重复电刺激对肌萎缩侧索硬化的应用价值及散发性肌萎缩侧索硬化基因突变与多态性研究
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摘要
背景目前神经电生理诊断神经肌肉接头病变有两种方法：重复神经电刺激(Repeative Nerve Stimulation，RNS)和单纤维肌电图(Single fiberelectromyography，SFEMG)。RNS临床最常用于重症肌无力及肌无力综合症的诊断，SFEMG)临床上最常用于对重症肌无力的诊断，还可用于肌萎缩侧索硬化，和肌肉病等的辅助诊断。研究发现：肌萎缩侧索硬化(Amyotrophic lateralsclerosis，ALS)除上下运动神经元损害外，再生的神经末梢也可引起神经肌肉接头处功能紊乱，SFEMG可发现异常改变，这有助于ALS鉴别诊断。SFEMG虽然敏感性较高但存在技术要求高、病人需主动配合及有创、费用高、难以推广的弊端，因此临床上希望有一种能替代SFEMG的检查，用以研究ALS病人神经肌肉接头的功能和对预后进行判断。国外已有研究认为ALS病人可出现RNS低频递减现象，但均为对单一神经小样本的研究，缺乏对RNS与ALS病情进展速度、起病部位关系的详细研究，更缺乏对ALS患者的RNS与SFEMG的比较性研究及RNS在非ALS肌肉萎缩无力中的鉴别诊断意义的研究。并且仍有国际的诊断标准认为ALS的RNS低频递减不应超过20％。本研究将在较大样本的ALS确诊和拟诊病例临床和电生理研究基础上，对6条神经给予RNS及部分病人同时SFEMG检查。
目的(1)探讨ALS患者RNS阳性率，RNS阳性部位及RNS与运动波幅、神经电生理指数(NI指数)、起病部位、病情进展速度，病程、性别年龄、病情分级关系。(2)RNS与SFEMG比较诊断吻合率。RNS与FD，Jitter、Block关系。(3)RNS在非ALS肌萎缩无力中的阳性率。探讨RNS对于ALS诊断和鉴别诊断的应用价值及对预后判断的价值。
方法自2008年5月至2009年4月期间，对在北京协和医院神经科门诊或病房确诊或拟诊ALS的101名患者进行相关资料登记。所有患者行肌电图和RNS检查，部分患者(43例)同时行SFEMG检查。另有对门诊40例非ALS肌肉萎缩无力的患者行RNS检查。
结果(1)RNS在ALS中低频递减阳性率为53.5%。无一例出现高频递增。(2)所检部位阳性率顺序为腋神经(30.6%))副神经(25%))桡神经(15.5%))尺神经(7.8%))面神经(1%))胫神经(0%)。(3)RNS阳性与性别,年龄无关(P>0.05);肢体起病者较球部起病者RNS阳性率高(P<0.05);RNS阳性组病情进展速度较RNS阴性组明显增加(P<0.05);RNS阳性组尺神经运动波幅明显低于RNS阴性组(P<0.05);RNS阳性率在病程长短组(≥1年,(1年)和临床疾病分级(轻.中.重.危重)无统计学差异。(4)RNS在ALS诊断方面与SFEMG比较有较好的吻合性(Kappa=0.47,P=0.001)。(5)RNS阴性和阳性组FD无明显差异。RNS阳性组Jitter、Block异常程度明显高于RNS阴性组。桡神经RNS波幅递减与Jitter值呈成相关。(6)RNS在非ALS肌萎缩无力患者(40例)中阳性率仅为7.5%。与ALS患者的阳性率比较有统计意义。结论RNS在ALS患者中有较高的阳性率,而在非ALS肌无力萎缩患者中阳性率低,有助于ALS的诊断和鉴别诊断。RNS与SFEMG比较有较好的诊断吻合率,低频递减高于20%不应作为ALS的排除标准。因RNS阳性率较高,具有操作简单,费用低耗时短,无创,不需病人特殊配合,近远端肌肉均可操作,易于推广的特点,可广泛用于各级医院对ALS患的辅助诊断和随诊中。并且ALS患者RNS阳性者是疾病活跃的表现,因而病情进展速度明显快,有利于对患者预后做出判断及随诊。另外发现RNS阳性与病程和临床疾病分级(轻.中.重.危重)均无关。本研究创新点(1)首次在国内建立了大样本的ALS患者RNS数据库。(2)首次同时对ALS患者行RNS和SFEMG比较性研究,并与多种非ALS
肌肉萎缩无力的RNS结果对比研究。明确RNS与SFEMG比较对诊断有
较好一致性,肯定了RNS对于ALS有辅助诊断和鉴别诊断价值。(3)首次通过对多根神经RNS的研究,提出RNS与ALS患者病情进展速度
明确相关。可用于判断预后及随诊。背景肌萎缩侧索硬化(ALS)是由脑和脊髓运动神经元进行性退变引起的一种致死性瘫痪性疾病,散发性ALS(SALS)占患病人群的近90%。铜、锌超氧化物歧化酶(SOD1)基因突变存在于1-7%散发性患者人群中。中国有关SALS的SOD突变报道很少。ALS被认为是一种复杂性疾病。目前已经有数个关于ALS的全基因组关联分析的研究,并先后报道若干与增加ALS发病风险相关的单核苷酸多态性(SNP)位点。
目的继续筛查我院2008-09年初散发性患者人群中SOD1基因突变;在以中国人群组成的样本中研究增加SALS致病风险相关的SNP。方法提取样本外周血基因组DNA,PCR扩增SOD1 5个外显子,产物复性结合饱和荧光后进行高分辨熔解突变筛选,可疑样本送测序;不对称PCR扩增包含目标SNP在内的片段,高分辨熔解完成非标记探针的基因分型。
结果(1)2008-09年我院收集的58位SALS患者的SOD1突变筛选。共发现3例突变。突变率为5.2%。第一例在2号外显子第5534位由C突变为T,相应编码的氨基酸由缬氨酸valine变为Aline的V47A突变;第二例在5号外显子第10207位由C突变为T,位于SOD1编码区,属于无意突变,基因库尚未有该变异的报道。第三例在4号外显子8964位由A突变为C,相应编码的氨基酸由GAC天冬氨酸变(Asp)变为GCC丙氨酸(Ala)的D90A突变。(2)由中国人群组成的98名病人与101名对照之间完成Rs2306677一个位点的基因分型,统计分析之后未得出显著差异(x_2=0.2746,P>0.05)
