Charcot—Marie—Tooth病的遗传,临床和电生理观察（附20例临床分析）

本文报道 ２０例 Ｃｈａｒｃｏｔ－Ｍａｒｉｅ－Ｔｏｏｔｈ病的遗传、临床和电生理资料。其中男 １６例,女 ４例,平均发病年龄为２６．７５岁。发现４例显性遗传,３例隐性遗传,１０例散发,３例遗传情况不详。主要症状有高弓足、垂足、鹤腿和腱反射消失;上肢前臂有肌萎缩者占１／４。所有病人电生理检查均有失神经现象,特别是ＭＣＶ有明显减慢。且发现ＭＣＶ的减慢和临床严重程度无相关联系。     

Advances in the genetics of movement disorders: implications for molecular diagnosis

Recent developments in molecular genetics have had a profound influence on the diagnosis and classification of inherited movement disorders. Huntington’s disease is caused by the expansion of an unstable trinucleotide repeat sequence. Molecular diagnosis can now be performed by a simple PCR-based assay, and the study of the effects of the repeat expansion on the function of the encoded protein will allow to elucidate the molecular pathogenesis of the disease. Wilson’s disease is caused by a large number of different mutations, which complicates molecular diagnosis. Genes for a number of inherited dystonic syndromes have been mapped, one of them, the gene for dopa-responsive dystonia, has already been identified. The genetic basis of several other prevalent movement disorders, such as essential tremor and the restless-legs syndrome however, is still obscure. Current research is also directed at the identification of inherited risk-factors in genetically complex movement disorders, such as Parkinson’s disease. Received: 21 September 1996 Accepted: 18 October 1996     

Motor unit number index correlates with disability in Charcot-Marie-Tooth disease

Objective

The aim of this study was to assess the usefulness of motor unit number index (MUNIX) technique in Charcot-Marie-Tooth disease and test the correlation between MUNIX and clinical impairment.

Differential diagnosis of Charcot-Marie-Tooth disease and related neuropathies

Abstract. The diagnosis of Charcot-Marie-Tooth disease (CMT) and related neuropathies (e. g. Déjèrine-Sottas disease; hereditary neuropathy with liability to pressure palsies) appears to be easy. However, the incredible advances in molecular genetics have greatly complicated the classification of these disorders, and the proper diagnosis of the CMT subtype may be important for correct genetic counselling and prognosis. Moreover, these diseases may be confused with potentially treatable acquired and inherited neuropathies, such as dysimmune neuropathies, familial amyloid polyneuropathy, and Refsums disease. A number of clinical, laboratory, electrophysiological, morphological and neuroradiological features that may help in the diagnostic process are reviewed in the present paper. DNA investigations are fundamental but need to be properly addressed. Currently, great interest is focused on the role of the immune system in hereditary neuropathies, and surprising findings are coming from research on animal models.     

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。     

Charcot-Marie-Tooth disease: Frequency of genetic subtypes in a German neuromuscular center population

Charcot-Marie-Tooth (CMT) neuropathies belong to the most common neurogenetic disorders. To date, mutations in more than 40 genes are known to be able to cause CMT. This genetic heterogeneity is a challenge for genetic diagnostics. Data on frequencies of mutations in CMT genes from large patient cohorts are needed to develop strategies for efficient genetic testing. In this study we have analysed patient histories, electrophysiological and genetic testing data in our cohort of 776 patients. In electrophysiologically demyelinating CMT, PMP22 duplication was the most common genetic cause, followed by mutations in GJB1 and MPZ. In axonal CMT, GJB1 was the most commonly affected gene, followed by MFN2 and MPZ. In CMT1, the clearance rate was 66%, in CMT2 it was 35%. Overall, the genetic clearance rate in our patient cohort was 58%. We found a higher rate of genetic diagnosis in patients seen in our neuromuscular center compared to out-of-clinic patients whose DNA was tested in our laboratory.This study provides further data on frequencies of CMT genes and subtypes and points to the importance of a thorough clinical and electrophysiological work-up for the direction of genetic testing.     

