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)

We examined 11 subjects with inherited amyotrophic lateral sclerosis (familial amyotrophic lateral sclerosis, FALS) associated with the most common copper/zinc superoxide dismutase 1 (SOD1) mutation, an alanine for valine substitution in codon 4 (A4V). Autopsies were performed on 5 subjects. The clinical and pathological findings are described and compared with those of 9 sporadic ALS (SALS) subjects. There was no clinical evidence of upper motor neuron (UMN) involvement in 10 FALS A4V subjects. All subjects had lower motor neuron (LMN) signs and electrophysiological evidence of denervation in at least three limbs. All SALS subjects had signs of both UMN and LMN involvement. Pathological studies found severe abnormalities of LMNs in all FALS and SALS subjects. UMN involvement was either absent or mild in the A4V SOD1 FALS subjects and severe in the SALS subjects. Pathological abnormalities in systems other than the motor neurons were more frequent in the FALS A4V subjects. This information suggests that current diagnostic criteria for ALS, requiring dinical evidence for both upper and lower motor neuron involvement, should be modified; ie, the diagnosis should be deemed established when there is evidence of denervation in three or more limbs and a mutation in the gene for SOD1, even without dinical signs of UMN involvement.
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PMID:Limited corticospinal tract involvement in amyotrophic lateral sclerosis subjects with the A4V mutation in the copper/zinc superoxide dismutase gene. 962 37

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the premature death of motor neurons. In approximately 10% of the cases the disease is inherited as autosomal dominant trait (FALS). It has been found that mutations in the Cu/Zn superoxide dismutase gene (SOD1) are responsible for approximately 15% of FALS kindreds. We screened affected individuals from 70 unrelated FALS kindreds and identified 10 mutations, 6 of which are novel. Surprisingly, we have found a mutation in exon 3, which includes most of the active site loop and Zn2+ binding sites, a region where no previous SOD1 mutations have been found. Our data increase the number of different SOD1 mutations causing FALS to 55, a significant fraction of the 154 amino acids of this relatively small protein.
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PMID:Identification of six novel SOD1 gene mutations in familial amyotrophic lateral sclerosis. 970 19

Mutations in copper-zinc superoxide dismutase (CuZn-SOD) have been implicated in the familial form of the motor neuron disease amyotrophic lateral sclerosis (Lou Gehrig's disease). We have expressed and purified recombinant human wild type (hWT) and G93A (hG93A) CuZn-SOD, and we have used pulse radiolysis to measure their superoxide dismutase activities and their rates of deactivation upon exposure to hydrogen peroxide or heat. Both hG93A and hWT CuZn-SOD were found to have high SOD activities in their copper and zinc containing as-isolated forms as well as when remetallated entirely with copper (CuCu). Rates of deactivation by hydrogen peroxide of the as-isolated hWT and hG93A enzymes were determined and were found to be similar, suggesting that the FALS mutant enzyme is not inactivated at a higher rate than wild type by generation of and subsequent reaction with hydroxyl radical, .OH, when it is in the CuZn form. However, rates of deactivation by hydrogen peroxide of the CuCu derivatives of both hWT and hG93A were significantly greater than those of the copper and zinc containing as-isolated enzymes. Rates of thermal deactivation were also similar for the mutant and hWT as-isolated CuZn forms but were greater for the CuCu derivatives of both enzymes. Reactions of hydrogen peroxide with the Cu(II)Cu(II) derivative of the WT enzyme demonstrate that the copper ion in the copper site is reduced much more rapidly than the copper in the zinc site, leading to the conclusion that reaction of hydrogen peroxide with Cu(I) in the copper site is the source of deactivation in the CuCu as well as the CuZn enzymes.
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PMID:Reactions of hydrogen peroxide with familial amyotrophic lateral sclerosis mutant human copper-zinc superoxide dismutases studied by pulse radiolysis. 980 64