结论(1)我们发现的一例SOD1 V47A突变患者是我院发现的第二例V47A突变,该类型突变在世界上尚无报导,这两个V47A突变患者临床表型有很大不同;D90A是在欧洲常见的SOD变异,一般认为有很强的区域特异性,国内目前尚无报导。另一无意突变为第10207位由C突变为T,基因库尚无报导。2006年到现在,本研究组已经完成188名SALS和两个FALS家系中的SOD1突变研究,共发现了8个突变位点。(2)我们的研究未发现Rs2306677位点和增加SALS的致病风险相关,这可能和ALS本复杂的遗传异质性相关。
Background and Objectives Thereare two neural electrophysiological ways to diagnosis neuromuscular junction disease:repetitive nerve stimulation(RNS) and single fiber electromyography(SFEMG).RNS is the most common method used to diagnosis myasthenia gravis and myasthenia syndrome.SFEMG is used to MG,ALS, and muscle diseases.Amyotrophic lateral sclerosis can induce neuromuscular disorders in addition to upper and lower motor neuron damage.SFEMG is generally used for diagnosis and differential diagnosis of ALS.However,there are some defects of SFEMG,such as technically demanding,time consuming,more invasive and so on although the high sensitivity of it.Therefore,there is a clinical need to find a new method to alternative to SFEMG.Some studies suggest that ALS patients may be a decrement with stimulation at slow rate on RNS.But,small samples were used in all of these studies.Moreover,there are international standards that the reduced low-frequency RNS in ALS should not exceed 20%.In addition,those were unknown what is the relationship between RNS and onset of the detailed parts,clinical severity,disease staging or disease progression,what is the consistency in the comparison of RNS and SFEMG,and what's the meaning of the differential diagnosis by RNS study between muscle atrophy in non-ALS and in ALS patient.In this study, larger samples of ALS cases confirmed and suspected by clinical and electrophysiological study have been exanimated using RNS and SFEMG at the same time.We performed following works:(1) To investigate the RNS positive rate and the decrement degree of ALS patients,the area difference of responses to RNS, and if NI index,onset site,clinical disease classification(light-in-weight-critical), progression rate of disease,gender and age are related with RNS.(2) To compare RNS with SFEMG in the diagnosis of ALS.(3) To investigate the RNS positive rate in non-ALS with muscular atrophy and weakness,and if RNS can be used for ALS diagnosis and differential diagnosis.
Methods 101 ALS patients registered with detailed information in the neurology out-patient or ward of Beijing Union Medical College Hospital Since May 2008 to April 2009.RNS examination was employed for all patients and SFEMG examination only for Some patients(43cases) at the same time.Another 40 cases of non-ALS out-patient with muscle atrophy and weakness were examinated by RNS.
