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Insights on altered mitochondrial function and dynamics in the pathogenesis of neurodegeneration 被引量:9
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作者 Joseph McInnes 《Translational Neurodegeneration》 SCIE CAS 2013年第1期72-78,共7页
In neurons,mitochondria are enriched to provide energy and calcium buffering required for synaptic transmission.Additionally,mitochondria localize to the synapse,where they are critical for the mobilization of reserve... In neurons,mitochondria are enriched to provide energy and calcium buffering required for synaptic transmission.Additionally,mitochondria localize to the synapse,where they are critical for the mobilization of reserve pool vesicles and for neurotransmitter release.Previously,functional defects in mitochondria were considered to be downstream effects of neurodegenerative diseases.However,more recent findings suggest mitochondria may serve as key mediators in the onset and progression of some types of neurodegeneration.In this review,we explore the possible roles of altered mitochondrial function and dynamics in the pathogenesis of neurodegenerative disorders,with a particular focus on Alzheimer’s disease(AD)and Parkinson’s disease(PD),which have highlighted the important role of mitochondria in neurodegeneration.While inheritable diseases like Charcot-Marie-Tooth disease type 2A are concretely linked to gene mutations affecting mitochondrial function,the cause of mitochondrial dysfunction in primarily sporadic diseases such as AD and PD is less clear.Neuronal death in PD is associated with defects in mitochondrial function and dynamics arising from mutations in proteins affecting these processes,including α-synuclein,DJ-1,LRRK2,Parkin and Pink1.In the case of AD,however,the connection between mitochondria and the onset of neurodegeneration has been less clear.Recent findings,however,have implicated altered function of ER-mitochondria contact sites and amyloid beta-and/or tau-induced defects in mitochondrial function and dynamics in the pathogenesis of AD,suggesting that mitochondrial defects may act as key mediators in the pathogenesis of AD as well.With recent findings at hand,it may be postulated that defects in mitochondrial processes comprise key events in the onset of neurodegeneration. 展开更多
关键词 MITOCHONDRIA NEURODEGENERATION Parkinson’s Alzheimer’s charcot-marie-tooth
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Mutation Analysis of Gap Junction Protein Beta 1 and Genotype-Phenotype Correlation in X-linked Charcot-Marie- Tooth Disease in Chinese Patients 被引量:6
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作者 Bo Sun Zhao-HuiChen +4 位作者 Li Ling Yi-Fan Li Li-Zhi Liu Fei Yang Xu-Sheng Huang 《Chinese Medical Journal》 SCIE CAS CSCD 2016年第9期1011-1016,共6页
Background: Among patients with Charcot-Marie-Tooth disease (CMT), the X-linked variant (CMTX) caused by gap junction protein beta 1 (GJB1) gene mutation is the second most frequent type, accounting for approxi... Background: Among patients with Charcot-Marie-Tooth disease (CMT), the X-linked variant (CMTX) caused by gap junction protein beta 1 (GJB1) gene mutation is the second most frequent type, accounting for approximately 90% of all CMTX. More than 400 mutations have been identified in the GJB1 gene that encodes connexin 32 (CX32). CX32 is thought to form gap junctions that promote the diffusion pathway between cells. GJB1 mutations interfere with the formation of the functional channel and impair the maintenance of peripheral myelin, and novel mutations are continually discovered. Methods: We included 79 unrelated patients clinically diagnosed with CMT at the Department of Neurology of the Chinese People's Liberation Army General Hospital from December 20, 2012, to December 31, 2015. Clinical examination, nerve conduction studies, and molecular and bioinformatics analyses were performed to identify patients with CMTX 1. Results: Nine GJBI mutations (c.283G〉A, c.77C〉T, c.643C〉T, c.515C〉T, c.191G〉A, c.610C〉T, c.490C〉T, c.491G〉A, and c.44G〉A) were discovered in nine patients. Median motor nerve conduction velocities of all nine patients were 〈 38 m/s, resembling CMT Type 1. Three novel mutations, c.643C〉T, c.191G〉A, and c.610C〉T, were revealed and bioinformatics analyses indicated high pathogenicity. Conclusions: The three novel missense mutations within the GJB1 gene broaden the mutational diversity ofCMT1X. Molecular analysis of family members and bioinformatics analyses of the afflicted patients confirmed the pathogenicity of these mutations. 展开更多
