Clinical classification and gene mutation of Chinese probands with Charcot-Marie-Tooth disease Analysis of 57 cases

Charcot-Marie-Tooth （CMT） disease is the most common inherited peripheral neuropathic disorder. CMT is clinically and genetically heterogeneous. To date, 27 genes associated with the disease have been cloned. The present study carried out clinical classification according to clinical, electrophysiological and pathological features, conducted inheritance classification according to inheritance patterns, and performed mutation analysis of 13 CMT disease genes （PMP22, CX32, HSPB1, MNF2, MPZ, HSPB8, GDAP1, NFL, EGR2, SIMPLE, RAB7, LMNA, MTMR2） in 57 Chinese probands with CMT. Five cases of AD-CMT1 and 13 cases of sporadic CMT1 were diagnosed as CMT1A; five cases of X-CMT1, one case of X-CMT2 and one case of sporadic CMT1 were diagnosed as CMTXl; four cases of AD-CMT2 were diagnosed as CMT2F; one case of AD-CMT2 and one case of sporadic CMT2 were diagnosed as CMT2A2; one case of AD-CMT2 was diagnosed as CMT2L; one case of AD-CMT2 was diagnosed as CMT2J; one case of AR-CMT1 was diagnosed as CMT4A. Among the 57 CMT probands, seven genotypes were determined among 34 patients, with a detection rate of 59.6%. The results indicated that the clinical classification and inheritance classification are indispensable for selecting potential disease genes for mutation detection, and for efficient molecular diagnosis.

Anatomical distributional defects in mutant genes associated with dominant intermediate Charcot-Marie-Tooth disease type C in an adenovirus-mediated mouse model

Dominant intermediate Charcot-Marie-Tooth disease type C（DI-CMTC） is a dominantly inherited neuropathy that has been classified primarily based on motor conduction velocity tests but is now known to involve axonal and demyelination features.DI-CMTC is linked to tyrosyl-t RNA synthetase（YARS）-associated neuropathies,which are caused by E196 K and G41 R missense mutations and a single de novo deletion（153-156 del VKQV）.It is well-established that these YARS mutations induce neuronal dysfunction,morphological symptoms involving axonal degeneration,and impaired motor performance.The present study is the first to describe a novel mouse model of YARS-mutation-induced neuropathy involving a neuron-specific promoter with a deleted mitochondrial targeting sequence that inhibits the expression of YARS protein in the mitochondria.An adenovirus vector system and in vivo techniques were utilized to express YARS fusion proteins with a Flag-tag in the spinal cord,peripheral axons,and dorsal root ganglia.Following transfection of YARS-expressing viruses,the distributions of wild-type（WT） YARS and E196 K mutant proteins were compared in all expressed regions; G41 R was not expressed.The proportion of Flag/green fluorescent protein（GFP） double-positive signaling in the E196 K mutant-type mice did not significantly differ from that of WT mice in dorsal root ganglion neurons.All adenovirus genes,and even the empty vector without the YARS gene,exhibited GFP-positive signaling in the ventral horn of the spinal cord because GFP in an adenovirus vector is driven by a cytomegalovirus promoter.The present study demonstrated that anatomical differences in tissue can lead to dissimilar expressions of YARS genes.Thus,use of this novel animal model will provide data regarding distributional defects between mutant and WT genes in neurons,the DICMTC phenotype,and potential treatment approaches for this disease.

A novel transgenic mouse model of Chinese CharcotMarie-Tooth disease type 2L

We previously found that the K141N mutation in heat shock protein B8 （HSPB8） was responsible for Charcot-Marie-Tooth disease type 2L in a large Chinese family. The objective of the present study was to generate a transgenic mouse model bearing the K141N mutation in the human HSPB8 gene, and to determine whether this K141NHSPB8 transgenic mouse model would manifest the clinical phenotype of Charcot-Marie-Tooth disease type 2L, and consequently be suitable for use in studies of disease pathogenesis. Transgenic mice overexpressing K141N HSPB8 were generated using K141N mutant HSPB8 cDNA cloned into a pCAGGS plasmid driven by a human cytomegalovirus expression system. PCR and western blot analysis confirmed integration of the KI41NHSPB8 gene and widespread expression in tissues of the transgenic mice. The K141N HSPB8 transgenic mice exhibited decreased muscle strength in the hind limbs and impaired motor coordination, but no obvious sensory disturbance at 6 months of age by behavioral assessment. Electrophysiological analysis showed that the compound motor action potential amplitude in the sciatic nerve was significantly decreased, but motor nerve conduction velocity remained normal at 6 months of age. Pathological analysis of the sciatic nerve showed reduced myelinated fiber density, notable axonal edema and vacuolar degeneration in K141N HSPB8 transgenic mice, suggesting axonal involvement in the peripheral nerve damage in these animals. These findings indicate that the KI4mHSPB8 transgenic mouse successfully models Charcot-Marie-Tooth disease type 2L and can be used to study the pathogenesis of the disease.

