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)

To determine the possible role of Cu/Zn superoxide dismutase (SOD1) in the pathophysiology of sporadic amyotrophic lateral sclerosis (SALS), we measured SOD1 activity in red blood cell lysates in patients with SALS. SOD1 activity in red blood cell lysates was independent of age and sex in control patients, and no significant difference was found between the levels of SOD1 activity in controls (1174.8 +/- 213, n = 29) and SALS patients (1203.4 +/- 214, n = 27). These results suggest that point mutations in the SOD1 gene are apparently unrelated to SALS.
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PMID:Red blood cell Cu/Zn superoxide dismutase activity in sporadic amyotrophic lateral sclerosis. 769 87

Familial amyotrophic lateral sclerosis (FALS) is an autosomal dominant, adult onset, neurological disorder caused by the degeneration of motor neurons of the cortex, brainstem and spinal cord. Recently, the defective gene in some FALS families was identified as the Cu/Zn superoxide dismutase (SOD1) gene. However, SOD1 mutations are present in approximately 20% of patients with FALS. We have tested the genes of two more free radical detoxifying enzymes, Mn superoxide dismutase (SOD2) and catalase by single strand conformation analysis (SSCA) for mutations in the remaining FALS cases. No mutations were found in the catalase enzyme in 73 unrelated FALS cases; mutations were not detected in the 66% of the SOD2 gene analyzed. FALS does not appear to be caused by mutations in the SOD2 nor the catalase genes.
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PMID:Absence of mutations in the Mn superoxide dismutase or catalase genes in familial amyotrophic lateral sclerosis. 771 45

Some cases of autosomal-dominant familial amyotrophic lateral sclerosis (FALS) have been associated with mutations in SOD1, the gene that encodes Cu/Zn superoxide dismutase (Cu/Zn SOD). We determined the concentrations (microgram of Cu/Zn SOD/mg of total protein), specific activities (U/microgram of total protein), and apparent turnover numbers (U/mumol of Cu/Zn SOD) of Cu/Zn SOD in erythrocyte lysates from patients with known SOD1 mutations. We also measured the concentrations and activities of Cu/Zn SOD in FALS patients with no identifiable SOD1 mutations, sporadic ALS (SALS) patients, and patients with other neurologic disorders. The concentration and specific activity of Cu/Zn SOD were decreased in all patients with SOD1 mutations, with mean reductions of 51 and 46%, respectively, relative to controls. In contrast, the apparent turnover number of the enzyme was not altered in these patients. For the six mutations studied, there was no correlation between enzyme concentration or specific activity and disease severity, expressed as either duration of disease or age of onset. No significant alterations in the concentration, specific activity, or apparent turnover number of Cu/Zn SOD were detected in the FALS patients with no identifiable SOD1 mutations, SALS patients, or patients with other neurologic disorders. That Cu/Zn SOD concentration and specific activity are equivalently reduced in erythrocytes from patients with SOD1 mutations suggests that mutant Cu/Zn SOD is unstable in these cells. That concentration and specific activity do not correlate with disease severity suggests that an altered, novel function of the enzyme, rather than reduction of its dismutase activity, may be responsible for the pathogenesis of FALS.
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PMID:Superoxide dismutase concentration and activity in familial amyotrophic lateral sclerosis. 772 23

Although about 5 to 10% of amyotrophic lateral sclerosis (ALS) cases are familial, the pathophysiology of ALS remains unknown. A new point mutation in exon 4 of the Cu/Zn superoxide dismutase (SOD) gene, resulting in an amino acid substitution of leucine84 by valine (L84V), in a Japanese patient with familial ALS (FALS) was identified. This L84V substitution was not observed in 57 normal Japanese control subjects. The enzymatic activities of Cu/Zn SOD of skin fibroblasts were significantly reduced to 75% of the control level in the affected patient. The progression of the disease with this mutation is very rapid, but the age at onset varies with sex or generation within a family.
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PMID:Variance of age at onset in a Japanese family with amyotrophic lateral sclerosis associated with a novel Cu/Zn superoxide dismutase mutation. 775 63

Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset, neurodegenerative disorder characterized by the death of large motor neurons from the cerebral cortex, brainstem, and spinal cord. The etiology of ALS remains unknown; however, approximately 10% of the cases are familial in nature. In the majority of these families, the mode of transmission is autosomal dominant. Recently, linkage of an autosomal dominant familial ALS (FALS) gene to the locus ALS1 on chromosome 21q was established. In addition, evidence was provided for genetic heterogeneity, with approximately 55% of families most likely linked to chromosome 21. The development of a number of highly informative simple sequence repeat polymorphisms in the region of linkage-21q21 through 21q22.1-has permitted us to confirm both the assignment of ALS1 to 21q and the genetic heterogeneity of FALS. In addition, we have been able to refine the mapping of ALS1, based on recombination events in two of the linked families. Flanking markers for the FALS gene are D21S213 on the centromeric side and D21S219 on the telomeric side. The candidate region is approximately 4 Mb and contains the genes copper/zinc superoxide dismutase (CuZnSOD); the fourth member of the class II cytokine receptor family (CRF2-4); and the interferon-alpha receptor (IFNAR).
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PMID:Identification of flanking markers for the familial amyotrophic lateral sclerosis gene ALS1 on chromosome 21. 780 55