Reslts(1) ALS was manifest on RNS as a decrement with stimulation at slow rate.The ALS-positive rate was 53%.No case of high-frequency increments occurred.(2) The positive rate of axillary nerve,accessorius nerve,radial nerve, ulnar nerve,facial nerve,tibial nerve is 30.6%,25%,15.5%,7.8%,1%,0%, respectively.(3) No correlation between RNS-positive group and sex,age(P>0.05); higher RNS-positive rate of limb onset than that of bublar onset(P<0.05);The progression rate of disease of RNS positive group was significantly increased than negative RNS group(P<0.05);The ulnar nerve CMAP(motor nerve action potential) of RNS positive group was significantly lower than the RNS negative group(P<0.05); No correlation between RNS positive rate and disease duration(
目的(1)探讨ALS患者RNS阳性率，RNS阳性部位及RNS与运动波幅、神经电生理指数(NI指数)、起病部位、病情进展速度，病程、性别年龄、病情分级关系。(2)RNS与SFEMG比较诊断吻合率。RNS与FD，Jitter、Block关系。(3)RNS在非ALS肌萎缩无力中的阳性率。探讨RNS对于ALS诊断和鉴别诊断的应用价值及对预后判断的价值。
方法自2008年5月至2009年4月期间，对在北京协和医院神经科门诊或病房确诊或拟诊ALS的101名患者进行相关资料登记。所有患者行肌电图和RNS检查，部分患者(43例)同时行SFEMG检查。另有对门诊40例非ALS肌肉萎缩无力的患者行RNS检查。
结果(1)RNS在ALS中低频递减阳性率为53.5%。无一例出现高频递增。(2)所检部位阳性率顺序为腋神经(30.6%))副神经(25%))桡神经(15.5%))尺神经(7.8%))面神经(1%))胫神经(0%)。(3)RNS阳性与性别,年龄无关(P>0.05);肢体起病者较球部起病者RNS阳性率高(P<0.05);RNS阳性组病情进展速度较RNS阴性组明显增加(P<0.05);RNS阳性组尺神经运动波幅明显低于RNS阴性组(P<0.05);RNS阳性率在病程长短组(≥1年,(1年)和临床疾病分级(轻.中.重.危重)无统计学差异。(4)RNS在ALS诊断方面与SFEMG比较有较好的吻合性(Kappa=0.47,P=0.001)。(5)RNS阴性和阳性组FD无明显差异。RNS阳性组Jitter、Block异常程度明显高于RNS阴性组。桡神经RNS波幅递减与Jitter值呈成相关。(6)RNS在非ALS肌萎缩无力患者(40例)中阳性率仅为7.5%。与ALS患者的阳性率比较有统计意义。结论RNS在ALS患者中有较高的阳性率,而在非ALS肌无力萎缩患者中阳性率低,有助于ALS的诊断和鉴别诊断。RNS与SFEMG比较有较好的诊断吻合率,低频递减高于20%不应作为ALS的排除标准。因RNS阳性率较高,具有操作简单,费用低耗时短,无创,不需病人特殊配合,近远端肌肉均可操作,易于推广的特点,可广泛用于各级医院对ALS患的辅助诊断和随诊中。并且ALS患者RNS阳性者是疾病活跃的表现,因而病情进展速度明显快,有利于对患者预后做出判断及随诊。另外发现RNS阳性与病程和临床疾病分级(轻.中.重.危重)均无关。本研究创新点(1)首次在国内建立了大样本的ALS患者RNS数据库。(2)首次同时对ALS患者行RNS和SFEMG比较性研究,并与多种非ALS
肌肉萎缩无力的RNS结果对比研究。明确RNS与SFEMG比较对诊断有
较好一致性,肯定了RNS对于ALS有辅助诊断和鉴别诊断价值。(3)首次通过对多根神经RNS的研究,提出RNS与ALS患者病情进展速度
明确相关。可用于判断预后及随诊。背景肌萎缩侧索硬化(ALS)是由脑和脊髓运动神经元进行性退变引起的一种致死性瘫痪性疾病,散发性ALS(SALS)占患病人群的近90%。铜、锌超氧化物歧化酶(SOD1)基因突变存在于1-7%散发性患者人群中。中国有关SALS的SOD突变报道很少。ALS被认为是一种复杂性疾病。目前已经有数个关于ALS的全基因组关联分析的研究,并先后报道若干与增加ALS发病风险相关的单核苷酸多态性(SNP)位点。
目的继续筛查我院2008-09年初散发性患者人群中SOD1基因突变;在以中国人群组成的样本中研究增加SALS致病风险相关的SNP。方法提取样本外周血基因组DNA,PCR扩增SOD1 5个外显子,产物复性结合饱和荧光后进行高分辨熔解突变筛选,可疑样本送测序;不对称PCR扩增包含目标SNP在内的片段,高分辨熔解完成非标记探针的基因分型。
结果(1)2008-09年我院收集的58位SALS患者的SOD1突变筛选。共发现3例突变。突变率为5.2%。第一例在2号外显子第5534位由C突变为T,相应编码的氨基酸由缬氨酸valine变为Aline的V47A突变;第二例在5号外显子第10207位由C突变为T,位于SOD1编码区,属于无意突变,基因库尚未有该变异的报道。第三例在4号外显子8964位由A突变为C,相应编码的氨基酸由GAC天冬氨酸变(Asp)变为GCC丙氨酸(Ala)的D90A突变。(2)由中国人群组成的98名病人与101名对照之间完成Rs2306677一个位点的基因分型,统计分析之后未得出显著差异(x_2=0.2746,P>0.05)
结论(1)我们发现的一例SOD1 V47A突变患者是我院发现的第二例V47A突变,该类型突变在世界上尚无报导,这两个V47A突变患者临床表型有很大不同;D90A是在欧洲常见的SOD变异,一般认为有很强的区域特异性,国内目前尚无报导。另一无意突变为第10207位由C突变为T,基因库尚无报导。2006年到现在,本研究组已经完成188名SALS和两个FALS家系中的SOD1突变研究,共发现了8个突变位点。(2)我们的研究未发现Rs2306677位点和增加SALS的致病风险相关,这可能和ALS本复杂的遗传异质性相关。
Background and Objectives Thereare two neural electrophysiological ways to diagnosis neuromuscular junction disease:repetitive nerve stimulation(RNS) and single fiber electromyography(SFEMG).RNS is the most common method used to diagnosis myasthenia gravis and myasthenia syndrome.SFEMG is used to MG,ALS, and muscle diseases.Amyotrophic lateral sclerosis can induce neuromuscular disorders in addition to upper and lower motor neuron damage.SFEMG is generally used for diagnosis and differential diagnosis of ALS.However,there are some defects of SFEMG,such as technically demanding,time consuming,more invasive and so on although the high sensitivity of it.Therefore,there is a clinical need to find a new method to alternative to SFEMG.Some studies suggest that ALS patients may be a decrement with stimulation at slow rate on RNS.But,small samples were used in all of these studies.Moreover,there are international standards that the reduced low-frequency RNS in ALS should not exceed 20%.In addition,those were unknown what is the relationship between RNS and