腓骨肌萎缩症的分子遗传学研究进展

本文就腓骨肌萎缩症已克隆基因的结构、功能,基因突变的特点进行综述。     

腓骨肌萎缩症的分子生物学研究进展

腓骨肌萎缩症(CMT)是一种最常见的周围神经遗传病。随着分子生物学的进展,目前有将近30个不同的遗传位点被定位,20个基因被相继克隆,为阐明不同表型腓骨肌萎缩症的内在共同发病机制提供了分子基础。文章综述了CMT的分子遗传学进展,并从异常的旺氏细胞/轴索的相互作用、轴索运输功能缺陷、蛋白质转运障碍、小分子热休克蛋白相关的神经退行性变等方面总结了CMT发病机理研究进展。     

腓骨肌萎缩症治疗研究进展

腓骨肌萎缩症(CMT)是人类最常见的遗传性周围神经病,目前临床对CMT-1A尚无特殊治疗。到目前为止,孕酮拮抗剂、维生素C、神经营养因子-3(NT-3)等对CMT-1A有效的药物已经经过了临床前检验,前景广阔。姜黄的疗效也十分显著。另外尚有一些存在争议的治疗方法,如免疫调节等。顺铂、长春新碱等因其副作用大,安全性受到怀疑。本文旨在对使用CMT动物模型研究治疗方案的进展进行综述。     

腓骨肌萎缩症的基因学研究进展

腓骨肌萎缩症 (Charcot marie tooth disease,CMT)是一类高发病率的周围神经系统单基因遗传病 ,发病率为 1/2 50 0 ,其遗传方式有常染色体显性遗传 (AD)、常染色体隐性遗传 (AR)及 X连锁显性或隐性遗传 (XD或 XR)。其主要临床表现为胫前腓骨肌及手部肌萎缩伴无力 ,足下垂 ,跨越步态 ,弓形足 ,膝踝反射减弱或消失 ,儿童、青少年、成年期均可发病 ,慢性进行性病程 ,致残率高。临床上根据 CMT的病理和电生理特点分为两型 ,即脱髓鞘型 (CMT1型 )和轴突型(CMT2型 ) ,其中 CMT1型约占 CMT总数的 70 %。目前世界上对 CMT的基因研究已…     

腓骨肌萎缩症的临床和遗传特点

目的探讨腓骨肌萎缩症(CMT)的临床和遗传特点。方法对70个CMT家系110例患者的临床资料和遗传史进行回顾性分析。结果本组男：女为2．03：1,发病年龄1～61岁,平均19．1岁,30岁以前发病者占78．2％;有家族史者70例(63．6％),其中常染色体显性遗传17个家系,近亲结婚者5个家系(6．9％)。表现双下肢肌萎缩106例(96．4％),双上肢远端肌无力与肌萎缩48例(43．6％),鹤立腿64例(58．2％),弓形足68例(61．8％),踝反射减弱及消失108例(98．2％)。肌电图检查均为神经源性损害,肌活检37例均为神经源性肌萎缩;神经活检25例,髓鞘脱失和雪旺细胞增生和／或“洋葱头”样改变20例,轴索变性5例,未发现腊肠样结构。结论CMT多于儿童期至青少年期发病,男性多于女性;遗传方式以常染色体显性遗传多见。神经电生理及病理检查对CMT的诊断和分型有重要作用。     

腓骨肌萎缩症2型的临床特点研究

目的研究腓骨肌萎缩症2型(CMT2)的临床特点。方法回顾性分析9例CMT2患者的临床资料。结果本组男5例,女4例;平均发病年龄21.7岁。平均神经病残疾评分32.6分,平均CMT评分13.3分。均为隐匿性起病,缓慢进展,主要表现为慢性对称性四肢远端肌无力和肌萎缩,感觉症状轻微。1例患者伴有限制性心肌病,临床罕见。9例患者神经电生理检查示运动、感觉神经传导动作电位波幅降低或消失,1例患者伴神经传导速度减慢(<38 m/s),周围神经病变严重。4例腓肠神经及腓短肌肌肉病理学检查符合CMT2典型神经肌肉病理表现。MFN2基因突变分析发现,1例MFN2基因第18外显子发生L710P突变。结论 CMT2的主要临床特点为对称性四肢远端肌无力和肌萎缩,周围神经损害严重但功能相对良好。限制性心肌病可能是该病的表现型之一。MFN2基因L710P突变可能为CMT2致病基因的突变型之一。     