关键词 Connexin 32 ELECTROPHYSIOLOGY Gap Junction Protein Beta 1 Genetic Mutation X-linked charcot-marie-tooth Disease
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The MORC2 p.S87L mutation reduces proliferation of pluripotent stem cells derived from a patient with the spinal muscular atrophy-like phenotype by inhibiting proliferation-related signaling pathways 被引量:1
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作者 Sen Zeng Honglan Yang +8 位作者 Binghao Wang Yongzhi Xie Ke Xu Lei Liu Wanqian Cao Xionghao Liu Beisha Tang Mujun Liu Ruxu Zhang 《Neural Regeneration Research》 SCIE CAS CSCD 2024年第1期205-211,共7页
Mutations in the microrchidia CW-type zinc finger protein 2(MORC2)gene are the causative agent of Charcot-Marie-Tooth disease type 2Z(CMT2Z),and the hotspot mutation p.S87L is associated with a more seve re spinal mus... Mutations in the microrchidia CW-type zinc finger protein 2(MORC2)gene are the causative agent of Charcot-Marie-Tooth disease type 2Z(CMT2Z),and the hotspot mutation p.S87L is associated with a more seve re spinal muscular atrophy-like clinical phenotype.The aims of this study were to determine the mechanism of the severe phenotype caused by the MORC2 p.S87L mutation and to explore potential treatment strategies.Epithelial cells were isolated from urine samples from a spinal muscular atrophy(SMA)-like patient[MORC2 p.S87L),a CMT2Z patient[MORC2 p.Q400R),and a healthy control and induced to generate pluripotent stem cells,which were then differentiated into motor neuron precursor cells.Next-generation RNA sequencing followed by KEGG pathway enrichment analysis revealed that differentially expressed genes involved in the PI3K/Akt and MAP K/ERK signaling pathways were enriched in the p.S87L SMA-like patient group and were significantly downregulated in induced pluripotent stem cells.Reduced proliferation was observed in the induced pluripotent stem cells and motor neuron precursor cells derived from the p.S87L SMA-like patient group compared with the CMT2Z patient group and the healthy control.G0/G1 phase cell cycle arrest was observed in induced pluripotent stem cells derived from the p.S87L SMA-like patient.MORC2 p.S87Lspecific antisense oligonucleotides(p.S87L-ASO-targeting)showed significant efficacy in improving cell prolife ration and activating the PI3K/Akt and MAP K/ERK pathways in induced pluripotent stem cells.Howeve r,p.S87L-ASO-ta rgeting did not rescue prolife ration of motor neuron precursor cells.These findings suggest that downregulation of the PI3K/Akt and MAP K/ERK signaling pathways leading to reduced cell proliferation and G0/G1 phase cell cycle arrest in induced pluripotent stem cells might be the underlying mechanism of the severe p.S87L SMA-like phenotype.p.S87L-ASO-targeting treatment can alleviate disordered cell proliferation in the early stage of pluripotent stem cell induction. 展开更多
关键词 antisense oligonucleotides cell cycle arrest charcot-marie-tooth disease 2Z induced pluripotent stem cells MAPK/ERK PI3K/Akt PROLIFERATION spinal muscular atrophy-like
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腓骨肌萎缩症1A型患者和慢性炎性脱髓鞘性多发性神经病患者F波改变的比较 被引量:3
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作者 刘小璇 张朔 +3 位作者 马妍 孙阿萍 张英爽 樊东升 《北京大学学报(医学版)》 CAS CSCD 北大核心 2023年第1期160-166,共7页
目的:分析比较腓骨肌萎缩症1A型(Charcot-Marie-Tooth1A,CMT1A)患者和慢性炎性脱髓鞘性多发性神经病(chronic inflammatory demyelinating polyneuropathy,CIDP)患者F波改变的特点和原因。方法:收集自2012年1月到2018年12月在北京大学... 目的:分析比较腓骨肌萎缩症1A型(Charcot-Marie-Tooth1A,CMT1A)患者和慢性炎性脱髓鞘性多发性神经病(chronic inflammatory demyelinating polyneuropathy,CIDP)患者F波改变的特点和原因。方法:收集自2012年1月到2018年12月在北京大学第三医院诊治的CMT1A和CIDP患者各30例,记录临床资料、电生理指标(神经传导速度和F波、H反射)、神经功能等级评分等,部分患者行臂丛和腰丛的磁共振影像检查,分析比较结果。结果:CMT1A患者的正中神经平均运动传导速度为(21.10±10.60)m/s,CIDP患者为(31.52±12.46)m/s,二者差异有统计学意义(t=-6.75,P<0.001),CMT1A患者中约43.3%(13/30)未引出尺神经F波,明显高于CIDP未引出F波的患者比例(4/30,13.3%),χ^(2)=6.65,P=0.010。在可引出F波的患者中,CMT1A组患者的F波潜伏期为(52.40±17.56)ms,CIDP组为(42.20±12.73)ms,二者差异有统计学意义(t=2.96,P=0.006),F波的出现率CMT1A组是34.6%±39%,CIDP组是70.7%±15.2%,二者差异有统计学意义(t=-5.13,P<0.001)。神经束蛋白155(neurofascin 155,NF155)患者的正中神经传导速度为23.22 m/s,F波潜伏期为62.9~70.7 ms,出现率为85%~95%。CMT1A型臂丛和腰丛神经增粗的比例分别为83.3%(5/6)和85.7%(6/7),CIDP患者臂丛和腰丛神经增粗的比例仅为25.0%(1/4,2/8)。NF155抗体阳性患者可见臂丛和腰丛MRI神经根明显增粗。结论:CMT1A患者F波延长反应了近端和远端周围神经的均一性改变,可以作为与局灶性脱髓鞘受损为主的CIDP患者的鉴别方法,但同时需要注意与神经结蛋白病NF155引起的周围神经损害相鉴别。F波虽然经常作为反应近端神经受累的指标,但是运动神经元兴奋性、前角细胞和运动神经髓鞘病变均可以影响它的潜伏期和出现率,F波异常需要结合患者的病因和其他电生理指标及影像学等检查手段综合分析。 展开更多
