Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autosomal dominant inheritance is exhibited by about 10% of cases of amyotrophic lateral sclerosis (ALS), a paralytic disorder characterized by the death of motor neurons in the brain and spinal cord. A subgroup of these familial cases are linked to mutations in the gene which codes for Cu/Zn superoxide dismutase (SOD1). We report three additional mutations occurring in the SOD1 gene in ALS patients and two single base pair variant changes. The single base pair change in an ALS family causes a glycine 93 to valine substitution, which is the fifth distinct amino acid change reported for the glycine 93 residue. One missense mutation in exon 5 would substitute neutral valine for the negatively-charged aspartate 124 (aspartate 124 to valine). An individual with an apparently sporadic case of ALS carries a three base pair deletion in exon 5 of the SOD1 gene. These three mutations bring to 38 the total number of distinct SOD1 mutations associated with familial ALS.
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PMID:Three novel mutations and two variants in the gene for Cu/Zn superoxide dismutase in familial amyotrophic lateral sclerosis. 893

Accumulated evidence implies that mutations in the gene coding for Cu/Zn superoxide dismutase (SOD) are associated with the pathogenesis of the familial form of amyotrophic lateral sclerosis (ALS). The clinical and pathological similarities of the familial and the sporadic forms of the disease may suggest that abnormal SOD activity takes also part in the pathogenesis of sporadic ALS. We therefore measured serum SOD activity in fifteen sporadic ALS patients. Mean serum SOD activity was 1.15 +/- 0.40 u/ml in ALS patients, 1.50 +/- 0.45 u/ml. in patients with other neurological disorders and 1.45 +/- 0.45 u/ml in.healthy controls (p < 0.021 and p < 0.031 respectively). If this sporadic ALS-related reduction in serum SOD activity will be confirmed in the diseased nervous system tissue, it may suggest that abnormal SOD activity is also associated with the motor neuron damage in the sporadic form of ALS.
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PMID:Serum Cu/Zn superoxide dismutase activity is reduced in sporadic amyotrophic lateral sclerosis patients. 941 46

This report concerns a case of sporadic amyotrophic lateral sclerosis (ALS) with dementia and Lewy body-like hyaline inclusions (LBHIs). The patient was a 70-year-old woman who initially showed memory disturbance and later developed bulbar palsy, muscle atrophy and weakness. The total clinical course was 51 months. The postmortem examination revealed superficial sponginess and subcortical gliosis in the frontotemporal cortices. Ubiquitin-positive intraneuronal inclusions were found in small cortical neurons of the frontotemporal lobe. Neuronal loss was marked in the spinal anterior horn with degeneration of the pyramidal tracts. The anterior horn cells had ubiquitin-immunoreactive skein-like inclusions and Bunina bodies. LBHIs were present in the lumbar horn; ultrastructurally they were composed of randomly arranged thick filamentous structures studded with granules. The LBHIs were intensely stained with anti-ubiquitin antibody. As in familial ALS and in certain cases of sporadic ALS, some of these inclusions reacted with an antibody against Cu/Zn superoxide dismutase, the enzyme whose gene was recently found to be mutated in some forms of familial ALS.
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PMID:Sporadic amyotrophic lateral sclerosis with dementia and Cu/Zn superoxide dismutase-positive Lewy body-like inclusions. 899 56

The mutant Cu/Zn superoxide dismutase (SOD1) associated with familial amyotrophic lateral sclerosis (FALS) with a 2 bp deletion was produced in two protein expression systems. The mutant SOD1, expressed as a fusion protein in E. coli, had immunoreactivity to an anti-human SOD1 antibody but no SOD activity. It was more susceptible to proteolysis and its immunoreactivity decreased more rapidly than the wild type. The mutant SOD1, expressed in Cos1 cells, was not detected by either SOD activity staining or Western blot analysis, although expression of its mRNA was confirmed. These results suggest that the mutant SOD1 is seriously unstable in mammalian cells.
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PMID:Instability of expressed Cu/Zn superoxide dismutase with 2 bp deletion found in familial amyotrophic lateral sclerosis. 900 May 23