Molecular cell biology of Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease (CMT), also named hereditary motor and sensory neuropathies, includes a clinically and genetically heterogeneous group of disorders affecting the peripheral nervous system. Traditionally, the different classes of CMT have been divided into demyelinating forms (CMT1, CMT3, and CMT4) and axonal forms (CMT2), a clinically very useful distinction. However, investigations of the underlying molecular and cellular disease mechanisms, mainly accomplished using cell culture and animal models, as well as specific re-examination of appropriate patient cohorts, have revealed that the pathological signs of myelinopathies and axonopathies are often intermingled. These findings, although only recently fully appreciated, are not surprising given the dependence and intimate cellular interactions of Schwann cells and neurons, mainly during nerve development and, as indicated by the pathology of CMT, also in the adult organism. This review is intended to summarize our current knowledge about the molecular and cellular basis of CMT, with a particular emphasis on the role of Schwann cell/axon interactions. Such a view is particularly timely since approximately ten genes have now been identified as culprits in different forms of CMT. This collection revealed novel crucial players in the interplay between Schwann cells and neurons. The analysis of these genes and their encoded proteins will provide additional insights into the molecular and cellular basis of neuropathies and valuable information about the biology and interactions of Schwann cells, their associated neurons, endoneurial fibroblasts, and the nerve-surrounding and protecting perineurial sheath. Electronic Publication     

Motor and sensory conduction velocity in Charcot-Marie-Tooth disease

Zusammenfassung Leitgeschwindigkeit in den peripheren Nerven (sensiblen, motorischen und gemischten Fasern) wurde bei 23 Patienten von Charcot-Marie-Tooth-Krankheit durchgeführt. Es wurde in den meisten Fällen eine starke Verminderung der Leitgeschwindigkeit, in allen 3 Gruppen von Fasern, insbesondere in den distalen Segmenten (Finger und Zehen) der sensiblen Fasern beobachtet. Trotzdem waren die Mittelwerte der sensiblen, motorischen und gemischten Fasern nicht sehr verschieden. Diese Befunde weisen auf eine segmentale Demyelinisierung hin, in den meisten Fällen.     

腓骨肌萎缩症治疗进展

腓骨肌萎缩症是临床最常见的具有高度临床和遗传异质性的周围神经系统单基因遗传病,目前已克隆出80余种致病基因。通常于儿童期或青少年期发病,临床主要表现为慢性进行性四肢远端肌无力和肌萎缩、感觉减退和腱反射消失,伴高弓足和脊柱侧弯等骨骼畸形。尽管目前尚无逆转病程的特异性治疗方法,但康复训练、外科矫形手术和药物治疗等对症支持治疗可以改善运动功能、提高生活质量。基于发病机制的治疗研究有望提供精准有效的靶向治疗。     

腓骨肌萎缩症的临床特点与心肌酶学改变

目的 研究腓骨肌萎缩症的临床特点、心肌酶学改变及其两者之间的关系。方法 对34例腓骨肌萎缩症患者的临床特点、肌电图(EMG)、神经传导速度(NCV)、脑干听觉诱发电位(BAEP)、神经肌肉活检及心肌酶学结果进行回顾性分析。结果 34例患者中有8例肌酸激酶(CK)升高(231．6～883IU／L)，CK正常组与增高组之间的性别组成、发病年龄、病程、阳性家族史、手部肌肉受累、感觉障碍、腱反射改变及骨骼畸形情况比较均无显著性差异。结论腓骨肌萎缩症患者可以出现心肌酶学增高，心肌酶学正常组与增高组临床表现无显著性差异。     

Intermediate Charcot-Marie-Tooth disease

Charcot-Marie-Tooth（CMT） disease is a common neurogenetic disorder and its heterogeneity is a challenge for genetic diagnostics. The genetic diagnostic procedures for a CMT patient can be explored according to the electrophysiological criteria： very slow motor nerve conduction velocity（MNCV）（〈15 m/s）, slow MNCV（15–25 m/s）, intermediate MNCV（25–45 m/s）, and normal MNCV（〉45 m/s）. Based on the inheritance pattern, intermediate CMT can be divided into dominant（DI-CMT） and recessive types（RI-CMT）. GJB1 is currently considered to be associated with X-linked DI-CMT, and MPZ, INF2, DNM2, YARS, GNB4, NEFL, and MFN2 are associated with autosomal DI-CMT. Moreover, GDAP1, KARS, and PLEKHG5 are associated with RI-CMT. Identification of these genes is not only important for patients and families but also provides new information about pathogenesis. It is hoped that this review will lead to a better understanding of intermediate CMT and provide a detailed diagnostic procedure for intermediate CMT.     

