神经轻、中度受累。结论 CMTX的遗传方式可为X连锁显性、X连锁隐性遗传,也可为散发。根据临床和电生理特点分为CMTI型或CMT中间型,多为周围神经轻、中度受累,男性患者的症状通常较女性重。在没有检测到PMP22基因大片段重复突变和无男传男的CMT家系中应首先进行Cx32基因突变分析。     

A MYH3 mutation identified for the first time in a Chinese family with Sheldon-Hall syndrome (DA2B)

Sheldon-Hall syndrome is the most common type of distal arthrogryposis syndromes, also known as distal arthrogryposis 2B (DA2B). Sheldon-Hall syndrome is caused by mutations in the TPM2, TNNI2, TNNT3 or MYH3 gene and characterized by ulnar deviation, camptodactyly, overlapping fingers and scoliosis from birth. We investigated a Chinese family with multiple members who clinically presented with distal arthrogryposis of the hands. In total, 261 subjects including one proband and ten family members from the non-consanguineous Chinese family and 250 healthy volunteers were included and had their genomic DNA extracted. A novel missense mutation in exon 13 of the MYH3 gene, c.1160A > G (p.Tyr387Cys), was identified in the proband and his father through whole-exome sequencing. The proband and six affected family members were confirmed to carry this mutation by Sanger sequencing, although the mutation was not detected in the four unaffected individuals or 250 volunteers. This is the first report of a novel MYH3 mutation being identified as the cause of DA2B in a Chinese family. Our findings confirm that MYH3 gene mutations can be a pathogenic cause of DA2B in Asian patients. This study increases the mutational spectrum in MYH3 and aids genetic counseling and prenatal diagnosis.     

A novel mutation of the glycyl-tRNA synthetase (GARS) gene associated with Charcot–Marie–Tooth type 2D in a Chinese family

Abstract

Objective:

To explore the clinical features of a novel glycyl-tRNA synthetase (GARS) gene mutation in a family with Charcot–Marie–Tooth disease type 2D (CMT2D).

Methods:

Exome capture with the next-generation sequencing technique was used to detect gene mutations. The mutations were verified by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) technique combined with DNA sequencing.

Results:

In this pedigree, eight members were affected; seven males and one female. The affected members initially manifested with the onset of hand muscle weakness and atrophy in adolescence followed by gradual development of distal lower limb involvement and minor sensory involvement. Electrophysiological studies revealed that this disease mainly involves axonal damage. Genetic detection showed that all affected family members had a heterozygous missense mutation, c.999G>T (p.E333D), of the GARS gene.

Conclusions:

The c.999G>T mutation is a novel mutation of the GARS gene that has not been previously reported. The phenotype of this family is CMT2D, which is first reported in Chinese population.     

Novel GARS mutation presenting as autosomal dominant intermediate Charcot‐Marie‐Tooth disease

We report the first family with a glycyl‐tRNA synthetase (GARS) mutation with autosomal dominant intermediate Charcot‐Marie‐Tooth disease (DI‐CMT). The proband and the proband's father presented with gait disturbance and hand weakness. Both patients displayed moderately decreased conduction velocities (MNCV) (ranging from 29.2 to 37.8 m/s). A sural nerve biopsy of the father revealed evidence of both axonal loss and demyelination. On exome sequencing, in both the proband and his father, we identified a novel missense mutation (c.643G > C, p.Asp215His) in the GARS gene in a heterozygous state, which is considered to be pathogenic for this DI‐CMT family. The present study broadens current knowledge about intermediate CMT and the phenotypic spectrum of defects associated with GARS.