Mutations of the Cu/Zn superoxide dismutase (SOD-1) gene were recently implicated in the pathogenesis of familial amyotrophic lateral sclerosis (ALS). We measured SOD-1 mRNA levels in motorneurons of the more common sporadic form of the disease and found a 42% increase in ALS motorneurons (P = 0.058) as compared with controls. These results suggest that oxidative stress may also play a role in the pathogenesis of sporadic ALS.
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PMID:Copper/zinc superoxide dismutase mRNA levels are increased in sporadic amyotrophic lateral sclerosis motorneurons. 782 Jun 74

Cu/Zn superoxide dismutase (SOD)-like immunoreactivity (LI) was found within Lewy body-like inclusions (LBIs) in the spinal cords of patients with sporadic amyotrophic lateral sclerosis (ALS) by using an antibody to human Cu/ZnSOD. LBIs were detected in the anterior horn cells in 10 of 20 patients with sporadic ALS. In each of these patients, 7 to 60% of LBIs showed Cu/ZnSOD-LI. No Cu/ZnSOD-LI was detected in intact neurons and glia in the 20 ALS patients, as well as in these cells in 10 normal control individuals. The skein-like inclusions and Bunina bodies, which were found in all of the 20 ALS cases, showed no Cu/ZnSOD-LI. Thus, Cu/ZnSOD appears to play roles in the production and/or degradation process of LBIs.
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PMID:Cu/Zn superoxide dismutase-like immunoreactivity in Lewy body-like inclusions of sporadic amyotrophic lateral sclerosis. 784 11

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting motor neurons. Although most cases of ALS are sporadic, approximately 10% are inherited as an autosomal dominant trait. Mutations in the Cu/Zn superoxide dismutase gene (SOD 1) are responsible for a fraction of familial ALS (FALS). Screening our FALS kindreds by SSCP, we have identified mutations in 15 families, of which 9 have not been previously reported. Two of the new mutations alter amino acids that have never been implicated in FALS. One of them affects a highly conserved amino acid involved in dimer contact, and the other one affects the active-site loop of the enzyme. These two mutations reduce significantly SOD 1 enzyme activity in lymphoblasts. Our results suggest that SOD 1 mutations are responsible for > or = 13% of FALS cases.
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PMID:Identification of new mutations in the Cu/Zn superoxide dismutase gene of patients with familial amyotrophic lateral sclerosis. 788 12

Mutations in the gene for Cu/Zn superoxide dismutase (SOD1) have been detected in some families with an autosomal dominant form of amyotrophic lateral sclerosis; these mutations appear to reduce the activity of this enzyme. To determine whether decreased SOD activity could contribute to motor neuron loss, SOD1 was inhibited chronically with either antisense oligodeoxynucleotides or diethyldithiocarbamate in spinal cord organotypic cultures. Chronic inhibition of SOD resulted in the apoptotic degeneration of spinal neurons, including motor neurons, over several weeks. Motor neuron loss was markedly potentiated by the inhibition of glutamate transport. In this paradigm, motor neuron toxicity could be entirely prevented by the antioxidant N-acetylcysteine and, to a lesser extent, by the non-N-methyl-D-aspartate glutamate receptor antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride. These data support the hypothesis that the loss of motor neurons in familial amyotrophic lateral sclerosis could be due to a reduction in SOD1 activity, possibly potentiated by inefficient glutamate transport.
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PMID:Chronic inhibition of superoxide dismutase produces apoptotic death of spinal neurons. 791 Apr 2

Amyotrophic lateral sclerosis (ALS) usually presents as a sporadic disorder of motor neurons. However, familial forms of ALS have been described--autosomal dominant forms (ALS1, ALS3), clinically indistinguishable from the sporadic form, and autosomal recessive forms with early onset and slower progression of symptoms (ALS2). To localize the gene for one of the autosomal recessive forms of ALS, we applied linkage analysis to a large inbred family from Tunisia. A lod score maximum of Zmax = 8.2 at theta = 0.00 was obtained with marker D2S72 located on chromosome 2q33-q35. The fine mapping of this region suggested that the ALS2 locus lies in the 8 cM segment flanked by D2S155 and D2S115.
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PMID:Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35. 792 Jun 63


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