Astrocytic hyaline inclusions contain advanced glycation endproducts in familial amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutation: immunohistochemical and immunoelectron microscopical analyses

To clarify the neuropathological significance of the deposition of N ^ɛ -carboxymethyl lysine (CML), an advanced glycation endproduct, in astrocytic hyaline inclusions in familial amyotrophic lateral sclerosis (FALS), autopsy specimens from five members of two different families who had the superoxide dismutase 1 (SOD1) gene mutations were analysed. Immunohistochemically, most of the neuronal and astrocytic hyaline inclusions were intensely stained by the antibody against CML. The distributions and intensities of the immunoreactivities for CML and SOD1 were similar in the inclusions in both cell types. Immunoelectron microscopy showed that both inclusions consisted of CML-positive granule-coated fibrils and granular materials. No significant CML or SOD1 immunoreactivity was observed in the neurons and astrocytes of the normal control subjects. Our results suggest that astrocytic hyaline inclusions contain CML and SOD1 in FALS patients with SOD1 gene mutations, and that the formation of CML-modified protein (probably CML-modified SOD1) is related to the cell degeneration. Received: 3 July 1998 / Revised, accepted: 21 September 1998     

中国家族性肌萎缩侧索硬化患者超氧化物歧化酶1基因突变分析

目的 肌萎缩侧索硬化(ALS)是上、下运动神经元退变引起的一种进行性致死性疾病,家族性ALS占10%～20%,铜锌SOD1基因突变存在于20%的家族性患者和少数散发性患者,某些突变还具有地域分布和特殊临床表型的规律性.我们旨在分析我国3个家族性ALS家系SOD1基因突变特点,并与不同国家和地区SOD1突变比较,分析其临床表型的特征性.方法 提取患者外周血基因组DNA,采用SOD1基因的5对引物对其5个外显子进行PCR扩增,产物直接测序.归纳整理患者临床表型资料,进行表型-基因型关联分析.结果 家系1中SOD1基因外显子2的H46R杂合突变,即CAT→CGT,使得46位由编码组氨酸变为编码精氨酸.先证者48岁,女性,43岁起病,主要表现为肢体无力和萎缩.家系中其他3例患者首发症状与先证者相似,病情进展均较缓慢,生存期较长.家系2中先证者20岁,男性,临床表现为延髓性麻痹,病程进展快速,生存期1年,位于3号外显子的杂合突变,即G72C突变.其父亲也出现同样的突变,但无ALS临床表现,其姑姑也有类似病史.家系3中5例患者5号外显子的E133V杂合突变,先证者中年起病,病程逐渐进展,生存期5年.结论 H46R的杂合突变国内未见报道,国外日本人曾多次报道及巴基斯坦有1个家系报道,欧美均未见报道,推测此突变可能为亚裔所特有.G72C突变的家系,临床表型为较早发病,病程进展迅速,生存期1年,突变外显率低导致家族成员不发病,常被诊断为散发病例,因此对于散发性患者及其家族成员同时检测SOD1基因突变十分必要.E133V突变的家系为国际首先报道.     

中国家族性肌萎缩侧索硬化患者超氧化物歧化酶1基因突变与临床表型

目的 通过对43个中国家族性肌萎缩侧索硬化(FALS)家系先证者进行铜、锌超氧化物歧化酶(SOD)1基因突变检测,分析其与临床表型的关系,探讨中国FAIS患者SOD1基因的突变分布谱及其与临床表型之间的关联性.方法 采集2008-2011年确诊的43个FALS家系的临床资料.利用PCR技术和直接测序方法,检测先证者SOD1基因突变,进一步与临床表型做关联分析.结果 43个FALS家系均呈常染色体显性遗传,先证者男女比例为1∶0.6,起病年龄(48.1±11.8)岁,上肢起病23例,占53.5％,下肢起病18例,占41.9％,延髓部起病2例,占4.6％.在10例先证者中共发现9种SOD1突变类型,其中2种为未报道的新突变.9种突变类型中8种为错义突变,1种为缺失突变.SOD1基因突变总检出率为23.3％.结论 中国FALS患者SOD1基因突变类型由原来的11种增加到19种.具有SOD1突变的FALS患者以下运动神经元损害为主.大多数SOD1突变的临床表型在不同的家系甚至同一家系中变异均较大.     