Surgical Treatment of Scoliosis in Patients with Charcot-Marie-Tooth Disease

Objective:Apparently, scoliosis occurs in approximately one-third of patients with Charcot-Marie-Tooth disease. Little is known about the response of these curves to treatment. The purpose of this study was to evaluate the results of spinal surgery in these peculiar patients. Methods: We retrospectively evaluated the results of spinal surgery in eight patients who had scoliosis due to clinically and electrophysiologically proven Charcot-Marie-Tooth disease. Radiographs were reviewed. The location and direction of the curve pattern, the age at the time of surgery, type of surgery, number of levels fused, instrumentations used, intra or postoperative complications, and results and need for reoperation were recorded. Results: Eight patients associated with Charcot-Marie-Tooth disease who underwent scoliotic surgery were identified. The average age and curve at the time of surgery were 21.1 years and 56.4° respectively. 62.5% of the curves had left thoracic component and more than one third was associated with thoracic hyperkyphosis. Long posterior spinal fusion was performed most often, with an average of 11.5 spinal segments fused. Instrumentation was used in all posterior fusions. At an average of 39 months (range, 24 to 72 months) postoperatively, the fusion appeared to be solid in all patients. Conclusion: Scoliosis in patients with Charcot-Marie-Tooth disease differs from that in patients with idiopathic scoliosis in regarding to the etiology and the prevalence of thoracic hyperkyphosis, but the surgical management appears to be similar. Spondylodesis does not appear to be associated with a high rate of complications.

Advances in the molecular diagnosis of Charcot-Marie-Tooth disease

Charcot-Marie-Tooth(CMT) disease or hereditary motor and sensory neuropathy is the most common inherited neuromuscular disorder affecting at least 1 in 2500. CMT disease is pathologically and genetically heterogeneous and is characterized by a variable age of onset, slowly progressive weakness and muscle atrophy, starting in the lower limbs and subsequently affecting the upper extremities. Symptoms are usually slowly progressive, especially for the classic and late-onset phenotypes, but can be rather severe in early-onset forms. CMT is grouped into demyelinating, axonal and intermediate forms, based on electrophysiological and pathological findings. The demyelinating types are characterized by severely reduced motor nerve conduction velocities(MNCVs) and mainly by myelin abnormalities. The axonal types are characterized by normal or slightly reduced MNCVs and mainly axonal abnormalities. The intermediate types are characterized by MNCVs between 25 m/s and 45 m/s and they have features of both demyelination and axonopathy. Inheritance can be autosomal dominant, X-linked, or autosomal recessive. Mutations in more than 30 genes have been associated with the different forms of CMT, leading to majoradvancements in molecular diagnostics of the disease, as well as in the understanding of pathogenetic mechanisms. This editorial aims to provide an account that is practicable and efficient on the current molecular diagnostic procedures for CMT, in correlation with the clinical, pathological and electrophysiological findings. The most frequent causative mutations of CMT will also be outlined.

Subarachnoid and Peripheral Nerve Block in a Patient with Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease (CMT) is a hereditary peripheral neuropathy characterized by progressive distal muscle weakness and wasting. If conservative treatment fails, or is not appropriately initiated, deformity, immobility and chronic pain may result. In severe cases, surgical intervention may be required. With the exception of case reports and case series, limited safety and efficacy data exists regarding the use of neuraxial and regional anesthesia for patients with CMT. This paper describes an anesthetic case report of a patient with CMT, and also provides a review of general and regional anesthetic considerations for this cohort. The purpose of this report is to highlight the potential benefits of neuraxial and regional anesthesia in patients with neuromuscular disorders, especially in settings where intra- and post-operative resources may be limited.

The Role of Orthotic Service in Modern Rehabilitation of Patients with Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth (CMT) disease, which encompasses several hereditary motor and sensory neuropathies, is one of the most common neuro-muscular disorders. 80% of patients having CMT disease are diagnosed with per cavus deformity. Orthosis is widespread and varies widely in forms. The paper arises the necessity of habilitation at the earliest possible stage as only a few patients use it. The meta-analysis of 412 scientific papers concerning this problem demonstrates the getting better gate, balance and the stopping CMT progression which is scientifically proven. It is also shown that patients with CMT use low prevalence of orthotics, and demonstrate low compliance of patients (for various reasons), high expectations from this habilitation technique.