肩胛腓骨肌萎缩症1例

先证者 ( 1 3) :男 ,38岁 ,以“进行性肌无力、萎缩十二年 ,加重伴胸闷 ,气短半年”,于 2 0 0 0年 3月 7日入住我院。该患 12年前无明显原因出现行走时摔倒 ,骑车无力 ,生活能够自理。 3个月后自觉下肢尤其是膝部以下萎缩 ,活动能力无明显降低。一年前开始卧床 ,生活能力明显下降 ,吃饭、穿衣均靠人帮助才能完成。半年前出现胸闷气短 ,呼吸费力 ,为求诊治来我院。入院查体 :T36 .0℃ ,P80次 /分 ,Bp14 /11Kpa,R2 4次 /分 ,神清语明 ,表情略痛若 ,唇发绀 ,呼吸动度减小 ,双肺呼吸音较弱 ,心脏听诊未见异常 ,腹部平软 ,无压痛。神经科查体 :…     

腓骨肌萎缩症的临床、电生理和遗传学特点(附1家系报告)

目的 探讨腓骨肌萎缩症(CMT)的临床、电生理和遗传学特点.方法 对1例CMT患者的临床资料及其家系调查资料进行回顾性分析.结果 本例患者主要表现为先天性慢性进行性双下肢远端肌无力和肌肉萎缩,伴有双上肢受累;腱反射减弱或消失,下肢感觉障碍.神经电生理检查示周围神经损害.家系调查显示为常染色体显性遗传.结论 CMT的临床特点为下肢远端肌无力、萎缩,神经电生理检查为周围神经损害,主要呈常染色体显性遗传.     

中国腓骨肌萎缩症的临床特点

总结国内文献报道及本院腓骨肌萎缩症的临床特点并与国外资料比较，发现国内患者男较女多，平均发病年龄１５．０岁。７６．５％Ⅰ型患者在２０岁前起病，５０％Ⅱ型于２０岁后起病。７９．０％先累及下肢，上肢肌萎缩，感觉障碍踝反射降低及消失，弓形足分别为６３．６％，３９．６％，９７．０％，７４．２％。     

腓骨肌萎缩症研究概述

腓骨肌萎缩症(Charcot-Marie-Tooth,CMT)病是一组由不同致病基因引起的临床表型基本相似的遗传性周围神经病,不同人群中CMT的发病率略有不同,约在17/100, 00～40/100, 000之间~([1]).     

Molecular genetics of X-linked Charcot-Marie-Tooth disease

The X-linked form of Charcot-Marie-Tooth disease (CMT1X) is the second most common molecularly designated form of hereditary motor and sensory neuropathy. The clinical phenotype is characterized by progressive distal muscle atrophy and weakness, areflexia, and variable sensory abnormalities. Affected males have moderate-to-severe symptoms, whereas heterozygous females are usually mildly affected or even asymptomatic. Several patients also have manifestations of central nervous system involvement or hearing impairment. Electrophysiological and pathological studies of peripheral nerves show evidence of demyelinating neuropathy with prominent axonal degeneration. A large number of mutations in the GJB1 gene encoding the gap junction (GJ) protein connexin32 (C×32) cause CMT1X. C×32 is expressed by Schwann cells and oligodendrocytes, as well as by other tissues, and the GJ formed by C×32 play an important role in the homeostasis of myelinated axons. The reported CMT1X mutations are diverse and affect both the promoter region as well as the coding region of GJB1. Many C×32 mutants fail to form functional GJ, or form GJ with abnormal biophysical properties. Furthermore, C×32 mutants are often retained intracellularly either in the endoplasmic reticulum or Golgi in which they could potentially have additional dominant-negative effects. Animal models of CMT1X demonstrate that loss of C×32 in myelinating Schwann cells causes a demyelinating neuropathy. No definite phenotype-genotype correlation has yet been established for CMT1X and effective molecular based therapeutics for this disease, remain to be developed.     