Iron accumulation in the basal ganglia and spheroid formation are pathological hallmarks of Hallervorden-Spatz disease (HS). Since an overaccumulation of iron (iron thesaurosis) that exceeds the binding capacity of ferritin could cause oxidative damage, we studied the possible role of oxidative stress in the pathogenesis of HS. The basal ganglia and spinal cord from patients with HS were investigated at autopsy, using histochemistry for iron and immunohistochemistry for Cu/Zn superoxide dismutase (SOD1), Mn superoxide dismutase (SOD2) and ferritin. SOD1-like immunoreactivity (IR), SOD2-IR and ferritin-IR occurred frequently in spheroids observed in the basal ganglia, and associated iron accumulation indicated the possible existence of increased oxidative stress in HS patients. Spheroids in the spinal cord showed intense SOD1-IR and SOD2-IR in HS, in sharp contrast with the occasional weak SOD1-IR and SOD2-IR observed in spheroids from patients with amyotrophic lateral sclerosis (ALS). Neither increased ferritin-IR nor iron accumulation were observed in spinal spheroids from HS and ALS patients. These data may suggest that, at least in the spinal cord, SOD1-IR and SOD2-IR in spheroids in HS patients do not result from oxidative stress directly related to iron accumulation.
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PMID:Superoxide dismutase-like immunoreactivity in spheroids in Hallervorden-Spatz disease. 900 53

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder of unknown etiology. ALS onset is rare before age 40 and increases with age thereafter. Men are at higher risk than women (ratio 1.3:1). Other than age and gender, the only indisputable risk factor for ALS is genetic susceptibility, with familial cases occurring in about 10% of most case series. Genetic linkage studies have provided evidence that a mutant form of the gene that codes for Cu/Zn superoxide dismutase, an endogenous free radical scavenger, is important in 15-20% of familial cases. Epidemiologic studies have identified associations of sporadic ALS with work in occupations that involve toxicant exposure. Environmental toxicants may act against a background of increased genetic susceptibility; however, genetically acquired biochemical defects have not been identified in sporadic ALS patients. Other epidemiologic theories of disease etiology have emphasized the potential role of physical trauma, electrical shock, and vigorous physical exertion, but evidence regarding these factors is inconsistent.
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PMID:Epidemiology of ALS. 902 Dec 53

We determined the activity, content and mRNA of Cu/Zn superoxide dismutase (SOD1), and copper ion concentration in a Japanese pedigree of familial amyotrophic lateral sclerosis (FALS) having two basepair deletion in the 126th codon of the SOD1 gene. The activity and concentration of the SOD1 were low in red blood cells from the patients and the unaffected subjects with the SOD1 mutation. The SOD activity stain and Western blot analysis of the brain from one of the patients showed low SOD1 activity and the absence of the mutant SOD1. The mRNA due to the mutant SOD1 gene was, however, confirmed. Availability of the copper ions for oxidative catalytic DNA damage in the brain from the patient was 1.9-fold higher than those in the controls. We propose that the decrease of SOD1 activity and increased copper ions play a role in the neuronal death in this FALS.
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PMID:Absence of the mutant SOD1 in familial amyotrophic lateral sclerosis (FALS) with two base pair deletion in the SOD1 gene. 908 86