Rapid genetic screening of Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies patients

We used the allele-specific PCR-double digestion method on peripheral myelin protein 22 （PMP22） to determine duplication and deletion mutations in the proband and family members of one family with Charcot-Marie-Tooth disease type 1 and one family with hereditary neuropathy with liability to pressure palsies. The proband and one subclinical family member from the Charcot-Marie-Tooth disease type 1 family had a PMP22 gene duplication; one patient from the hereditary neuropathy with liability to pressure palsies family had a PMP22 gene deletion. Electron microscopic analysis of ultrathin sections of the superficial peroneal nerve from the two probands demonstrated demyelination and myelin sheath hyperplasia, as well as an ＇onion-like＇ structure in the Charcot-Marie-Tooth disease type 1A patient. We observed an irregular thickened myelin sheath and ＇mouse-nibbled＇-Iike changes in the patient with hereditary neuropathy with liability to pressure palsies. In the Charcot-Marie-Tooth disease type 1A patient, nerve electrophysiological examination revealed moderate-to-severe reductions in the motor and sensory conduction velocities of the bilateral median nerve, ulnar nerve, tibial nerve, and sural nerve. Moreover, the compound muscle action potential amplitude was decreased. In the patient with hereditary neuropathy with liability to pressure palsies, the nerve conduction velocity of the bilateral tibial nerve and sural nerve was moderately reduced, and the nerve conduction velocity of the median nerve and ulnar nerve of both upper extremities was slightly reduced.

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。

Charcot-Marie-Tooth病的诊治

Charcot-Marie-Tooth病(CMT)是最常见的一种遗传性周围神经病,是一组具有显著临床异质性和遗传异质性的疾病,主要表现为肢体远端肌肉进行性无力和萎缩,伴有轻到中度感觉减退,腱反射减弱和足部畸形等.近20年CMT致病基因的不断被克隆,其疾病分型、临床表型和基因表型的关系发生了巨大变化.本文主要阐述CMT的疾病分型演变、基因诊断策略、临床治疗进展.

剔除小鼠神经微管运动蛋白Kif1b基因导致类似Charcot-Marie-Tooth病动物模型

目的研究杂合子小鼠Kiflb基因剔除后导致的表现型,探讨其作为类似Charcot-Marie-Tooth (CMT)病动物模型的可行性。方法用Southern blotting和PCR检测同源重组和基因型,Western blotting测定杂合子KIF1B蛋白表达量,行为学实验观察其表现型。结果杂合子Kif1b基因剔除小鼠的KIF1B蛋白表达量减少了一半以上,行为学实验结果表明,杂合子基因剔除小鼠在运动和感觉方面均有异常。Rota-rod实验,Rod walking实验和Wire hanging实验中,野生型小鼠的停留时间均明显长于Kif1b基因剔除小鼠。同时,杂合子Kif1b基因剔除小鼠在热板实验和福尔马林实验中,表现出对温度觉和痛觉反应的迟钝,其反应时间与野生型小鼠相比明显延长,反应强度降低。结论杂合子Kif1b基因剔除小鼠的表现型与人类腓骨肌萎缩症相似,作为疾病模型具备可行性。

Charcot-Marie-Tooth病的研究与诊断进展

Charcot-Marie-Tooth病,是一组最常见的在遗传和临床上都具有高度异质性的家族性周围神经病,约占全部遗传性神经病的90%。其基本临床表现相似,目前已知的亚型多达35种,为该病的确诊带来极大困难。因此,本文综述该病各亚型的临床、电生理、周围神经病理、致病基因及有效诊断方法。

一个Charcot-Marie-Tooth病家系的分子遗传学分析

目的鉴定一个Charcot-Marie-Tooth病(CMT)家系的致病突变。方法根据家族史、临床表现和肌电图检查结果判断家系CMT分型。采集16名家系成员外周血,提取基因组DNA。针对CMT1的6个亚型,选择微卫星标记进行连锁分析。针对PMP22基因重复突变,采用实时定量PCR检测家系成员。结果本家系疾病呈常染色体显性遗传。患者均有青少年发病、缓慢进展的下肢无力症状。部分患者经查体发现下肢腱反射减弱、痛触觉减弱,下肢神经传导速度均小于30 m/s,提示为CMT1型。通过连锁分析排除了CMT1A、CMT1E以外的其他4个亚型,证实患者基因组内PMP22基因存在重复突变。结论此家系患者表型为CMT1A,其致病突变为染色体17p11.2区域内PMP22基因的重复。

Charcot-Marie-Tooth病2S型合并重度僵硬性脊柱侧凸1例及文献复习

Charcot-Marie-Tooth病(Charcot-Marie-Tooth disease,CMT),又称进行性神经性腓骨肌萎缩症,亦称遗传性运动感觉周围神经病,发病率约为2/10000[1]。CMT具有遗传异质性,迄今已发现多种致病基因[2]。依据临床表现及遗传学特点,分为8种类型,40多种亚型,其中CMT2S型非常罕见.