onset of the detailed parts,clinical severity,disease staging or disease progression,what is the consistency in the comparison of RNS and SFEMG,and what's the meaning of the differential diagnosis by RNS study between muscle atrophy in non-ALS and in ALS patient.In this study, larger samples of ALS cases confirmed and suspected by clinical and electrophysiological study have been exanimated using RNS and SFEMG at the same time.We performed following works:(1) To investigate the RNS positive rate and the decrement degree of ALS patients,the area difference of responses to RNS, and if NI index,onset site,clinical disease classification(light-in-weight-critical), progression rate of disease,gender and age are related with RNS.(2) To compare RNS with SFEMG in the diagnosis of ALS.(3) To investigate the RNS positive rate in non-ALS with muscular atrophy and weakness,and if RNS can be used for ALS diagnosis and differential diagnosis.
Methods 101 ALS patients registered with detailed information in the neurology out-patient or ward of Beijing Union Medical College Hospital Since May 2008 to April 2009.RNS examination was employed for all patients and SFEMG examination only for Some patients(43cases) at the same time.Another 40 cases of non-ALS out-patient with muscle atrophy and weakness were examinated by RNS.
Reslts(1) ALS was manifest on RNS as a decrement with stimulation at slow rate.The ALS-positive rate was 53%.No case of high-frequency increments occurred.(2) The positive rate of axillary nerve,accessorius nerve,radial nerve, ulnar nerve,facial nerve,tibial nerve is 30.6%,25%,15.5%,7.8%,1%,0%, respectively.(3) No correlation between RNS-positive group and sex,age(P>0.05); higher RNS-positive rate of limb onset than that of bublar onset(P<0.05);The progression rate of disease of RNS positive group was significantly increased than negative RNS group(P<0.05);The ulnar nerve CMAP(motor nerve action potential) of RNS positive group was significantly lower than the RNS negative group(P<0.05); No correlation between RNS positive rate and disease duration(
引文
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[22]Henderson RD,Daube JR.Decrement in surfaced recorded motor unit potentials in amyotrophic lateral sclerosis.Neurology,2004,63:1670-1674.
[23]Drachman DB.The role of acetylcholine as a neurotrophic transmitter.Ann NY Acad Sci,1974,228:89-104.
[24]Kaires PA.Prognostic value of decremental responses to repetitive nerve stimulation in ALS patients.Neurology,2001,57:897-899.
[25]Killian JM,W ilfong AA,Burnett L.Decrem ental motor responses to repetitive nerve stimulation in ALS.Muscle Nerve,1994,17:747-754.
[26]Bernstein LP,Antel JP.Motor neuron disease:decremental responses to repetitive nerve stimulation.Neurology,1981,31:204-207.
[27]Singh P,Mann KA,Mangat HK,et al.Prolonged glutamate excitotoxicity:effects on mitochondrial antioxidants and antioxidant enzymes.Mol Cell Biochem,2003,243:139-145.
[1]Singh P,Mann KA,Mangat HK,et al.Prolonged glutamate excitotoxicity:effects on mitochondrial antioxidants and antioxidant enzymes.Mol Cell Biochem,2003,243:139-145.
[2]Rao SD,Yin HZ,Weiss JH.Disruption of glial glutamate transport by reactive oxygen species produced in motor neurons.J Neurosci,2003,23:2627-2633.
[3]Koutsilieri E,Scheller C,Tribl F,et al.Degeneration of neuronal cells due to oxidative stress-microglial contribution Parkinsonism.Relat Disord,2002,8;401-406.
[4]Cutler RG,PedeRsen WA,Camandola S,et al.Evidence that accumulation of ceramides and cholesterol esteRs mediates oxidative stress-induced death of motor neurons in amyotrophic lateral sclerosis.Ann Neurol,2002,52:448-457.
[5]Rakhit R,Cunningham P,Furtos-Matei A,et al.Oxidation-induced misfolding and aggregation of superoxide dismutase and its implications for amyotrophic lateral sclerosis.J Biol Chem,2002,277:47551-47556.
[6]Peter MA.Genetics of sporadic ALS,ALS and other motor neuron.disordeRs 2001,2:S37-S41.