Charcot-Marie-Tooth disease: study of a large kinship with an intermediate form

Summary A clinical, genetic, electrophysiological and ultrastructural study of a large kinship with peroneal muscular atrophy is reported. There was a noteworthy homogeneity in the phenotype as well as in the electrophysiological characteristics encountered in 15 affected members aged between 7 and 72 years. The symptoms appeared first in the second decade of life and stabilized by the fourth decade. There was no evidence of linkage of the neuropathy gene to the Duffy blood group locus on chromosome 1. The electrophysiological data in this family as well as the ultrastructural findings confirm that there is heterogeneity in hereditary motor and sensory neuropathy type I, and support the concept of an intermediate form of Charcot-Marie-Tooth disease.     

伴有炎性改变的腓骨肌萎缩症二例病理报告

目的 报道2例经基因诊断明确的腓骨肌萎缩症患者的病理特点.方法 对2例经基因诊断明确为连接蛋白32（connexin 32,Cx32）基因突变所致的腓骨肌萎缩症患者进行腓肠神经和腓肠肌活检,肌肉切片采用HE染色,腓肠神经半薄切片采用美蓝染色,另采用免疫组织化学（SP法）检测腓肠神经是否有炎症细胞浸润.所用抗体为抗CD68抗体和抗白细胞共同抗原（LCA）抗体.结果 2例患者腓肠肌活检均可见肌间质大量炎性细胞浸润,脂肪增生.腓肠神经半薄切片未见明显洋葱球样结构形成,可见有髓纤维密度明显减少,大量薄髓鞘有髓神经纤维和有髓神经纤维再生簇形成.免疫组织化学见2例患者腓肠神经CD68和LCA表达均呈阳性.结论 腓骨肌萎缩症患者可表现为炎性病理改变,临床上要注意与慢性炎症性脱髓鞘性多发性神经病等鉴别.     

腓骨肌萎缩症基因重复异常的检测

目的应用分子生物学方法对腓骨肌萎缩症(CMT)患者进行外周髓鞘蛋白(PMP22)基因重复异常的检测。方法应用多聚酶链反应(PCR)加双酶切的方法,对临床上诊断为腓骨肌萎缩症14个家系的先证者和47例散发患者及20例正常人进行基因重复异常研究,根据有无1760bp大小的酶切片断来判断是否为PMP22基因重复异常。结果13个家系检测出PMP22基因重复异常,占所收集家系的92.86%;28例散发者检出PMP22基因重复异常,占散发病例59.57%。结论PCR-双酶切法检测CMT基因重复异常比较快速、简单、易操作,目前为CMT1A型基因诊断首选方法。     

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。     

Sensory manifestations in Charcot-Marie-Tooth disease

Involvement of sensory nerves in Charcot-Marie-Tooth (CMT) disease is well known, however, sensory symptoms are usually overlooked. To assess the frequency and features of sensory symptoms in a cohort of patients with CMT, we investigated in a prospective study 52 consecutive CMT patients, diagnosed on the basis of clinical, neurophysiological, and genetic features and classified in CMT type 1 (CMT1) (20 patients, including 14 with CMT1A) and CMT type 2 (CMT2) (32 patients). Positive sensory symptoms were reported by 28 patients (54%), including neuropathic pain in 6 patients. Pain, either neuropathic or nociceptive, was present in 29 patients (56%) and in 15 patients as a main symptom. Positive sensory symptoms were present in 24 of 32 CMT2 patients (75%) and in 4 of 20 CMT1 patients (20%) (p < 0.001); there was a presenting manifestation in 11/32 CMT2 patients vs. 1/20 in CMT1 patients (p = 0.018), and one of the main features in 6/32 CMT2 patients vs. 1/20 CMT1 patients. Frequency of positive sensory symptoms in CMT1A patients was similar to that of the entire CMT1 group. Within the CMT2 group, patients with positive sensory symptoms as a main or onset feature (11 patients) had significantly later onset (median 57 vs. 25 years; p = 0.042) and less severely impaired motor action potentials than CMT2 patients without positive sensory symptoms (8 patients). Nociceptive pain was especially frequent in CMT1A patients (10/14, 71%). Sensory manifestations in CMT seem more frequent than previously thought, especially in CMT2; however, their frequency may be different in the genetic subtypes of the disease and/or an expression of phenotypic variability. Sensory symptoms, and in particular pain, may represent an important issue in the management of CMT patients, especially in a physical medicine approach.     