Familial amyotrophic lateral sclerosis with a mutation in the Cu/Zn superoxide dismutase gene

Several missense mutations within exons 1, 2, 4 and 5 of the gene for Cu/Zn-binding superoxide dismutase (SOD1) have been discovered to be involved in the development of chromosome 21q-linked familial amyotrophic lateral sclerosis (FALS). We describe here an autopsied patient with FALS, in whom we have recently identified a novel missense mutation in exon 1 of the SOD1 gene. The neuropathological findings were compatible with those described previously in patients with FALS with posterior column involvement. This suggests that mutations of the SOD1 gene may be responsible for this form of FALS.Supported in part by a research grant for CNS degenerative discases from the Ministry of Health and Welfare, Japan     

Neuropathology of familial amyotrophic lateral sclerosis patients with superoxide dismutase 1 gene mutation

More than 60 mutations of the copper/zinc superoxide dismutase 1 (SOD1) gene have been identified. We are aware of 19 reported autopsied cases of familial amyotrophic lateral sclerosis (ALS) linked to these mutations. A review of these cases disclosed remarkable heter-ogenicity of ALS, not only in molecular genetics but also clinicopathologically. However, it is noteworthy that all patients with alanine to valine substitution at codon 4 (A4V) mutation of SOD1 in familial ALS apparently disclose a distinct characteristic phenotype. All these patients manifested a rapid course of progressive muscular atrophy and died less than 1 year after the onset of illness. Microscopic findings were essentially identical in three cases: (i) marked loss of anterior horn neurons and Clarke's nuclei; (ii) the presence of intracytoplasmic Lewy body like hyalin inclusions and cord-like enlargements of the processes in some of the affected neurons. The Lewy body like inclusions were also recognized by antibodies to phos-phorylated neurofilaments protein, ubiquitin, and SOD1. Under electron microscopy, the inclusions consisted of a network of 10 nm neurofilaments intermingled with ill-defined coarse linear structures; (iii) degeneration of spinocerebellar tracts, and middle root zone of the posterior column.     

Red cell superoxide dismutase activity in sporadic amyotrophic lateral sclerosis

Specific biologic markers are not available for definitive diagnosis and monitoring of disease progression in sporadic amyotrophic lateral sclerosis (SALS). Oxidative stress plays a role in ALS pathogenesis. The purpose of this study was to determine the association between Cu/Zn superoxide dismutase (SOD1) activity, diagnosis and prognosis. The present study included 25 SALS patients (SALS group; age 51+/-12 years) and 10 healthy subjects (age 45+/-5 years) as a control group. Patients were divided into groups representing four levels of diagnostic certainty of ALS in accordance with the El Escorial Revisited criteria. The disease state was determined using the modified ALS health state scale of Riviere et al. (Arch Neurol 1998:55;526-8). Red-cell SOD1 activity was determined by spectrophotometry. SOD1 activity in red cells was compared statistically with diagnostic criteria and disease state. Red cell SOD1 activity was high in all SALS patients, but there was no significant association between enzyme activity and diagnostic criteria and disease state. In this preliminary study, we did not find any correlation between SOD1 activity level and diagnosis or prognosis. Measured SOD1 activity sometimes supports ALS diagnosis, but it is neither a specific nor a prognostic factor.     