[7]AndeRsen PM.Amyotrophic lateral sclerosis associated with mutations in the CuZn superoxide dismutase gene.Curr Neurol Neurosci Rep,2006,6:37-46.
[8]李彪,陈润.复杂疾病关联分析进展.Acta Acad Med Sin,2006,28:271-277.
[9]van Es MA,van Vught PW,Blauw HM,Franke Let al.Genetic variation in DPP6is associated with susceptibility to amyotrophic lateral sclerosis.Nat Genet,2008,40:29-31.
[10]Michael AE,Paul WVV,Hylke MB,et al.ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis:a genome-wide association study Lancet Neurol.2007,6:841-843.
[11]Schymick JC,Scholz SW,Fung HC et al.Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls:fiRst stage analysis and public release of data.Lancet Neurol,2007,6:322-328.
[12]Michael A van Es,Paul WJ van Vught,Hylke M Blauw.Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis.Nat Genet,2008,40:29-31.
[13]LinksDunckley T,Huentelman MJ,et al.Whole-genome analysis of sporadic amyotrophic lateral sclerosis.N Engl J Med,2007,357:775-788.
[14]McGeer PL,Itagaki S,McGeer EG.Expression of the histocompatibility glycoprotein HLA-DR in neurological disease.Acta Neuropathol(Berl),1988,76:550-557.
[15]Kawamata T,Akiyama H.Yamada T,et al.Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue.Am J Pathol,1992,140:691-707.
[16]Troost D,Van den Oord JJ,Vianney de Jong JM.Immunohistochemical characterization of the inflammatory infiltrate in amyotrophic lateral sclerosis.Neuropathol Appl Neurobiol,1990,16:401-410.
[17]Bordo D,Matak D,Dijnovic,Carugo K,et al.Characterization of the Spectroscopic Properties of the Cu,Co Cluster in a Prokaryotic Superoxide Dismutase.J Mol Biol,1999,285:283-296.
[18]Schymick JC,Talbotand K,Traynor BJ,et al.Genetics of sporadic amyotrophic lateral sclerosis,Human.Molecular Genetics,2007,16:R233-R242.
[19]Koji Abe,Kei Fukada,Saburo Sakoda et al.Clinical and pathological studies of familial amyotrophic lateral sclerosis(FALS)with SODl H46R mutation in large Japanese families,Acta Neuropathol,2003,106:561-568.
[20]Svetlana Antonyuk,Jennifer Stine Elam,Michael A,et al.Structural consequences of the familial amyotrophic lateral sclerosis SODl mutant His46Arg,Protein Science,2005,14:1201-1213.
[21]Cinzia Gellera,Genetics of ALS in Italian families,ALS and other motor neuron.disorders,2001,2:S43-S46.
[22]AndeRsen PM.Genetic of sporadic ALS.Amyotroph Lateral Scle Other Motor Neuron Disord.2001,2:s37-S41.
[23]AndeRsen PM,FoRsgren L,Binzer M,Nilsson P,et al.Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation.A clinical and genealogical study of 36 patients.Brain,1996,119:1153-1172.
[1]Mulder DW,Lambert EH,Eaton LM.Myasthenic syndrome in patient with amyotrophic lateral sclerosis.Neurology,1959,9:627-631.
[2]Denys EH,Norris FH Jr.Amyotrophic lateral sclerosis.Impairment of neuromuscular transmission.Arch Neurol,1979,36:202-205.
[3]Killian JM,Wilfong AA,Burnett L,Appel SH,Boland D.Decremental motor responses to repetitive nerve stimulation in ALS.Muscle Nerve,1994,17:747-754.
[4]Wang FC,De Pasqua V,G(?)rard P,Delwaide PJ,et al.Prognostic value of decremental responses to repetitive nerve stimulation in ALS patients.Neurology,2001;57:897-899.
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[6]张为西 吕建敏,运动神经元病的重复电刺激的研究临床神经病学杂志,1997,10:227-228.
[7]Fischer LR,Culver DG,Tennant P,Davis AA,et al.Amyotrophic lateral sclerosis is a distal axonopathy:evidence in mice and man.Exp Neurol,2004,185:232-240.
[8]Appel SH,Smith RG,Engelhm,et al.Evidenee for autoimmunity in amyotrophic lateral sclerosis.J Neurol Sci,1993,118-169.
[9]Magleby KL.Neuromuscular transmission.In:Engel AG,Franzini-Armstrong C,eds.Myology,2d ed.New York:McGRAW-Hill,1994:442-463.
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[12]Walter G,et al.Recent views on amyotrophre lateral scleroses with emphases on electrophysiological studies.Muscle & Nerve.1987,10:490.
[13]Jokic N,Gonzalez de Aguilar JL,Dimou L.The neurite outgrowth inhibitor Nogo-A promotes denervation in an amyotrophic lateral sclerosis model.Embo Rep,2006,7:1162-1167.
[14]Drachman DB.The role of acetylcholine as a neurotrophic transmitter.Ann NY Acad Sci,1974,228:89-104.