Charcot-Marie-Tooth disease associated with retinal pigment dystrophy and protanopia

Summary Neurological, ophthalmological and genetic investigations were performed on a family, a member of which presented with a rare association of tapeto-retinal degeneration, protanopia and Charcot-Marie-Tooth disease (CMT), and asked for genetic counselling. The neurological enquiry was completed by measurement of motor nerve conduction velocity in several members of the family. The propositus was submitted to a muscle biopsy. The ophthalmological examination included ophthalmoscopy, fluorescein angiography, electroretinogram and electrooculogram. The propositus, a woman aged 40, had typical CMT disease and her father also had a mild form of it. She had protanopia as had her father, her son and her nephew. In addition she had large macular pigmented changes, described as retinal dystrophy, flavus flavimaculatus. Her mother had only senile pigmented modification of the fundus and her three daughters had mild macular pigmented changes, like salt and pepper. Two genes are probably involved: one for protanopia with X linked recessive inheritance, the other responsible of CMT and tapetoretinal degeneration, with an autosomal dominant inheritance, giving a 50% risk of recurrence.Work supported by grants from the FRSM of Belgium and the Free University of Brussels     

Mutations in the X-linked form of Charcot-Marie-Tooth disease in the French population

The present study reports eight additional mutations in the connexin32 gene associated with the X-linked form of Charcot-Marie-Tooth disease. One of these mutations was found twice in two apparently unrelated families. This form of the disease is demyelinating and dominant. However, patient selection for mutational screening should not be limited to these criteria since presentation can either be familial or sporadic, and some patients may be incorrectly classified as suffering from an ‘axonal’ form. These new mutations complete our previously published work on 12 other mutations and enable meaningful observation in a representative sample of the French population. Mutations are found in all regions of the gene. The most frequently observed mutations were those affecting arginines and mainly involved CpG sequences. Compared with other sources, some of the mutations were present at a higher frequency in the French population. Received May 23, 1997; Revised and Accepted June 24, 1997     

X-Linked Charcot-Marie-Tooth disease caused by a novel point mutation in the connexin-32 gene

We report the clinical and electrophysiological findings of a patient with X-linked Charcot-Marie-Tooth disease and a novel point mutation in the connexin-32 gene. A 31-year-old man presented with a 5 year history of progressive imbalance and distal weakness in his legs. Electrophysiological studies confirmed an asymmetric, predominantly axonal sensorimotor neuropathy with some demyelinating features. Genetic testing revealed a G/A transition (Ala40Thr) in a conserved transmembrane region of the connexin-32 gene. Received: 13 April 2002 / Accepted in revised form: 18 June 2002 Correspondence to R.P. Grewal     

Clinical and electrophysiological aspects of Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous group of disorders sharing the same clinical phenotype, characterized by distal limb muscle wasting and weakness, usually with skeletal deformities, distal sensory loss, and abnormalities of deep tendon reflexes. Mutations of genes involved in different functions eventually lead to a length-dependent axonal degeneration, which is the likely basis of the distal predominance of the CMT phenotype. Nerveconduction studies are important for classification, diagnosis, and understanding of pathophysiology. The subdivision into demyelinating CMT1 and axonal CMT2 types was a milestone and is still valid for the majority of patients. However, exceptions to this partition are increasing. Intermediate conduction velocities are often found in males with X-linked CMT (CMTX), and different intermediate CMT types have been identified. Moreover, for some genes, different mutations may result either in demyelinating CMT with slow conduction, or in axonal CMT. Nerve conduction slowing is uniform and diffuse in the most common CMT1A associated with the 17p12 duplication, whereas it is often asymmetric and nonhomogeneous in CMTX, sometimes rendering difficult the differential diagnosis with acquired inflammatory neuropathies. The demyelinating recessive forms, termed CMT4, usually have early onset and run a more severe course than the dominant types. Pure motor CMT types are now classified as distal hereditary motor neuronopathy. The diagnostic approach to the identification of the CMT subtype is complex and cannot be based on the clinical phenotype alone, as different forms are often clinically indistinguishable. However, there are features that may be of help in addressing molecular investigation in a single patient. Late onset, prominent or peculiar sensory manifestations, autonomic nervous system dysfunction, cranial nerve involvement, upper limb predominance, subclinical central nervous system abnormalities, severe scoliosis, early-onset glaucoma, neutropenia are findings helpful for diagnosis.