Transgenic mouse model for familial amyotrophic lateral sclerosis with superoxide dismutase‐1 mutation

Familial amyotrophic lateral sclerosis (ALS) with mutations in the gene for superoxide dismutase‐1 (SOD1) is clinicopathologically reproduced by transgenic mice expressing mutant forms of SOD1 detectable in familial ALS patients. Motor neuron degeneration associated with SOD1 mutation has been thought to result from a novel neurotoxicity of mutant SOD1, but not from a reduction in activity of this enzyme, based on autosomal dominant transmission of SOD1 mutant familial ALS and its transgenic mouse model, clinical severity of the ALS patients independent to enzyme activity, no ALS‐like disease in SOD1 knockout or wild‐type SOD1‐over‐expressing mice, and clinicopathological severity of mutant SOD1 transgenic mice dependent on transgene copy numbers. Proposed mechanisms of motor neuron de‐generation such as oxidative injury, peroxynitrite toxicity, cytoskeletal disorganization, glutamate excitotoxicity, disrupted calcium homeostasis, SOD1 aggregation, car‐bonyl stress and apoptosis have been discussed. Intracy‐toplasmic vacuoles, indicative of increased oxidative damage to the mitochondria and endoplasmic reticulum, in the neuropil and motor neurons appear in high expressors of mutant SOD1 transgenic mice but not in low expressors of the mice or familial ALS patients, suggesting that overexpression of mutant SOD1 in mice may enhance oxidative stress generation from this enzyme. Thus, transgenic mice carrying small transgene copy numbers of mutant SOD1 would provide a beneficial animal model for SOD1 mutant familial ALS. Such a model would contribute to elucidating the pathomechanism of this disease and establishing new therapeutic agents.     

A novel SOD1 gene mutation in a Korean family with amyotrophic lateral sclerosis

BACKGROUND: Superoxide dismutase 1 (SOD1) gene mutations are responsible for approximately 20% of all familial amyotrophic lateral sclerosis (ALS) cases. However, these cases, especially those with SOD1 gene mutations, have not been reported in Korea. OBJECTIVES: The SOD1 gene in Korean family with ALS was screened for potential mutations and the clinical data was collected. MATERIALS AND METHODS: The clinical histories and neurological findings of the family members were obtained. Genomic DNA was isolated from the leukocytes of whole blood samples and the coding region of the SOD1 gene was analyzed by PCR and sequencing. RESULTS: The family with ALS showed a novel missense mutation in the SOD1 gene, which was heterozygous for the mutation, GGC to GTT, causing the substitution of valine for glycine at codon 10 (Gly10Val) in exon 1. Clinically, the patients exhibited early onset and rapid disease progression. CONCLUSIONS: Familial ALS with a novel Gly10Val mutation in the SOD1 gene showed severe clinical features. The mutation lies in a region involved in a dimer contact in the three-dimensional structure of the SOD1 protein. This study expands the number of ALS-associated SOD1 gene mutations.     

Coexistence of Huntington’s disease and familial amyotrophic lateral sclerosis: case presentation

We present the clinical, molecular genetic and neuropathological findings of an 81-year-old man with concurrent Huntington’s disease (HD) and familial amyotrophic lateral sclerosis (FALS). His mother had been diagnosed clinically as having ALS. There was no known family history of HD, but a maternal uncle had died in a chronic care psychiatric hospital. The diagnosis of HD in the patient was suspected at age 66, after 8 years of personality change, hallucinations, agitation, cognitive decline and choreoathetosis. No symptoms of motor neuron disease were noticed at that time, but progressive weakness developed later. Postmortem examination revealed cerebral atrophy, marked atrophy of basal ganglia (grade 3), and atrophy of brain stem and spinal cord. The neostriatum displayed massive neuronal loss and gliosis. The neocortex showed changes characterisitic of Alzheimer’s disease. Pathological lesions also included loss of neurons and gliosis in the anterior horns, Clarke’s columns and the hypoglossal nuclei; degeneration of the lateral corticospinal tracts, dorsal spinocerebellar tracts and fasciculus gracilis; and rare Bunina bodies and ubiquitin-positive filamentous skeins in motor-neuron perikarya. Molecular analysis demonstrated chromosome 4p16.3 expansion of trinucleotide repeats characteristic of HD. Analysis of Cu,Zn superoxide dismutase gene and heavy neurofilament subunit gene failed to demonstrate mutations. The concurrence of HD and FALS in our patient and three previously reported cases did not appear to be associated with cosegregation in other family members. Received: 4 December 1995 / Revised: 19 February 1996 / Accepted: 26 February 1996     