[15]Kaires PA.Prognostic value of decremental responses to repetitive nerve stimulation in ALS patients.Neurology.2001,57:897-899.
[16]Brooks BR El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis.Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial“Clinical limits of amyotrophic lateral sclerosis”workshop contributors.J Neurol Sci,1994,124:96-107.
[17]Daube JR.Electrodiagnostic studies in amyotrophic lateral sclerosis and other motor neuron didorders.Muscle & Nerve.2000:1488-1502.
[18]Dan YF,Leoh TH,Tan YE,Lo YL,et al.Ecrement in area of muscle responses to repetitive nerve stimulation.Muscle Nerve,2003,27:494-496.
[1]Berridge MJ.Unlocking the secrets of cell signaling.Annu Rev Physiol,2005,67:1-21
[2]Maeda N,Kawasaki T,Nakade S,et al.Structural and functional characterization of inositol 1,4,5-trisphosphate receptor channel from mouse cerebellum.J Biol Chem,1991,266:1109-1116.
[3]Cardenas C,Liberona JL,Molgo J,et al.1 Nuclear inositol 1,4,52 trisphosphate receptors regulate local Ca2+ transients and modulate cAMP response element binding protein phosphorylation.J Cell Sci,2005,118:3131-3140.
[4]Taylor CW,da Fonseca PC,Morris EP.IP3 receptors:the search for structurel Trends Biochem Sci,2004,29:210-219.
[5]Bosanac I,Alattia JR,Mai TK,et al.Structure of the inositol 1,4,52triphosphate receptor binding core in complex with its ligand.Nature,2002,420:696-700.
[6]Vazquez G,Wedel BJ,Bird GS,et al.An inositol 1,4,5 trisphosphate receptor2 dependent cation entry pathway in DT40 B lymphocytesl EMBO J,2002,21:4531-4538.
[7]Ideatifietion of cycle ADP-ribose—binding proteins by photo affnity labeling.Walseth TF,Aarhus R.Kerr J A,et al.J Biol Chem,1993,268:266-286.
[8]Thorburn A.Death receptor-induced cell killing,2004,16:139-144.
[9]Li P,Nijhawan D,Budihardjo I,Srinivasula SM,et al.Cytochrome c and dATP-dependent formation of Apaf-l/caspase-9 complex initiates an apoptotic protease cascade.Cell,1997,91:479-489.
[10]Strasser A,O'Connor L,Dixit VM.Apoptosis signaling.Annu Rev Biochem.2000,69:217-245.
[11]Schanne FA,Kane AB,Young EE,Farber JL.Calcium dependence of toxic cell death:a final common pathway.,1979,206:700-702.
[12]Orrenius S,Zhivotovsky B,Nicotera P.Regulation of cell death:the calcium-apoptosis link.Nat Rev Mol Cell Biol.2003,4:552-565.
[13]Leonard JP,Salpeter MM.Agonist-induced myopathy at the neuromuscular junction is mediated by calcium.J Cell Biol.1979,82:811-819.
[14]Crompton M,Costi A,Hayat L.Evidence for the presence of a reversible Ca2+-dependent pore activated by oxidative stress in heart mitochondria.Biochem J,1987,245:915-918.
[15]Berridge MJ,Lipp P,Bootman MD.The versatility and universality of calcium signalling.Nat Rev Mol Cell Biol,2000,1:11-21.
[16]Jayaraman T,Marks AR.T cells deficient in inositol 1,4,5-trisphosphate receptor are resistant to apoptosis.Mol Cell Biol.1997,17:3005-3012.
[17]Blackshaw S,Sawa A,Sharp AH,et al.Type 3 inositol 1,4,5-trisphosphate receptor modulates cell death.FASEB J,2000,14:1375-1379.
[18]郭静,蒲永梅,张东才.钙离子信号和细胞凋亡,生物物理学报,2005,21.
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[20]Jokic N,Gonzalez de Aguilar JL,Dimou L.The neurite outgrowth inhibitor Nogo-A promotes denervation in an amyotrophic lateral sclerosis model.Embo Rep,2006,7:1162-1167.
[21]Brown WF.The physiological and technical basis of electromyography.Boston,Butterworth,1984:201-231.
[22]Henderson RD,Daube JR.Decrement in surfaced recorded motor unit potentials in amyotrophic lateral sclerosis.Neurology,2004,63:1670-1674.
[23]Drachman DB.The role of acetylcholine as a neurotrophic transmitter.Ann NY Acad Sci,1974,228:89-104.
[24]Kaires PA.Prognostic value of decremental responses to repetitive nerve stimulation in ALS patients.Neurology,2001,57:897-899.
[25]Killian JM,W ilfong AA,Burnett L.Decrem ental motor responses to repetitive nerve stimulation in ALS.Muscle Nerve,1994,17:747-754.
[26]Bernstein LP,Antel JP.Motor neuron disease:decremental responses to repetitive nerve stimulation.Neurology,1981,31:204-207.
[27]Singh P,Mann KA,Mangat HK,et al.Prolonged glutamate excitotoxicity:effects on mitochondrial antioxidants and antioxidant enzymes.Mol Cell Biochem,2003,243:139-145.