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative neuromuscular disease that shows familial, autosomal dominant inheritance in 10%-15% of cases. Previous genetic analysis of one large family linked a recessive form of familial ALS (FALS-AR type 3) to the chromosome 2q33-35 region. Using additional polymorphic markers, we have narrowed the size of the linked region to approximately 1.7 cM by linkage and haplotype analysis. We have also established a yeast artificial chromosome contig across the locus that covers an approximate physical distance of 3 million bases. Based on this contig, genes and expressed sequences that map near the 2q33 region have been examined to determine whether they are located within this ALS2 candidate locus. Five identified genes and 34 expressed sequence tags map within the region defined by crossover analysis and merit further consideration as candidate genes for this disease.
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PMID:Refined mapping and characterization of the recessive familial amyotrophic lateral sclerosis locus (ALS2) on chromosome 2q33. 993 98

Amyotrophic lateral sclerosis (ALS) is a progressive disorder resulting from degeneration of motor neurons in the brain and spinal cord. Sporadic ALS (SALS) accounts for the majority of patients and the familial form (FALS) represents fewer than 10% of all cases. Since it was found that there are Cu/Zn superoxide dismutase (SODI) gene mutations in 20% of FALS patients and that FALS and SALS patients show similar clinical features, it has been postulated that both may share a common physiopathological mechanism. We studied Cu/Zn SOD1 activity in cytosolic extracts of erythrocytes from 125 normal individuals and 40 SALS patients. We found that enzyme activity does not change with age in control subjects and tends to decrease in most SALS patients older than 60 years. A subpopulation of five SALS patients had significantly increased SOD1 activity; four of these patients over 70 years old. There was no correlation between enzyme activity and time of onset of the disease, or clinical forms of the illness. The variation in SOD1 activity in ageing SALS patients compared with younger patients suggests that they may undergo an oxidative disbalance contributing to the development of the disease.
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PMID:Cu/Zn superoxide dismutase activity at different ages in sporadic amyotrophic lateral sclerosis. 1006 66

We report the absence of superoxide dismutase (SOD-1) gene mutations in 30 patients with amyotrophic lateral sclerosis (ALS) including individuals with a confirmed family history of ALS (familial ALS/FALS), ALS with an unclear family history (UFALS) and sporadic ALS (SALS). Single strand conformation polymorphism (SSCP) and sequence analysis of the 5 SOD-1 gene exons were undertaken to improve the accuracy of the mutation detection. Our preliminary data appear to diverge from the results of studies by other groups using different populations. We discuss the possible reasons for this disparity and the apparent heterogeneous distribution of ALS with SOD-1 gene mutations among different ethnic groups.
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PMID:Heterogeneous distribution of amyotrophic lateral sclerosis patients with SOD-1 gene mutations: preliminary data on an Italian survey. 1020 88

Amyotrophic lateral sclerosis (ALS), whether sporadic or familial (FALS), is a progressive, fatal neurodegenerative disorder involving the motor neurons of the cortex, brain stem, and spinal cord. In some studies, the male/female ratio of ALS patients was as high as 2 to 1. In FALS mice, disease onset and mortality were earlier among males than among females. This sexual dimorphism was due to estrogen, as treatment with genistein, a phytoestrogen, eliminated the observed sexual dimorphism in FALS mice. Genistein treatment also protected against oxygen singlet-induced cerebral damage in vivo. However, sexual dimorphism was not observed in this model of stroke; and genistein was equally effective in males and females. These data suggest that genistein has both estrogen-dependent and estrogen-independent neuroprotective activities and it should be investigated as a prophylactic agent against pathologic conditions such as ALS and stroke.
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PMID:Genistein is neuroprotective in murine models of familial amyotrophic lateral sclerosis and stroke. 1032 46