Upregulation of protein-tyrosine nitration in the anterior horn cells of amyotrophic lateral sclerosis

Objective: Neuropathy caused by vincristine toxicity can be diagnosed by electrophysiological examination. The purpose of this study is to demonstrate the electrophysiological features of vincristine toxicity.

Methods: Electrophysiological data from 25 children receiving vincristine treatment and 25 normal controls were evaluated retrospectively. Nerve conduction study (NCS) parameters were compared. Additionally amplitude and negative peak duration (NPD) of distal compound muscle action potentials (CMAP) were analysed by factor analysis.

Results: Distal CMAP amplitudes in the patient group were significantly lower and the distal CMAP NPDs were prolonged. There were no significant differences in other motor and sensory NCS parameters.

Conclusion: Contrary to generally accepted sensorimotor involvement, motor NCS abnormalities are more pronounced in vincristine toxicity. The current study is the first time prolonged distal CMAP NPDs were detected and indicated in vincristine-related weakness, which may be a clue to understanding its mechanism, as well as differentiating from other situations.     

A novel mutation of SOD-1 (Gly 108 Val) in familial amyotrophic lateral sclerosis

A novel mutation of the SOD-1 gene which encodes the enzyme copper-zinc superoxide dismutase was identified in a family manifesting amyotrophic lateral sclerosis (ALS) in three generations. The mutation is a heterozygote point mutation in exon 4, codon 108 (GGA to GTA), predicting the substitution of valine for glycine. The mutation creates a new restriction site for the endonuclease AccI. The mutation was demonstrated in two affected members of the family, who show features of autosomal dominant inheritance of ALS, but variable age at onset ranging from 48 to 72 years. Over 30 different mutations of SOD-1 have now been identified in families with ALS. The definition of the different mutations causing human disease may allow further investigation of their pathogenicity in transgenic animal models, and also offers insight into the variable phenotypic disease expression both within and between genotypes.     

Advanced glycation endproduct-modified superoxide dismutase-1 (SOD1)-positive inclusions are common to familial amyotrophic lateral sclerosis patients with SOD1 gene mutations and transgenic mice expressing human SOD1 with a G85R mutation

To clarify the biological significance of the neuronal Lewy body-like hyaline inclusions and astrocytic hyaline inclusions characteristically found in patients with familial amyotrophic lateral sclerosis with superoxide dismutase-1 (SOD1) gene mutations and in transgenic mice expressing human SOD1 with G85R mutation, the detailed protein composition in both types of inclusions was immunohistochemically analyzed using 45 different antibodies. Both types of inclusions had very strong immunoreactivity for SOD1. The SOD1-positive inclusions in both cell types were also immunoreactive for the insoluble advanced glycation endproducts (AGEs) such as N ^ɛ-(carboxymethyl)lysine (CML), pyrraline and pentosidine: both inclusions in both conditions were ultrastructurally composed of the granule-coated fibrils that had immunoreactivities to CML and pyrraline. Both types of inclusions were negative for stress-response proteins (SRPs), 4-hydroxy-2-nonenal (HNE), acrolein, nitric oxide synthases (NOSs) and nitrotyrosine as representative markers of oxidative stress. The neurons and astrocytes of the normal individuals and non-transgenic mice showed no significant immunoreactivity for SOD1, AGEs, SRPs, HNE, acrolein, NOSs or nitrotyrosine. Our results suggest that a portion of the SOD1 composing both type of inclusions, probably toxic mutant SOD1, is modified by the AGEs, and that the formation of the AGE-modified SOD1 is one of the mechanisms responsible for the aggregation involving no significant oxidative mechanisms. Received: 20 December 1999 / Accepted: 16 February 2000     