[1]Singh P,Mann KA,Mangat HK,et al.Prolonged glutamate excitotoxicity:effects on mitochondrial antioxidants and antioxidant enzymes.Mol Cell Biochem,2003,243:139-145.
[2]Rao SD,Yin HZ,Weiss JH.Disruption of glial glutamate transport by reactive oxygen species produced in motor neurons.J Neurosci,2003,23:2627-2633.
[3]Koutsilieri E,Scheller C,Tribl F,et al.Degeneration of neuronal cells due to oxidative stress-microglial contribution Parkinsonism.Relat Disord,2002,8;401-406.
[4]Cutler RG,PedeRsen WA,Camandola S,et al.Evidence that accumulation of ceramides and cholesterol esteRs mediates oxidative stress-induced death of motor neurons in amyotrophic lateral sclerosis.Ann Neurol,2002,52:448-457.
[5]Rakhit R,Cunningham P,Furtos-Matei A,et al.Oxidation-induced misfolding and aggregation of superoxide dismutase and its implications for amyotrophic lateral sclerosis.J Biol Chem,2002,277:47551-47556.
[6]Peter MA.Genetics of sporadic ALS,ALS and other motor neuron.disordeRs 2001,2:S37-S41.
[7]AndeRsen PM.Amyotrophic lateral sclerosis associated with mutations in the CuZn superoxide dismutase gene.Curr Neurol Neurosci Rep,2006,6:37-46.
[8]李彪,陈润.复杂疾病关联分析进展.Acta Acad Med Sin,2006,28:271-277.
[9]van Es MA,van Vught PW,Blauw HM,Franke Let al.Genetic variation in DPP6is associated with susceptibility to amyotrophic lateral sclerosis.Nat Genet,2008,40:29-31.
[10]Michael AE,Paul WVV,Hylke MB,et al.ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis:a genome-wide association study Lancet Neurol.2007,6:841-843.
[11]Schymick JC,Scholz SW,Fung HC et al.Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls:fiRst stage analysis and public release of data.Lancet Neurol,2007,6:322-328.
[12]Michael A van Es,Paul WJ van Vught,Hylke M Blauw.Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis.Nat Genet,2008,40:29-31.
[13]LinksDunckley T,Huentelman MJ,et al.Whole-genome analysis of sporadic amyotrophic lateral sclerosis.N Engl J Med,2007,357:775-788.
[14]McGeer PL,Itagaki S,McGeer EG.Expression of the histocompatibility glycoprotein HLA-DR in neurological disease.Acta Neuropathol(Berl),1988,76:550-557.
[15]Kawamata T,Akiyama H.Yamada T,et al.Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue.Am J Pathol,1992,140:691-707.
[16]Troost D,Van den Oord JJ,Vianney de Jong JM.Immunohistochemical characterization of the inflammatory infiltrate in amyotrophic lateral sclerosis.Neuropathol Appl Neurobiol,1990,16:401-410.
[17]Bordo D,Matak D,Dijnovic,Carugo K,et al.Characterization of the Spectroscopic Properties of the Cu,Co Cluster in a Prokaryotic Superoxide Dismutase.J Mol Biol,1999,285:283-296.
[18]Schymick JC,Talbotand K,Traynor BJ,et al.Genetics of sporadic amyotrophic lateral sclerosis,Human.Molecular Genetics,2007,16:R233-R242.
[19]Koji Abe,Kei Fukada,Saburo Sakoda et al.Clinical and pathological studies of familial amyotrophic lateral sclerosis(FALS)with SODl H46R mutation in large Japanese families,Acta Neuropathol,2003,106:561-568.
[20]Svetlana Antonyuk,Jennifer Stine Elam,Michael A,et al.Structural consequences of the familial amyotrophic lateral sclerosis SODl mutant His46Arg,Protein Science,2005,14:1201-1213.
[21]Cinzia Gellera,Genetics of ALS in Italian families,ALS and other motor neuron.disorders,2001,2:S43-S46.
[22]AndeRsen PM.Genetic of sporadic ALS.Amyotroph Lateral Scle Other Motor Neuron Disord.2001,2:s37-S41.
[23]AndeRsen PM,FoRsgren L,Binzer M,Nilsson P,et al.Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation.A clinical and genealogical study of 36 patients.Brain,1996,119:1153-1172.
[1]Mulder DW,Lambert EH,Eaton LM.Myasthenic syndrome in patient with amyotrophic lateral sclerosis.Neurology,1959,9:627-631.
[2]Denys EH,Norris FH Jr.Amyotrophic lateral sclerosis.Impairment of neuromuscular transmission.Arch Neurol,1979,36:202-205.
[3]Killian JM,Wilfong AA,Burnett L,Appel SH,Boland D.Decremental motor responses to repetitive nerve stimulation in ALS.Muscle Nerve,1994,17:747-754.
[4]Wang FC,De Pasqua V,G(?)rard P,Delwaide PJ,et al.Prognostic value of decremental responses to repetitive nerve stimulation in ALS patients.Neurology,2001;57:897-899.
[5]Lawrence P,Bernstein,JP.Antel Motor neuron disease:Decremental responses torepetitive nerve stimulation.Neurology,31:202-204.