关键词 腓骨肌萎缩症 慢性炎性脱髓鞘性多发性神经病 肌电描记术
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Clinical classification and gene mutation of Chinese probands with Charcot-Marie-Tooth disease Analysis of 57 cases 被引量:4
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作者 Ruxu Zhang Xiaobo Li +5 位作者 Xiaohong Zi Shunxiang Huang Fufeng Zhang Kun Xia Qian Pan Beisha Tang 《Neural Regeneration Research》 SCIE CAS CSCD 2011年第9期706-711,共6页
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 pr... 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. 展开更多
关键词 charcot-marie-tooth disease clinical classification GENE mutation analysis
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CMT1A current gene therapy approaches and promising biomarkers 被引量:2
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作者 Marina Stavrou Kleopas AKleopa 《Neural Regeneration Research》 SCIE CAS CSCD 2023年第7期1434-1440,共7页
Charcot-Marie-Tooth neuropathies(CMT)constitute a group of common but highly heterogeneous,non-syndromic genetic disorders affecting predominantly the peripheral nervous system.CMT type 1A(CMT1A)is the most frequent t... Charcot-Marie-Tooth neuropathies(CMT)constitute a group of common but highly heterogeneous,non-syndromic genetic disorders affecting predominantly the peripheral nervous system.CMT type 1A(CMT1A)is the most frequent type and accounts for almost~50%of all diagnosed CMT cases.CMT1A results from the duplication of the peripheral myelin protein 22(PMP22)gene.Overexpression of PMP22 protein overloads the protein folding apparatus in Schwann cells and activates the unfolded protein response.This leads to Schwann cell apoptosis,dys-and de-myelination and secondary axonal degeneration,ultimately causing neurological disabilities.During the last decades,several different gene therapies have been developed to treat CMT1A.Almost all of them remain at the pre-clinical stage using CMT1A animal models overexpressing PMP22.The therapeutic goal is to achieve gene silencing,directly or indirectly,thereby reversing the CMT1A genetic mechanism allowing the recovery of myelination and prevention of axonal loss.As promising treatments are rapidly emerging,treatment-responsive and clinically relevant biomarkers are becoming necessary.These biomarkers and sensitive clinical evaluation tools will facilitate the design and successful completion of future clinical trials for CMT1A. 展开更多
关键词 axonal degeneration biomarkers charcot-marie-tooth disease gene therapy inherited neuropathy mouse models
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Drosophila models used to simulate human ATP1A1 gene mutations that cause Charcot-Marie-Tooth type 2 disease and refractory seizures
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作者 Yao Yuan Lingqi Yu +8 位作者 Xudong Zhuang Dongjing Wen Jin He Jingmei Hong Jiayu Xie Shengan Ling Xiaoyue Du Wenfeng Chen Xinrui Wang 《Neural Regeneration Research》 SCIE CAS 2025年第1期265-276,共12页
Certain amino acids changes in the human Na^(+)/K^(+)-ATPase pump,ATPase Na^(+)/K^(+)transporting subunit alpha 1(ATP1A1),cause Charcot-Marie-Tooth disease type 2(CMT2)disease and refractory seizures.To develop in viv... Certain amino acids changes in the human Na^(+)/K^(+)-ATPase pump,ATPase Na^(+)/K^(+)transporting subunit alpha 1(ATP1A1),cause Charcot-Marie-Tooth disease type 2(CMT2)disease and refractory seizures.To develop in vivo models to study the role of Na^(+)/K^(+)-ATPase in these diseases,we modified the Drosophila gene homolog,Atpα,to mimic the human ATP1A1 gene mutations that cause CMT2.Mutations located within the helical linker region of human ATP1A1(I592T,A597T,P600T,and D601F)were simultaneously introduced into endogenous Drosophila Atpαby CRISPR/Cas9-mediated genome editing,generating the Atpα^(TTTF)model.In addition,the same strategy