An immunohistochemical study of the neuronal expression of manganese superoxide dismutase in sporadic amyotrophic lateral sclerosis

Neuronal expression of manganese superoxide dismutase (MnSOD) in sporadic amyotrophic lateral sclerosis (sALS) was investigated by an immunohistochemical method. The brains and spinal cords from 11 patients with sALS and 20 normal controls (NCs) were used, and the following four nuclei (three motor nuclei and one autonomic nucleus) were examined: the oculomotor nucleus; the hypoglossal nucleus; the cervical motor nucleus; and Onuf's nucleus. Serial sections were stained by the Klüver-Barrera (KB) method and with human-MnSOD-specific antibodies. We counted the total number of neurons visible after KB staining and the total number of positive neurons after immunostaining. The average total number of neurons after KB staining was similar in sALS patients and NCs in both the oculomotor nucleus and Onuf's nucleus, but the number in the hypoglossal and cervical motor nuclei was significantly lower in sALS. The ratio of MnSOD-positive neurons to total neurons visible after KB staining, calculated as an index of the expression of MnSOD, was significantly higher in the oculomotor nucleus and Onuf's nucleus, and lower in the hypoglossal nucleus in sALS patients than in NCs. In the cervical motor nucleus, the ratio in sALS patients did not differ from that in NCs. These results suggest that production of toxic superoxide radicals might be increased in sALS, and that neurons that successfully induce the expression of sufficient MnSOD can survive the disease process, while those failing to activate adequate expression of the enzyme succumb to the toxic effects of the radicals and die.     

Respiratory function in amyotrophic lateral sclerosis

Abstract. The aim of this study was to examine the vital capacity (FVC) and forced expiratory volume in 1 s (FEV 1) in relation to the site of amyotrophic lateral sclerosis (ALS) onset and the duration of the disease. Respiratory involvement is the principal cause of death in ALS patients. The study was conducted at the Department of Neurology, University School of Medicine in Lublin. The study comprised 18 ALS patients. The average duration of ALS was 12 months. The patients were divided into two groups according to the site of ALS onset and into two groups according to the duration of the disease. FVC was significantly higher in the group of patients with a limb onset than in the group of patients with a bulbar onset of the disease. The study has shown respiratory function disturbances in ALS patients. FVC significantly depends on the site of ALS onset but not on the duration of the disease.     

TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation

Recently, 43-kDa TAR DNA-binding protein (TDP-43) was identified as a component of ubiquitinated inclusions (UIs) in sporadic amyotrophic lateral sclerosis (SALS). To clarify whether TDP-43 immunoreactivity is present in neuronal inclusions in familial ALS (FALS), we examined immunohistochemically the brains and spinal cords from four cases of FALS, two with Cu/Zn superoxide dismutase (SOD1) gene mutation and two without, together with three cases of SALS and three control subjects, using two antibodies, one polyclonal and one monoclonal, against TDP-43. Neuropathologically, the SOD1-related FALS cases were characterized by Lewy body-like hyaline inclusions (LBHIs) in the lower motor neurons. On the other hand, the SOD1-unrelated FALS cases showed degeneration restricted to the upper and lower motor neuron systems, with Bunina bodies (BBs) and UIs in the lower motor neurons, being indistinguishable from SALS. No cytoplasmic TDP-43 immunoreactivity was observed in the control subjects or SOD1-related FALS cases; LBHIs were ubiquitinated, but negative for TDP-43. UIs observed in the SALS and SOD1-unrelated FALS cases were clearly positive for TDP-43. BBs were negative for this protein. Interestingly, in these SALS and FALS cases, glial cells were also found to have cytoplasmic TDP-43-positive inclusions. These findings indicate that the histological and molecular pathology of SALS can occur as a phenotype of FALS without SOD1 mutation.     