[6]张为西 吕建敏,运动神经元病的重复电刺激的研究临床神经病学杂志,1997,10:227-228.
[7]Fischer LR,Culver DG,Tennant P,Davis AA,et al.Amyotrophic lateral sclerosis is a distal axonopathy:evidence in mice and man.Exp Neurol,2004,185:232-240.
[8]Appel SH,Smith RG,Engelhm,et al.Evidenee for autoimmunity in amyotrophic lateral sclerosis.J Neurol Sci,1993,118-169.
[9]Magleby KL.Neuromuscular transmission.In:Engel AG,Franzini-Armstrong C,eds.Myology,2d ed.New York:McGRAW-Hill,1994:442-463.
[10]Bjornskov EK,Dekker NP,Norris FH Jr,Stuart ME.End-plate morphology in amyotrophic lateral sclerosis.Arch Neurol.1975,32:711-712.
[11]Brown WF.The physiological and Technical Basis of Electromyography.Boston,Butterworth,1984,201-231.
[12]Walter G,et al.Recent views on amyotrophre lateral scleroses with emphases on electrophysiological studies.Muscle & Nerve.1987,10:490.
[13]Jokic N,Gonzalez de Aguilar JL,Dimou L.The neurite outgrowth inhibitor Nogo-A promotes denervation in an amyotrophic lateral sclerosis model.Embo Rep,2006,7:1162-1167.
[14]Drachman DB.The role of acetylcholine as a neurotrophic transmitter.Ann NY Acad Sci,1974,228:89-104.
[15]Kaires PA.Prognostic value of decremental responses to repetitive nerve stimulation in ALS patients.Neurology.2001,57:897-899.
[16]Brooks BR El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis.Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial“Clinical limits of amyotrophic lateral sclerosis”workshop contributors.J Neurol Sci,1994,124:96-107.
[17]Daube JR.Electrodiagnostic studies in amyotrophic lateral sclerosis and other motor neuron didorders.Muscle & Nerve.2000:1488-1502.
[18]Dan YF,Leoh TH,Tan YE,Lo YL,et al.Ecrement in area of muscle responses to repetitive nerve stimulation.Muscle Nerve,2003,27:494-496.
[1]Berridge MJ.Unlocking the secrets of cell signaling.Annu Rev Physiol,2005,67:1-21
[2]Maeda N,Kawasaki T,Nakade S,et al.Structural and functional characterization of inositol 1,4,5-trisphosphate receptor channel from mouse cerebellum.J Biol Chem,1991,266:1109-1116.
[3]Cardenas C,Liberona JL,Molgo J,et al.1 Nuclear inositol 1,4,52 trisphosphate receptors regulate local Ca2+ transients and modulate cAMP response element binding protein phosphorylation.J Cell Sci,2005,118:3131-3140.
[4]Taylor CW,da Fonseca PC,Morris EP.IP3 receptors:the search for structurel Trends Biochem Sci,2004,29:210-219.
[5]Bosanac I,Alattia JR,Mai TK,et al.Structure of the inositol 1,4,52triphosphate receptor binding core in complex with its ligand.Nature,2002,420:696-700.
[6]Vazquez G,Wedel BJ,Bird GS,et al.An inositol 1,4,5 trisphosphate receptor2 dependent cation entry pathway in DT40 B lymphocytesl EMBO J,2002,21:4531-4538.
[7]Ideatifietion of cycle ADP-ribose—binding proteins by photo affnity labeling.Walseth TF,Aarhus R.Kerr J A,et al.J Biol Chem,1993,268:266-286.
[8]Thorburn A.Death receptor-induced cell killing,2004,16:139-144.
[9]Li P,Nijhawan D,Budihardjo I,Srinivasula SM,et al.Cytochrome c and dATP-dependent formation of Apaf-l/caspase-9 complex initiates an apoptotic protease cascade.Cell,1997,91:479-489.
[10]Strasser A,O'Connor L,Dixit VM.Apoptosis signaling.Annu Rev Biochem.2000,69:217-245.
[11]Schanne FA,Kane AB,Young EE,Farber JL.Calcium dependence of toxic cell death:a final common pathway.,1979,206:700-702.
[12]Orrenius S,Zhivotovsky B,Nicotera P.Regulation of cell death:the calcium-apoptosis link.Nat Rev Mol Cell Biol.2003,4:552-565.
[13]Leonard JP,Salpeter MM.Agonist-induced myopathy at the neuromuscular junction is mediated by calcium.J Cell Biol.1979,82:811-819.
[14]Crompton M,Costi A,Hayat L.Evidence for the presence of a reversible Ca2+-dependent pore activated by oxidative stress in heart mitochondria.Biochem J,1987,245:915-918.
[15]Berridge MJ,Lipp P,Bootman MD.The versatility and universality of calcium signalling.Nat Rev Mol Cell Biol,2000,1:11-21.
[16]Jayaraman T,Marks AR.T cells deficient in inositol 1,4,5-trisphosphate receptor are resistant to apoptosis.Mol Cell Biol.1997,17:3005-3012.
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