was used to generate the corresponding single point mutations in flies(Atpα^(I571T),Atpα^(A576T),Atpα^(P579T),and Atpα^(D580F)).Moreover,a deletion mutation(Atpα^(mut))that causes premature termination of translation was generated as a positive control.Of these alleles,we found two that could be maintained as homozygotes(Atpα^(I571T)and Atpα^(P579T)).Three alleles(Atpα^(A576T),Atpα^(P579)and Atpα^(D580F))can form heterozygotes with the Atpαmut allele.We found that the Atpαallele carrying these CMT2-associated mutations showed differential phenotypes in Drosophila.Flies heterozygous for Atpα^(TTTF)mutations have motor performance defects,a reduced lifespan,seizures,and an abnormal neuronal morphology.These Drosophila models will provide a new platform for studying the function and regulation of the sodium-potassium pump. 展开更多
关键词 ATP1A1 Atpα bang-sensitive paralysis charcot-marie-tooth disease type 2 CRISPR/Cas9 homology-directed repair Na^(+)/K^(+)-ATPase point mutation seizures sodium pump
Nine-hole Peg Test and Ten-meter Walk Test for Evaluating Functional Loss in Chinese Charcot-Marie-Tooth Disease 被引量:2
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作者 Hui-Xia Niu Rui-Hao Wang +9 位作者 Hong-Liang Xu Bo Song Jing Yang Chang-He Shi Yu-Sheng Li Bing-Qian Zhang Shao-Ping Wang Quan Yong Yuan-Yuan Wang Yu-Ming Xu 《Chinese Medical Journal》 SCIE CAS CSCD 2017年第15期1773-1778,共6页
Background:The 9-hole peg test (9-HPT) and 10-meter walk test (10-MWT) are commonly used to test finger motor function and walking ability.The aim of this present study was to investigate the efficacy of these te... Background:The 9-hole peg test (9-HPT) and 10-meter walk test (10-MWT) are commonly used to test finger motor function and walking ability.The aim of this present study was to investigate the efficacy of these tests for evaluating functional loss in Chinese Charcot-Marie-Tooth (CMT) disease.Methods:Thirty-four Chinese CMT patients (CMT group) from August 2015 to December 2016 were evaluated with 9-HPT,10-MWT,CMT disease examination score,overall neuropathy limitation scale (ONLS),functional disability score,and Berg Balance Scale (BBS).Thirty-five age-and gender-matched healthy controls (control group) were also included in the study.Student's nonpaired or paired t-test were performed to compare data between two independent or related groups,respectively.The Pearson test was used to examine the correlations between recorded parameters.Results:The mean 9-HPT completion time in the dominant hand of CMT patients was significantly slower than that in the healthy controls (29.60 ± 11.89 s vs.19.58 ± 3.45 s;t =-4.728,P 〈 0.001).Women with CMT completed the 9-HPT significantly faster than men with CMT (dominant hand:24.74 ± 7.93 s vs.33.01 ± 13.14 s,t =2.097,P =0.044).The gait speed of the average self-selected velocity and the average fast-velocity assessed using 10-MWT for CMT patients were significantly slower than those in the control group (1.03 ± 0.18 m/s vs.1.44 ± 0.17 m/s,t =9.333,P 〈 0.001;1.31 ± 0.30 m/s vs.1.91 ± 0.25 m/s,t =8.853,P 〈 0.00 1,respectively).There was no difference in gait speed between men and women.Both 9-HPT and 10-MWT were significantly correlated with the ONLS,functional disability score,and BBS (P 〈 0.05 for all).Conclusion:The 9-HPT and 10-MWT might be useful for functional assessment in Chinese patients with CMT. 展开更多
关键词 charcot-marie-tooth Disease charcot-marie-tooth Disease Examination Score Nine-hole Peg Test Ten-meter Walk Test
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Intermediate Charcot-Marie-Tooth disease 被引量:3
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作者 Lei Liu Ruxu Zhang 《Neuroscience Bulletin》 SCIE CAS CSCD 2014年第6期999-1009,共11页
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 e... 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. 展开更多
关键词 charcot-marie-tooth disease intermediate CMT dominant type CMT recessive type CMT diagnostic procedure
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Screening for SH3TC2, PMP2, and BSCL2 Variants in a Cohort of Chinese Patients with Charcot-Marie-Tooth 被引量:3
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作者 Xin Zhao Ming-Ming Jiang +8 位作者 Yi-Zhou Yan Lei Liu Yong-Zhi Xie Xiao-Bo Li Zheng-Mao Hu Xiao-Hong Zi Kun Xia Bei-Sha Tang Ru-Xu Zhang 《Chinese Medical Journal》 SCIE CAS CSCD 2018年第2期151-155,共5页