Molecular analysis of the superoxide dismutase 1 gene in Spanish patients with sporadic or familial amyotrophic lateral sclerosis

We performed a genetic analysis of the Cu/Zn superoxide dismutase gene (SOD1) in Spanish patients with sporadic or familial amyotrophic lateral sclerosis (ALS). We found mutations in 2 of 11 families (18%) with ALS. In addition, 1 of the 87 sporadic ALS patients studied harbored a mutation in the same gene. We identified G37R in exon 2 of the SOD1 gene in 1 family. Another patient, with sporadic ALS, showed a novel N65S in exon 3. In addition, we found a novel I112M in exon 4 in another family. Our data highlight the genetic heterogeneity of patients with ALS harboring mutations in the SOD1 gene and confirm that families with autosomal dominant inheritance of the trait, regardless of their ethnic background, are more likely to carry mutations in such a gene.     

The physician-patient relationship in amyotrophic lateral sclerosis

The principal models of the physician-patient relationship are analysed in terms of their historical development. An outline is given of the clinical, psychological and ethical particularities of the approach to patients with amyotrophic lateral sclerosis. The peculiarities of this disease are so exclusive that they do not resemble other progressive diseases with a negative prognosis, and therefore require an equally exclusive approach to the physician-patient relationship. This approach should not only be informative, scientific and interpretative-deliberative, but most simultaneously be founded on a solid therapeutic alliance aimed at seeking the best interests of the patients while respecting their autonomy as well as their “good” (not only in the sense of physical well-being, but also in terms of respect for their personal values). This is the only way to confront the conflicts that inevitably arise (especially in advanced stages of the disease) without the risks associated with a desire to escape or to adopt extreme solutions (such as euthanasia and therapeutic insistence) and without the risk of burn-out. Received: 5 May 2000 / Accepted in revised form: 6 December 2000     

Familial amyotrophic lateral sclerosis and Cu/Zn superoxide dismutase mutation

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that involves mainly the motor neuron system. Five to 10 percent of the ALS cases are familial; most others are sporadic. Several mutations in the superoxide dismutase-1 (SOD1) gene have recently been shown to be associated with about 20% of familial ALS patients. The reduced enzyme activity of many mutant SOD1 points to the possibility that a loss-of-function effect of the mutant enzyme is responsible for the pathogenesis of the disease. However, this conflicts with the autosomal dominant inheritance of SOD1 mutation-associated ALS and the normal SOD1 activity in homozygous patients in a SOD1-linked ALS family. Current biochemical investigations have provided evidence that mutant SOD1 may catalyze the peroxynitrite-mediated nitration of protein tyrosine residues, release copper and zinc ions, facilitate apoptosis of neurons and have enhanced peroxidase activity. Immunocytochemical studies demonstrated the presence of intense SOD1 immunoreactivity in Lewy body-like inclusions, which are characteristic features of a certain form of familial ALS with posterior column involvement, in the lower motor neurons of patients in ALS families with different SOD1 mutations. More recently, strains of transgenic mice expressing mutant SOD1 have been established. These mice clinicopathologically develop a motor neuron disease mimicking human ALS with the exception of pronounced intraneuronal vacuolar degeneration. The overexpression of wild-type SOD1 in mice has failed to give rise to the disease. Only one transgene for mutant SOD1 is enough to cause motor neuron degeneration and the severity of clinical course correlates with the transgene copy number. These observations in SOD1-linked familial ALS and its transgenic mouse model suggest a novel neurotoxic function of mutant SOD1.     