Cases of familial amyotrophic lateral sclerosis (fALS; a neurodegenerative disorder) have been reported in which the gene for Cu/Zn superoxide dismutase (CuZnSOD) was mutated. Several studies with the fALS mutant CuZnSOD in transgenic mice and cells showed that the fALS mutations act through an as yet undefined dominant gain-of-function mechanism. Wild-type CuZnSOD catalyzes the dismutation of superoxide (O(2)(-).) but also produces hydroxyl radicals (.OH) with H(2)O(2) as substrate. Two laboratories have recently demonstrated that the .OH production ability was preferentially enhanced by the fALS mutant CuZnSOD, suggesting that this might be the function gained in fALS. In this study, we used transgenic CuZnSOD (Tg-CuZnSOD) mice with elevated levels of CuZnSOD to determine whether overexpression of wild-type CuZnSOD was also associated with increased .OH production and impaired muscle function. Enhanced formation of .OH was detected, by spin trapping, in brain and muscle extracts of the Tg-CuZnSOD mice. Three independently derived Tg-CuZnSOD lines showed muscle abnormalities, reflected by altered electromyography (EMG) and diminished performance in the rope grip test. After treatment with paraquat (PQ), a widely used herbicide and O(2)(-).-generating compound, muscle disability significantly deteriorated in Tg-CuZnSOD mice but not in control mice. The results indicate that elevated levels of CuZnSOD cause indigenous long-term oxidative stress leading to impairment of muscle function. These findings may provide valuable clues about the concurred role of indigenous oxidative stress and exogenous agents in the etiology of sporadic ALS and several other neurodegenerative diseases in which a specific subset of neurons is affected.
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PMID:Oxidative stress mediates impairment of muscle function in transgenic mice with elevated level of wild-type Cu/Zn superoxide dismutase. 910 73

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons in the spinal cord and brain stem. About 10% of all ALS cases are familial (FALS), inherited in an autosomal dominant manner. One fifth of FALS patients carry mutations in the Cu/Zn superoxide dismutase (SOD1) gene, and several lines of transgenic mice have been engineered to express mutant forms of the SOD1 gene that are linked to FALS. Significantly, many of these transgenic lines of mice develop a motor neuron disease (MND) that resembles human FALS. Oxidative stress induced by human SOD1 mutations is believed to play an important role in the pathogenesis of FALS and the FALS-like MND seen in the mutant SOD1 transgenic mice. For example, two lines of these mice showed prominent degeneration of mitochondria and endoplasmic reticulum in spinal cord neurons. Furthermore, recent studies have shown that neurofilament (NF)-rich spheroids. Lewy body-like NF inclusions, altered ubiquitin immunoreactivity, and Golgi fragmentation occur in the spinal cord motoneurons of these mutant SOD1 transgenic mice. Because these lesions recapitulate hallmark abnormalities of human ALS, mutant SOD1 transgenic mice provide a useful model for studies designed to elucidate the pathogenesis of ALS. Furthermore, transgenic mice that overexpress NF proteins also develop a clinical and pathologic phenotype similar to human MND, and polymorphisms in an NF gene have been linked to patients with ALS. Collectively, these observations implicate NF protein abnormalities in the pathogenesis of this disorder. Accordingly, this review summarizes recent insights into mechanisms of motor neuron degeneration in ALS that have emerged from studies of these new animal models of this neurodegenerative disease.
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PMID:Oxidative stress, mutant SOD1, and neurofilament pathology in transgenic mouse models of human motor neuron disease. 911 7

We report on an Austrian pedigree with autosomal dominant amyotrophic lateral sclerosis (ALS), diagnosed in six patients from two generations. The only surviving clinically affected family member was examined in our ALS clinic. Historical information on other affected individuals was obtained from knowledgeable family members. The mean +/- S.D. age of onset of the disease was 54 +/- 6.9 years, with a range of 43-66 years. The duration of the index patient's disease until death was 8 months. Using single strand conformational polymorphism (SSCP) analysis, we studied the index patient's exons 1, 2 and 4 of the Cu/Zn superoxide dismutase gene (SOD1) on chromosome 21. A variant banding pattern was observed for exon 1. Sequencing studies showed a previously undescribed T to A missense mutation at position 8 in exon 1 of the SOD1 gene. This mutation results in the elimination of an Eco57I restriction site. Whereas the index patient was heterozygous for this restriction site, 50 unrelated healthy controls and an unaffected brother were not. The mutation lies in a region involved in dimer contact in the three-dimensional structure of the SOD1 protein. This region comprises other known sites for ALS-causing mutations.
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PMID:A novel SOD1 mutation in an Austrian family with amyotrophic lateral sclerosis. 913 52


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