Research advance of underlying pathogenesis and target therapies in Charcot-Marie-Tooth disease type 1A / 中华医学遗传学杂志

Charcot-Marie-Tooth disease (CMT) is the commonest form of inherited neuropathy and has an incidence of 1/2500. CMT1A is the commonest subtype of CMT, which is caused by duplication of peripheral myelin protein 22 (PMP22) gene and accounts for approximately 50% of CMT diagnosed by genetic testing. Duplication of PMP22 may influence the production of PMP22 mRNA and protein, and interfere with the proliferation, differentiation and apoptosis of Schwann cells. In addition, deregulation of NRG1/ErbB pathway and lipid metabolism can also lead to dysfunction of Schwann cells. Such factors may disturb the myelination process, leading to axon degeneration, muscle weakness, and atrophy subsequently. Accordingly, drug therapies for CMT1A are developed by targeting such factors. PXT3003, antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) are supposed to down-regulate the level of PMP22 mRNA, while recombinant human NRG-1 (rhNRG1) and neurotrophin-3 (NT-3) may enhance Schwann cells survival and differentiation. In addition, lipid-supplemented diet may remedy the defect of lipid metabolism and maintain the proper structure of myelin. Other targeting drugs include ascorbic acid, progesterone antagonists, IFB-088, ADX71441, and ACE-083. This review is to sum up the pathogenesis of CMT1A and promising targeting drug therapies for further research.

Genetic and clinical features of sorbitol dehydrogenase gene-related Charcot-Marie-Tooth disease in Chinese population / 中华神经科杂志

Objective:To report the genetic and clinical features of sorbitol dehydrogenase (SORD) gene-related Charcot-Marie-Tooth disease (CMT) in Chinese population.Methods:Fifty-seven undiagnosed sporadic or autosomal recessive (AR) inherited CMT2 families were collected from the Department of Neurology of the Third Xiangya Hospital from 2009 through 2018 .Polymerase chain reaction combined with Sanger sequencing were used to detect the mutations of SORD gene, and the relative clinical features were summarized. Results:The homozygous SORD gene hot spot mutation c.757delG (p. Ala253GlnfsTer27) was detected in four sporadic patients, accounting for about 7% of the total. Two patients with CMT2 phenotype were characterized by progressive lower limb weakness and atrophy with electromyogram changes of axonal degeneration in both motor and sensory nerves. Two patients with distal hereditary motor neuropathy (dHMN) phenotype exhibited progressive lower limb weakness and atrophy with electromyogram changes of axonal degeneration in motor nerves only. The age of onset was between five and 16 years, and the CMT neuropathy score was 2-9.Conclusions:The homozygous hot spot mutation of SORD gene (c.757delG, p.Ala253GlnfsTer27), and related childhood or adolescence onset, mildly affected CMT2/dHMN phenotypes are firstly reported in Chinese population. SORD gene-related CMT might be the most common subtype of AR-CMT2.

Clinical application of assessment scales related to Charcot-Marie-Tooth disease / 中华神经科杂志

Charcot-Marie-Tooth (CMT) disease is the most common monogenic peripheral neuropathy with high clinical and genetic heterogeneity.With the development of orphan drugs for different genotypes of CMT,the use of standardized scales is essential for assessing the therapeutic effect of drugs and the natural course of the disease.At present,there are different types of outcome measures for assessing the severity of dysfunction,therapeutic effect,quality of life and prognosis of CMT patients.In this article the CMT-related assessment scales which are commonly used in clinical practice are reviewed.

The electrophysiological characteristics of the four most common genotypes of Charcot-Marie-Tooth disease / 中华神经科杂志

Objective To analyze the electrophysiological characteristics of Charcot-Marie-Tooth (CMT) disease 1A,1X,2A and myelin protein zero (MPZ)-related CMT in Chinese patients.Methods Baseline electrophysiological data from 36 CMT1A patients,78 CMT1X patients,31 CMT2A patients and 10 MPZ-related CMT patients in the Third Xiangya Hospital and Xiangya Hospital of Central South University during 2004-2018 were analyzed.Electrophysiological recordings were taken from the upper limbs (median nerve,ulnar nerve) and lower limbs (tibial nerve,peroneal nerve).Demyelination in different nerve segments was assessed by measurement of distal motor latency,motor nerve conduction velocity (MNCV),sensory nerve conduction velocity and F-wave latency,and calculation of conduction block,terminal latency index (TLI) and modified F ratio (MFR);Axonal degeneration was assessed by measuring compound motor action potential (CMAP) and sensory nerve action potential.The relationship between the gender,age at onset,duration,Overall Neuropathy Limitation Scale (ONLS) score and indexes of peripheral nerve electrophysiology was statistically analyzed.Results The peripheral nerves of CMT1A patients were characterized by uniform demyelination and axonal degeneration.MNCV ((21.39± 6.72) m/s) and CMAP amplitude (2.40 (3.50) mY) of median nerve of CMT1A patients were decreased.The peripheral nerves of CMT1X patients were also characterized by uniform demyelination and axonal degeneration.MNCV (35.20 (6.77) m/s) and CMAP amplitude (2.60 (3.79) mY) of median nerve of CMT1X patients were decreased.CMT2A patients showed axonal degeneration of the peripheral nerves and CMAP amplitude ((4.75 ±2.38) mV) of median nerve of CMT2A patients was decreased.The electrophysiological data in MPZ-related CMT patients demonstrated variability.The TLI and MFR for the median and ulnar nerves in these four subtypes were normal.MNCV (r=0.423,P=0.025) of median nerve in CMT1A patients was positively correlated with age at onset.MNCV (r=0.782,P=-0.013) of median nerve in MPZ-related CMT patients was positively correlated with age at onset.CMAP amplitude (r=0.652,P＜0.01) of median nerve in CMT2A patients was positively correlated with age at onset.Demyelination and axonal degeneration in male CMT1X patients were relatively more severe than those in female patients,and MNCV (Z=-3.300,P＜0.01) and CMAP amplitude (Z=-3.960,P＜0.01) of median nerve,MNCV (Z=-2.56,P=0.011) and CMAP amplitude (Z=-2.311,P=0.048) of ulnar nerve of male patients were lower than those of female patients.The ONLS score of CMT1A (r=-0.494,P＜0.01),CMT1X (r=-0.596,P＜0.01) and CMT2A patients (r=-0.494,P=0.012) was inversely associated with CMAP amplitude.Conclusions The electrophysiological characteristics of CMT1A,CMT1X,CMT2A and MPZ-related CMT are different.Electrophysiological examinations are the basis of clinical classification and could provide guidance for further genetic testing and diagnosis.CMAP amplitude may serve as an objective index to assess the severity of functional disability in CMT patients.