肌萎缩侧索硬化患者205例的神经传导特点分析

目的 分析肌萎缩侧索硬化(ALS)患者的神经传导和F波特点,并探讨其与肌力、病程和首发部位等之间的关系.方法 收集于1997年1月至2008年5月期间我院门诊或病房收治的ALS患者205例,均采用常规肌电图检查,测定其运动神经传导、F波以及感觉神经传导(SCV).结果 在205例ALS患者中,仅有3例SCV异常,正中神经、尺神经及胫后神经末端潜伏期(DML)延长者分别占24.9%(48/193)、15.3%(25/163)、21.2%(7/33),复合肌肉动作电位(CMAP)波幅下降者分别占57.0%(110/193)、49.7%(81/163)、39.4%(13/33);68.9%(122/177)患者F波出现率下降,其中31.1%(55/177)F波出现率为0,肌力下降者DML、CMAP波幅及F波出现率改变明显.肢体起病组正中神经CMAP波幅下降[81.5%(53/65)]和F波异常率[70.9%(44/62)出现率下降,45.1%(28/62)出现率为0]较延髓部起病者[32.4%(11/34);F波38.2%(13/34)出现率下降,14.7%(5/34)出现率为0]更明显,两组比较差异有统计学意义(x2=23.629、9.753、9.029,均P<0.01);DML异常两组间差异无统计学意义.Logistic回归分析显示CMAP波幅的降低与上肢远端肌力、首发部位、病程显著相关,F波出现率的降低与上肢远端肌力、首发部位相关.结论 ALS患者可出现DML延长和CMAP波幅降低(后者改变更显著),F波出现率明显下降而传导速度相对正常;DML、CMAP波幅及F波出现率的异常与肌力明显相关.首发部位为肢体和(或)上肢远端肌力下降者CMAP波幅及F波异常率更明显.

Abstract：

Objective To investigate the F-wave and nerve conduction in patients with amyotrophic lateral sclerosis (ALS) and explore the correlation between these parameters and muscle strength, disease duration and onset site.Methods The data of outpatients and inpatients diagnosed with ALS were collected in Peking Union Medical College Hospital from January 1997 to May 2008.Standard sensory and motor nerve conduction study of the median nerve, ulnar nerve and tibial nerve was performed in 205 patients with ALS.F-wave velocity and frequency was measured in median nerve.Parameters for analyses included sensory conduction velocity and amplitude, distal motor latency (DML), and compound muscle action potential (CMAP) amplitude.Correlation between muscle strength and DML, CMAP amplitude or F-wave frequency were also explored.Results Delayed DML of the median nerve, ulnar nerve and tibial nerve were found in 24.9% (48/193), 15.3% (25/163), 21.2% (7/33) of patients respectively.Decreased CMAP amplitudes were found in 57.0% (110/193), 49.7% (81/163), 39.4% (13/33) of patients respectively.Decreased F-wave frequency of the median nerve was found in 68.9% (122/177) of patients.The abnormality of DML,CMAP amplitude and F-wave frequency of median nerve were increased in weaker muscles.Decreased median nerve CMAP amplitude (81.5% (53/65)) and F-wave abnormality (decreased persistence 70.9%(44/62), absent responses 45.1% (28/62)) in spinal onset groups were significantly higher than those in bulbar onset groups (CMAP 32.4% (11/34); F-wave: decreased persistence 38.2% (13/34), absent responses 14.7% (5/34); x2 = 23.629, 9.753, 9.029,all P <0.01).Compared with the bulbar onset group,the abnormality of DML in spinal onset group was higher, but not reach statistical significance.Logistic regression revealed a strong direct association between decreased CMAP amplitudes and upperextremity muscles strength, disease duration and onset symptom.Abnormality of F-wave frequency was associated with upper-extremity muscles strength and onset symptom.Conclusions Delayed DML and decreased amplitude of CMAP are found in ALS patients.CMAP amplitude is a sensitive parameter related to the severity of ALS.F-wave velocity is relatively normal while F-wave frequency of the median nerve is correlated with muscle strength.Decreasing CMAP amplitude and F-wave frequency are correlated strongly with muscle weakening,disease duration and symptom onset over limbs.