Molecular genetics of autosomal-dominant demyelinating Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of disorders and is the most common inherited neuromuscular disorder, with an estimated overall prevalence of 17–40/10.000. Although there has been major advances in the understanding of the genetic basis of CMT in recent years, the most useful classification is still a neurophysiological classification that divides CMT into type 1 (demyelinating, median motor conduction velocity <38 m/s) and type 2 (axonal; median motor conduction velocity> 38 m/s). An intermediate type is also increasingly being described. Inheritance can be autosomal-dominant (AD), X-linked, or autosomal-recessive (AR). ADCMT1 is the most common type of CMT and was the first form of CMT in which a causative gene was described. This review provides an up-to-date overview of AD CMT1 concentrating on the molecular genetics as the clinical, neurophysiological, and pathological features have been covered elsewhere. Four genes (PMP22, MPZ, LITAF, and EGR2) have been described in the last 15 yr associated with AD CMTI and a further gene (NEFL), originally described as causing AD CMT2 can also cause AD CMT1 (by neurophysiological criteria) (Table 1, Figs. 1, and 2). Studies have shown many of these genes, when mutated, can cause a wide range of CMT phenotypes from the relatively mild CMT1 to the more severe Dejerine-Sottas disease and congenital hypomyelinating neuropathy, and even in some cases axonal CMT2 (Table 1). This review discusses what is known about these genes and in particular how they cause a peripheral neuropathy, when mutated.     

Molecular genetics of autosomal-dominant axonal Charcot-Marie-Tooth disease

The autosomal-dominant axonal peripheral neuropathies comprise a genetically heterogeneous group of disorders that are clinically subsumed under Charcot-Marie-Tooth disease type 2 (CMT2). A significant increase in the number of genes underlying major forms of CMT2 has improved the classification of specific CMT phenotypes. The molecular dissection of cellular functions of the related gene products has only begun and detailed pathophysiological models are still missing, but already the biological scope of genes linked to CMT2 is more diversified than CMT1. The known CMT2 genes present key players in these pathways and will likely prove as powerful tools in identifying eventual future targets for therapeutic intervention.     

Mitochondrial coupling defect in Charcot-Marie-Tooth type 2A disease

OBJECTIVE: Mutations of the mitofusin 2 gene (MFN2) may account for at least a third of the cases of Charcot-Marie-Tooth disease type 2 (CMT2). This study investigates mitochondrial cellular bioenergetics in MFN2-related CMT2A. METHODS: Mitochondrial network morphology and metabolism were studied in cultures of skin fibroblasts obtained from four CMT2A patients harboring novel missense mutations of the MFN2 gene. RESULTS: Although the mitochondrial network appeared morphologically unaltered, there was a significant defect of mitochondrial coupling associated with a reduction of the mitochondrial membrane potential. INTERPRETATION: Our results suggest that the sharply reduced efficacy of oxidative phosphorylation in MFN2-related CMT2A may contribute to the pathophysiology of the axonal neuropathy.     

Charcot-Marie-Tooth disease type 2 with restless legs syndrome

In a series of 44 consecutive patients with Charcot-Marie-Tooth disease (CMT), we found restless legs syndrome (RLS) in 10 of 27 CMT type 2 (CMT2) patients (37%) and in none of 17 CMT type 1 patients (p = 0.004). In the CMT2 patients, RLS was associated with positive sensory symptoms (10/10 versus 10/17; p = 0.026). This finding supports the view that a disorder of sensory input plays a role in the pathogenesis of RLS. Symptomatic treatment may benefit these patients.     

A family of early childhood-onset Charcot-Marie-Tooth disease type 2]

We reported a man and his son with Charcot-Marie-Tooth disease (CMT) type 2. Their age at onset was about 5 years. Their clinical examinations revealed muscle atrophy and weakness of both distal lower limbs, foot-drop, a reduction of the reflex in both Achilles tendons and sensory impairment of the glove and stocking type. Nerve conduction studies revealed remarkably low amplitude of compound muscle action potential compared to conduction velocity. The nerve biopsy of their sural nerves revealed loss of large myelinated fiber. We presumed that the clinical features of their disease were compatible with CMT2A or 2B. DNA analysis of our family members performed with microsatellite markers linked to the candidate regions of CMT2A and 2B, did not show apparent positive results. We speculate that this family was a novel gene locus of CMT type 2.