Relationship between collagenⅠgene COL1A2 polymorphisms and atherosclerotic cerebral infarction, stability of carotid arteriosclerotic plaque / 临床神经病学杂志

Objective To observe the relationship between rs42524 polymorphisms of collagen Ⅰ COL1A2 gene and atherosclerotic cerebral infarction, stability of carotid arteriosclerotic plaque.Methods Carotid ultrasound detection by Color Doppler ultrasonography was used to detect 289 patients with acute atherosclerotic cerebral infarction.These patients were divided into stable plaque and vulnerable plaque subgroups according to the carotid atherosclerotic plaque stability.Then 107 healthy individuals who had no carotid plaque were collected as the control group.Rs42524 polymorphism of COL1A2 gene was detected by PCR-restriction fragment length polymorphism.The results were analyzed.Results There were no significant differences of the frequencies of genotypes and alleles of rs42524 of COL1A2 gene between the cerebral infarction group and the control group (all P>0.05).According to the results of carotid ultrasound detection, the cerebral infarction group patients were divided into stable plaque subgroup including 108 cases, and vulnerable plaque subgroup including 181 cases.Rs42524 of COL1A2 gene showed no significant differences in the frequencies of alleles and genotypes between stable plaque subgroup and vulnerable plaque subgroup ( all P>0.05) .Conclusion Rs42524 polymorphism of COL1A2 gene is meaningless to the onset risk of atherosclerotic cerebral infarction and the stability of carotid atherosclerotic plaque.

Mutation of Cx32 gene,clinical and electrophysiological features in patients with Charcot-Marie-Tooth disease / 临床神经病学杂志

Objective To investigate the mutation of Cx32 gene,clinical and electrophysiological features of Chinese patients with Charcot-Marie-Tooth(CMT) disease.Methods 24 CMT probands were selected for Cx32 mutation screening after the exclusion of the CMT1A 1.5 Mb duplication and male-to-male transmission.The motor and sensory nerve conduction studies were performed in all probands and most of their affected family members to establish the clinical CMT1,CMT2 or CMT intermediate diagnosis.The presence of mutations in the coding region of Cx32 was detected by single-strand conformation polymorphism analysis combined with direct sequencing.Results It was found 7 different point mutations in the coding region of Cx32 in 1 sporadic CMT1 patient and 6 X-linked inherited families,including 4 families with CMT1 diagnosis and 2 families with CMT intermediate diagnosis.There were 20 male CMTX patients,6 female CMTX patients and 12 asymptomatic female carriers among 38 family members bearing Cx32 mutation.All of the 26 patients were mildly to moderately affected clinically.Conclusions Seven different Cx32 point mutations were detected and the percentage of Chinese CMT families with Cx32 mutation is about 10% in our study.The inheritance model of CMT secondary to Cx32 mutation could be X-linked dominant,X-linked recessive or sporadic.Male patients are usually more severly affected than females with slower nerve conduction velocities.Cx32 mutation screening should be firstly performed in those CMT families without male-to-male transmission and CMT1A duplication.

Study on the clinic, neuro-electrophysiology of Charcot-Marie-Tooth disease type 1A and its gene mutation analysis / 临床神经病学杂志

Objective To study the clinical, neuro-electrophysiology features of Charcot-Marie-Tooth disease type 1A (CMT1A) and its gene mutation analysis.Methods 9 members of the family with CMT1A underwent detailed clinical examinations and gene mutation analysis was carried out in 7 of them. The probands accepted electromyography and nerve, muscle biopsy.Results Five patients of the family were attacked and consistent with autosomal dominant inheritance type. Except one asymptomatic patient, age at onset was in the first or second decade. The clinical features were slowly progressive distal muscle weakness, atrophy and end-brush form sensory decrement, diminished or absent tendon reflexes, foot deformity(pes cavus).The probands showed highly decreased sensory and motor conduction velocities. Gene mutation analysis showed large fragment tandem duplication containing peripheral myelin protein 22(PMP22) gene in all four patients out of the seven family members who attended the gene diagnosis.Conclusion CMT1A is the most common form of CMT. The disease usually begins in childhood or adolescence. Clinical featurs include progressive distal muscle weekness and atrophy, diminished or absent tendon reflexes. The motor nerve conduction velocity is slowed below the limit of 38 m/s. Tandem duplication on chromosome 17p11.2, encompassing the PMP22 gene is the main mutation type of CMT1A.