周围髓鞘蛋白22基因重复异常的Charcot-Marie-Tooth病患者临床表型分析

目的分析Charcot-Marie-Tooth病(CMT)周围髓鞘蛋白22(PMP22)基因重复异常患者临床症状、体征和电生理特点。方法61例CMT患者,14例为有家族史的先证者,47例为散发患者,PCR-双酶切方法检测周围髓鞘蛋白22(PMP22)基因重复异常片断,详细问病史和神经系统查体、部分患者行腰穿和腓肠神经病理检查。结果检出PMP22基因重复异常患者41例,主要临床特点为以双足背屈力弱为主的双下肢无力,伴双侧小腿为主的四肢远端萎缩,80%伴上肢远端肌萎缩,97%踝反射减弱或消失,68%伴有深浅感觉障碍,少数脑脊液蛋白增高,神经电生理和腓肠神经病理提示为脱髓鞘伴有轴索变性。结论PMP22基因重复异常的CMT患者的临床表现为以下肢远端肌萎缩和肌无力为主,伴有感觉异常;周围神经髓鞘和轴索均有病变。

Charcot-Marie-Tooth病1X型的临床与分子遗传学研究进展

在Charcot-Marie-Tooth病(CMT)中,1X型发病率居于第2位,它由GJB1基因突变致Connexin32蛋白结构或功能异常,引起细胞间通道缺陷导致发病。文章综述了CMT1X的典型临床特征和分子遗传学进展,总结了CMT发病机制的研究。

X-连锁隐性遗传Charcot-Marie-Tooth病5型1例报告并文献复习

目的探讨X-连锁隐性遗传Charcot-Marie-Tooth病5型(CMTX 5)表型和基因型特点。方法回顾分析1例确诊CMTX 5患儿的临床资料,并复习相关文献。结果患儿男,自幼听力丧失,6岁时行走无力,步态异常,并进行性加重。肌电图提示多发性周围神经源性损害肌电改变,主要累及感觉、运动神经轴索损害伴脱髓鞘。基因测序提示PRPS1基因存在c.344 T>C半合子变异,患儿母亲该位点为杂合变异,父亲无异常。该变异位点既往已有报道,与以往报道的表型不完全相同,该患儿无视力受损。文献检索到8例CMTX 5患者,8种基因型,均为错义突变,8例患者均有听力丧失和周围神经病,4例出现视力障碍。结论即使CMTX 5的基因型相同,临床表型也不尽相同,表型与基因型相关性需进一步大样本研究。

《2020北美Charcot-Marie-Tooth病协会CMT病高弓内翻足管理共识》的解读

Charcot-Marie-Tooth(CMT)病是一种遗传性的运动感觉神经病变,易引起高弓内翻足畸形。有关CMT病高弓内翻足治疗的高质量研究证据比较缺乏,因此,CMT病协会召集了经验丰富的足踝外科医生和神经病学家,基于发表的文献和个人经验,讨论了CMT病的诊疗和手术治疗的诸多事项,达成了《2020北美Charcot-Marie-Tooth病协会CMT病高弓内翻足管理共识》。该共识统一了CMT病高弓内翻足相关的专用术语,商定了病史和体格检查的标准,推荐了CMT病高弓内翻足畸形的综合治疗方案。本文从足踝外科医生这一角度对这部共识进行解读,对共识提到的几个临床上的重点内容进行了梳理,力争为国内同行提供一个简明、可操作的指引。

合并惊厥发作的X连锁Charcot-Marie-Tooth病1型1例报告并文献复习

目的分析X连锁Charcot-Marie-Tooth病1型(CMT1X)的发病机制及出现惊厥的可能原因。方法回顾分析1例合并惊厥发作的CMT1X患儿的临床特征以及基因检测结果,并复习相关文献。结果男孩,7岁6个月,以可逆性脑白质病变为首发症状且出现惊厥;基因检测显示患儿缝隙连接蛋白Bl (GJB1)基因发生突变,C.425G>A(p.R142Q)。诊断为CMT1X。患儿与既往所报道病例的临床症状有差异。结论以惊厥为首发症状的CMT1X,系GJB1基因突变导致通道功能障碍所致,相同突变可出现不同临床表现。

遗传性感觉和自主神经障碍Ⅳ型导致儿童Charcot关节病

目的对遗传性感觉和自主神经障碍(HSAN)Ⅳ型导致儿童Charcot关节病的3例患者进行分析,增强对该疾病的认识。方法回顾性分析3例Charcot关节病资料。右膝关节活检1例,保守治疗1例,行右髋关节切开复位术1例。结果3例均为HSANⅣ型导致的Charcot关节病,主要是由于患儿对疼痛不敏感、缺乏保护意识、反复损伤而发病。结论HSANⅣ型可导致儿童Charcot关节病的发生,应引起临床重视。