Background: SH3TC2, PMP2, and BSCL2 genes are related to autosomal recessive (AR) Charcot-Marie-Tooth (CMT) disease type 1, autosomal dominant (AD)-CMTI, and AD-CMT2, respectively. Pathogenic variants in these ... Background: SH3TC2, PMP2, and BSCL2 genes are related to autosomal recessive (AR) Charcot-Marie-Tooth (CMT) disease type 1, autosomal dominant (AD)-CMTI, and AD-CMT2, respectively. Pathogenic variants in these three genes were not well documented in Chinese CMT patients. Therefore, this study aims to detect SH3TC2, PMP2, and BSCL2 pathogenic variants in a cohort of 315 unrelated Chinese CMT families. Methods: A total of 315 probands from 315 unrelated Chinese CMT families were recruited from the Department of Neurology of Third Xiangya Hospital and Xiangya Hospital. We screened for SH3TC2 pathogenic variants in 84 AR or sporadic CMT probands, PMP2 pathogenic variants in 39 AD or sporadic CMTI probands, and BSCL2 pathogenic variants in 50 AD or sporadic CMT2 probands, using polymerase chain reaction and Sanger sequencing. All these patients were out of 315 unrelated Chinese CMT families and genetically undiagnosed after exclusion of pathogenic variants of PMP22, MFN2, MPZ, GJB 1, GDAP1, HSPB1, HSPB8, EGR2, NEFL. and RABT. Candidate variants were analyzed based on the standards and guidelines of American College of Medical Genetics and Genomics (ACMG). Clinical features were reevaluated. Results: We identified three novel heterozygous variants such as p.L95V (c.283C〉G), p.L 1048P (c.3143T〉C), and p.V 1105 M (c.3313G〉A) of SH3TC2 gene and no pathogenic variants of PMP2 and BSCL2 genes. Although evaluation in silico and screening in the healthy control revealed that the three SH3TC2 variants were likely pathogenic, no second allele variants were discovered. According to the standards and guidelines of ACMG, the heterozygous SH3TC2 variants such as p.L95V, p.LI048P, and p.V1105M were considered to be of uncertain significance. Conclusions: SH3TC2, PMP2, and BSCL2 pathogenic variants might be rare in Chinese CMT patients. Further studies to confirm our findings are needed. 展开更多
关键词 BSCL2 charcot-marie-tooth Disease PMP2 SH3TC2
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Genetic factors for nerve susceptibility to injuries – lessons from PMP22 deficiency 被引量:3
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作者 Jun Li 《Neural Regeneration Research》 SCIE CAS CSCD 2014年第18期1661-1664,共4页
Genetic factors may be learnt from families with gene mutations that render nerve-injury sus- ceptibility even to ordinary physical activities. A typical example is hereditary neuropathy with liability to pressure pal... Genetic factors may be learnt from families with gene mutations that render nerve-injury sus- ceptibility even to ordinary physical activities. A typical example is hereditary neuropathy with liability to pressure palsies (HNPP). HNPP is caused by a heterozygous deletion of PMP22 gene. PMP22 deficiency disrupts myelin junctions (such as tight junction and adherens junctions), leading to abnormally increased myelin permeability that explains the nerve susceptibility to injury. This finding should motivate investigators to identify additional genetic factors contribut- ing to nerve vulnerability of injury. 展开更多
关键词 nerve injury peripheral myelin protein-22 PMP22 charcot-marie-tooth disease MYELIN tight junction adherens junction action potential propagation myelin permeability
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Mechanisms and treatment strategies of demyelinating and dysmyelinating Charcot-Marie-Tooth disease 被引量:1
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作者 Nadège Hertzog Claire Jacob 《Neural Regeneration Research》 SCIE CAS CSCD 2023年第9期1931-1939,共9页