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder caused by degeneration of motor neurons of the spinal cord and brain. The majority of ALS cases are sporadic (SALS). However, in 10-15% of ALS cases the disease is inherited as an autosomal dominant trait (familial ALS or FALS). We used a non-radioactive SSCP method, in combination with solid phase sequencing, to screen the entire SOD1 (Cu/Zn superoxide dismutase) coding region and flanking intronic sequences for mutations. Twenty-three patients from 11 ALS families and 69 SALS patients of Belgian origin were studied. Three different mutations were identified (L38V, D90A and G93C) in seven families. Importantly, the D90A was only found in the heterozygous state. In addition two single base pair variants (IVS1 + 19G > A and AAC139 AAT) were identified in two SALS patients. These results suggest that the SOD1 analysis is useful in FALS but less so in SALS cases. The SSCP analysis has proved fast and reliable for this purpose.
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PMID:Mutational analysis of the Cu/Zn superoxide dismutase gene in 23 familial and 69 sporadic cases of amyotrophic lateral sclerosis in Belgium. 1043 68

Effects of ex vivo GDNF gene delivery on the degeneration of motoneurons were studied in the G1H transgenic mouse model of familial ALS carrying a human superoxide dismutase (SOD1) with a Gly93Ala mutation (Gurney et al., 1994). Retroviral vectors were made to produce human GDNF or E. coli beta-galactosidase (beta-Gal) by transient transfection of the Phoenix cell line and used to infect primary mouse myoblasts. In 6-week-old G1H mice, 50,000 myoblasts per muscle were injected bilaterally into two hindlimb muscles. Untreated G1H and wild-type mice served as additional controls. At 17 weeks of age, 1 week before sacrifice, these muscles were injected with fluorogold (FG) to retrogradely label spinal motoneurons that maintained axonal projections to the muscles. There were significantly more large FG-labeled alpha motoneurons at 18 weeks in GDNF-treated G1H mice than in untreated and beta-Gal-treated G1H mice. A morphometric study of motoneuron size distribution showed that GDNF shifted the size distribution of motoneurons toward larger cells compared with control G1H mice, although the average size and number of large motoneurons in GDNF-treated mice were less than that in wild-type mice. GDNF also prolonged the onset of disease, delayed the deterioration of performance in tests of motor behavior, and slowed muscle atrophy. Quantitative, real-time RT-PCR and PCR showed persistence of transgene mRNA and DNA in muscle for up to 12 weeks postgrafting. These observations demonstrate that ex vivo GDNF gene therapy in a mouse model of FALS promotes the survival of functional motoneurons, suggesting that a similar approach might delay the progression of neurodegeneration in ALS.
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PMID:Intramuscular grafts of myoblasts genetically modified to secrete glial cell line-derived neurotrophic factor prevent motoneuron loss and disease progression in a mouse model of familial amyotrophic lateral sclerosis. 1044 25

To explore whether reactive oxygen species (ROS) play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS), a unique microdialysis or microcannula sampling technique was used in mice transfected with a mutant Cu,Zn-superoxide dismutase (SOD1) gene from humans with familial ALS, mice transfected with the normal human SOD1 gene, and normal mice. We demonstrate for the first time that the levels of hydrogen peroxide (H(2)O(2)) and the hydroxyl radical ((.)OH) are significantly higher, and the level of the superoxide anion (O(2)(.-)) is significantly lower in ALS mutant mice than in controls, supporting by in vivo evidence the hypothesis that the mutant enzyme catalyzes (.)OH formation by the sequence: O(2)(.-) --> H(2)O(2) --> (.)OH. This removes doubts regarding the relevance of elevated ROS in FALS raised by in vitro experiments. The levels of oxidation products are also significantly higher in the mutant mice than in controls, consistent with some previous reports. Only the superoxide concentration differs between two controls among all the measurements. Our findings correlate in vivo a gene mutation to both elevated H(2)O(2) and (.)OH and increased oxidation of cellular constituents. The elevated H(2)O(2) in mutant mice indicates impairment of its detoxification pathways, perhaps by changed interactions between SOD1 and H(2)O(2) detoxification enzymes.-Liu, D., Wen, J., Liu, J., Li, L. The roles of free radicals in amyotrophic lateral sclerosis: reactive oxygen species and elevated oxidation of protein, DNA, and membrane phospholipids.
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PMID:The roles of free radicals in amyotrophic lateral sclerosis: reactive oxygen species and elevated oxidation of protein, DNA, and membrane phospholipids. 1059 79


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