Schwann cells,the myelinating glia of the peripheral nervous system,wrap axons multiple times to build their myelin sheath.Myelin is of paramount importance for axonal integrity and fast axon potential propagation.How... Schwann cells,the myelinating glia of the peripheral nervous system,wrap axons multiple times to build their myelin sheath.Myelin is of paramount importance for axonal integrity and fast axon potential propagation.However,myelin is lacking or dysfunctional in several neuropathies including demyelinating and dysmyelinating Charcot-M arie-To oth disease.Charcot-Marie-To oth disease represents the most prevalent inherited neuropathy in humans and is classified either as axonal,demyelinating or dysmyelinating,or as intermediate.The demyelinating or dysmyelinating forms of Charcot-Marie-Tooth disease constitute the majority of the disease cases and are most frequently due to mutations in the three following myelin genes:peripheral myelin protein 22,myelin protein ze ro and gap junction beta 1(coding for Connexin 32) causing Charcot-M arie-Tooth disease type 1A,Charcot-Marie-Tooth disease type 1B,and X-linked Charcot-M arie-Tooth disease type 1,respectively.The resulting perturbation of myelin structure and function leads to axonal demyelination or dysmyelination and causes severe disabilities in affected patients.No treatment to cure or slow down the disease progression is currently available on the market,howeve r,scientific discoveries led to a better understanding of the pathomechanisms of the disease and to potential treatment strategies.In this review,we describe the features and molecular mechanisms of the three main demyelinating or dysmyelinating forms of Charcot-Marie-Tooth disease,the rodent models used in research,and the emerging therapeutic approaches to cure or counteract the progression of the disease. 展开更多
关键词 charcot-marie-tooth disease rodent models emerging treatments demyelination and dysmyelination endoplasmic reticulum stress gene therapy MYELIN repair Schwann cells unfolded protein response
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A Novel Missense Mutation in Peripheral Myelin Protein-22 Causes Charcot-Marie-Tooth Disease 被引量:2
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作者 Li-Xi Li Hai-Lin Dong +1 位作者 Bao-Guo Xiao Zhi-Ying Wu 《Chinese Medical Journal》 SCIE CAS CSCD 2017年第15期1779-1784,共6页
Background:Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy.A great number of causative genes have been described in CMT,and among them,the heterozygous duplication of peripheral... Background:Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy.A great number of causative genes have been described in CMT,and among them,the heterozygous duplication of peripheral myelin protein-22 (PMP22) is the major cause.Although the missense mutation in PMP22 is rarely reported,it has been demonstrated to be associated with CMT.This study described a novel missense mutation of PMP22 in a Chinese family with CMT phenotype.Methods:Targeted next-generation sequencing (NGS) was used to screen the causative genes in a family featured with an autosomal dominant demyelinating form of CMT.The potential variants identified by targeted NGS were verified by Sanger sequencing and classified according to the American College of Medical Genetics and Genomics standards and guidelines.Further cell transfection studies were performed to characterize the function of the novel variant.Results:Using targeted NGS,a novel heterozygous missense variant in PMP22 (c.320G〉A,p.G107D) was identified.In vitro cell functional studies revealed that mutant PMP22 protein carrying p.G 107D mutation lost the ability to reach the plasma membrane,was mainly retained in the endoplasmic reticulum,and induced cell apoptosis.Conclusions:This study supported the notion that missense mutations in PMP22 give rise to a CMT phenotype,possibly through a toxic gain-of-function mechanism. 展开更多
关键词 APOPTOSIS charcot-marie-tooth Disease Endoplasmic Reticulum Missense Mutation Peripheral Myelin Protein-22
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Gene Repair of iPSC Line with GARS (G294R) Mutation of CMT2D Disease by CRISPR/Cas9
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作者 Pei-jie LU Pei ZHANG +8 位作者 Yu-chun LIU Na JING Ya-nan GUO Peng-shuai WANG Lin-lin SU Qi GUO Qiang MA Yu-ming XU Shou-tao ZHANG 《Current Medical Science》 SCIE CAS 2023年第2期261-267,共7页
Objective Charcot-Marie-Tooth disease(CMT)severely affects patient activity,and may cause disability.However,no clinical treatment is available to reverse the disease course.The combination of CRISPR/Cas9 and iPSCs ma... Objective Charcot-Marie-Tooth disease(CMT)severely affects patient activity,and may cause disability.However,no clinical treatment is available to reverse the disease course.The combination of CRISPR/Cas9 and iPSCs may have therapeutic potential against nervous diseases,such as CMT.Methods In the present study,the skin fibroblasts of CMT type 2D(CMT2D)patients with the c.880G>A heterozygous nucleotide mutation in the GARS gene were reprogrammed into iPSCs using three plasmids(pCXLE-hSK,pCXLE-hUL and pCXLE-hOCT3/4-shp5-F).Then,CRISPR/Cas9 technology was used to repair the mutated gene sites at the iPSC level.Results An iPSC line derived from the GARS(G294R)family with fibular atrophy was successfully induced,and the mutated gene loci were repaired at the iPSC level using CRISPR/Cas9 technology.These findings lay the foundation for future research on drug screening and cell therapy.Conclusion iPSCs can differentiate into different cell types,and originate from autologous cells.Therefore,they are promising for the development of autologous cell therapies for degenerative diseases.The combination of CRISPR/Cas9 and iPSCs may open a new avenue for the treatment of nervous diseases,such as CMT. 展开更多
关键词 charcot-marie-tooth disease GARS CRISPR/Cas9 IPSCS gene therapy
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利用果蝇模型研究人类Ⅱ型腓骨肌萎缩症的进展
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作者 余凌奇 谢甲钰 +2 位作者 原垚 凌圣安 陈文锋 《中国细胞生物学学报》 CAS CSCD 2023年第1期122-132,共11页
腓骨肌萎缩症(Charcot-Marie-Tooth,CMT)通常是由神经元中某些蛋白质缺陷引起的一种常见家族遗传性外周神经系统疾病,患者表现为远端感觉和运动神经元的缺陷,行动能力不足,严重者可丧失行动能力。根据临床和电生理特征,CMT主要分为原发... 腓骨肌萎缩症(Charcot-Marie-Tooth,CMT)通常是由神经元中某些蛋白质缺陷引起的一种常见家族遗传性外周神经系统疾病,患者表现为远端感觉和运动神经元的缺陷,行动能力不足,严重者可丧失行动能力。根据临床和电生理特征,CMT主要分为原发性脱髓鞘病变CMT1、原发性轴突病变CMT2以及继发性脱髓鞘和轴突病变的DI-CMT。越来越多的研究利用果蝇模型来模拟人类疾病和人类健康相关过程的各个方面。果蝇没有被髓鞘包围的轴突,因此不适合建立脱髓鞘型的CMT模型,而比较适合轴突病变CMT2的研究。该文主要针对CMT2进行分析,总结了人类CMT2涉及的相关致病基因,以及如何利用果蝇模型进行CMT2模型构建和病理分析。这对于CMT2疾病的生物学和医学研究具有重要的意义。 展开更多
关键词 腓骨肌萎缩症 CMT2 果蝇 疾病模型
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X-linked Charcot-Marie-Tooth disease after SARS-CoV-2 vaccination mimicked stroke-like episodes: A case report
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作者 Qiang Zhang Yang Wang +3 位作者 Run-Tao Bai Bao-Rong Lian Yu Zhang Li-Ming Cao 《World Journal of Clinical Cases》 SCIE 2023年第2期464-471,共8页
BACKGROUND Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) vaccinations have been administered worldwide, with occasional reports of associated neurological complications. Specifically, the impact of vacci... BACKGROUND Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) vaccinations have been administered worldwide, with occasional reports of associated neurological complications. Specifically, the impact of vaccinations on individuals with Xlinked Charcot-Marie-Tooth disease type 1(CMTX1) is unclear. Patients with CMTX1 can have stroke-like episodes with posterior reversible encephalopathy syndrome on magnetic resonance imaging(MRI), although this is rare.CASE SUMMARY A 39-year-old man was admitted with episodic aphasia and dysphagia for 2 d. He received SARS-CoV-2 vaccination 39 d before admission. Physical examination showed pes cavus and reduced tendon reflexes. Brain MRI showed bilateral, symmetrical, restricted diffusion with T2 hyperintensities in the cerebral hemispheres. Nerve conduction studies revealed peripheral nerve damage. He was diagnosed with Charcot-Marie-Tooth disease, and a hemizygous mutation in the GJB1 gene on the X chromosome, known to be pathogenic for CMTX1, was identified. Initially, we suspected transient ischemic attack or demyelinating leukoencephalopathy. We initiated treatment with antithrombotic therapy and immunotherapy. At 1.5 mo after discharge, brain MRI showed complete resolution of lesions, with no recurrence.CONCLUSION SARS-CoV-2 vaccination could be a predisposing factor for CMTX1 and trigger a sudden presentation. 展开更多
关键词 X-linked charcot-marie-tooth disease SARS-CoV-2 vaccination Stroke-like episodes Reversible splenial lesion syndrome Demyelinating leukoencephalopathy Case report
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Advances in the molecular diagnosis of Charcot-Marie-Tooth disease
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作者 Paschalis Nicolaou Kyproula Christodoulou 《World Journal of Neurology》 2013年第3期42-55,共14页
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... 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. 展开更多
关键词 charcot-marie-tooth DISEASE charcot-marie-tooth NEUROPATHY GENETICS MOLECULAR diagnosis
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Clinical and Genetic Features of Chinese X-linked Charcot-Marie-Tooth Type 1 Disease 被引量:1
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作者 Yuan-Yuan Lu He Lyu +5 位作者 Su-Qin Jin Yue-Huan Zuo Jing Liu Zhao-Xia Wang Wei Zhang Yun Yuan 《Chinese Medical Journal》 SCIE CAS CSCD 2017年第9期1049-1054,共6页
Background: X-linked Charcot-Marie-Tooth type 1 (CMT1 X) disease is one of the most common forms of inherited neuropathy caused by mutations in the gap junction beta-1 protein (GJB1) gene (also known as connexin... Background: X-linked Charcot-Marie-Tooth type 1 (CMT1 X) disease is one of the most common forms of inherited neuropathy caused by mutations in the gap junction beta-1 protein (GJB1) gene (also known as connexin 32). This study presented the clinical and genetic features of a series of Chinese patients with GJB1 gene mutations. Methods: A total of 22 patients from unrelated families, who were referred to Department of Neurology, Peking University First Hospital from January 2005 to January 2016, were identified with GJBI mutations. Their clinical records and laboratory findings were retrospectively collected and reviewed. Mutations in the GJB1 gene were analyzed by targeted next-generation sequencing (NGS). Nucleotide alternations were confirnled with Sanger sequencing. Results: The CMT1X patients predominantly showed distal muscle weakness of lower limbs with mild sensory disturbance. The mean age of onset was 15.6 ± 8.7 years (ranging from 1 year to 42 years). The sudden onset of cerebral symptoms appeared in four patients ( 18.2%): two were initial symptoms. One case had constant central nervous system (CNS) signs. There were 19 different heterozygous mutations, including 15 known mutations and tbur novel mutations (c. II5G〉T, c.380T〉A, c.263C〉A, and c.818_819insGGGCT). Among the 22 Chinese patients with CMT1X, the frequency of the GJB1 mutation was 4.5% in transmembrane domain 1 (TM1), 4.5% in TM2, 27.7% in TM3, 9.1% in TM4, 4.5% in extracellular 1 (EC1), 27.3% in EC2, 9.1% in intracellular loop, 13.6% in the N-terminal domain, and 4.5% in the C-ternlinal domain. CMTIX with CNS impairment appeared in five (22.7%) of these patients. Conclusions: This study indicated that CNS impairment was not rare in Chinese CMT1X patients. Mutations in the EC2 domain of the GJBI gene were hotspot in Chinese CMT1X patients. 展开更多
关键词 Connexin 32 Gap Junction Beta-I Protein Neuropathy: X-linked charcot-marie-tooth Type 1
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Subarachnoid and Peripheral Nerve Block in a Patient with Charcot-Marie-Tooth Disease
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作者 Stinson T. Ritter Ryan J. Jense Joanna M. Davies 《Open Journal of Anesthesiology》 2013年第1期44-47,共4页
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, i... 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. 展开更多
关键词 charcot-marie-tooth Disease CMT REGIONAL ANESTHESIA Neuraxial ANESTHESIA
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A novel mitofusin 2 gene mutation causing Charcot-Marie-Tooth type 2A disease in a Chinese family
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作者 CHING Chor Kwan LAU Kwok Kwong +2 位作者 YU Kwok Wai CHAN Yan Wo Albert MAK Miu Chloe 《Chinese Medical Journal》 SCIE CAS CSCD 2010年第11期1466-1469,共4页
Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathies,comprises a genetically heterogeneous group of inherited peripheral neuropathies. Clinically it is characterized by progress... Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathies,comprises a genetically heterogeneous group of inherited peripheral neuropathies. Clinically it is characterized by progressive distal weakness, muscle atrophy, distal sensory loss and loss of deep tendon reflexes. Following electrophysiological criteria, CMT is divided into two main forms: 展开更多
关键词 charcot-marie-tooth type 2A mitofusin 2 gene Hong Kong
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