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 studied the relationships between the superoxide dismutase (SOD) activity, free radical (FR) levels and clinical data in patients with sporadic amyotrophic lateral sclerosis (SALS). The SOD activities and blood FR levels of 16 patients with SALS (mean age 58.6 +/- 10.2 years), 11 with other neurological disease, including myotonic dystrophy (ND, mean age 53.5 +/- 9.1 years), and 15 normal control subjects (mean age 56.2 +/- 7.3 years) were measured. The mean levels of FR in blood from the patients with SALS and ND and the SOD activities in red blood cells (RBC) from those with ND were significantly higher than the corresponding control values. There was a positive correlation between the SOD activities in RBC and blood hydroxyl radical levels in the patients with ND, but neither the patients with SALS nor the controls showed such a correlation. The SALS patients without pyramidal signs showed slow disease progression and their mean RBC SOD activity was significantly higher than the corresponding control value. We compared the FR levels and SOD activities of 8 patients who needed a respirator within 40 months after the onset of SALS (SALS40, mean age 58.7 +/- 9.4 years), 3 who needed a respirator over 100 months after the onset of SALS (SALS100, mean age 58.3 +/- 15.9 years) and the controls. The mean blood FR levels of the SALS40 and SALS100 patients were significantly higher than the corresponding control values. The mean SOD activity in RBC from the SALS100 group was significantly higher than the SALS40 and control group values. Therefore, we concluded that elevated blood FR levels do not induce RBC SOD in SALS patients and that the disease progressed more rapidly in SALS patients with low than high RBS SOD activities.
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PMID:Superoxide dismutase and free radicals in sporadic amyotrophic lateral sclerosis: relationship to clinical data. 874 43

Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder affecting primarily upper and lower motor neurons. In all cases of ALS, approximately 5-10% of cases are familial (FALS). Missense mutations in the Cu/Zn superoxide dismutase (SOD1) gene on chromosome 21 have been demonstrated in some families of FALS since 1993. We have also identified a novel missense mutation (substitution of Thr for Ala4) in exon 1 in a Japanese FALS family, and clarified the pathological findings of a patient in this family were typical of FALS with posterior column involvement. However, the mechanism by which the mutations in SOD1 lead to ALS is unknown. It is now clear that the mutations in SOD1 reduce total SOD activities only by 30-60%, and there is doubt whether a reduction in enzymatic function of this magnitude suffices to cause the neuronal loss. Recently, transgenic mice expressing the mutant SOD1 demonstrate motor neuron degeneration despite an increased level of SOD activity. The process of motor neuron degeneration in FALS might be mediated by some novel functions of the mutant SOD1 protein.
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PMID:[Familial amyotrophic lateral sclerosis and mutations in the Cu/Zn superoxide dismutase gene]. 875 59

The author reports the disappearance of amyotrophic lateral sclerosis (ALS) from Guam over past 30 years, which coincided with rapid changes in the ecology, socioeconomy, and westernization of the life style. This slow but steady decline is believed to be the consequences of radical changes from food collection to wage-based life style and dietary improvement in recent years and elimination of exogenous factors. Those risk factor(s) are believed to be the environmental trace metals which must have triggered the accelerated oxidative stresses in the motor neurons of genetically susceptible population. Changing Epidermiology: 1. The annual incidence of 70/100,000 in 1960s down to 7/100,000 in 1990s, and remained unchanged for past 15 years. 2. Upward shift of age at onset by 10 years and at death by 8 years and even out of sex ratio. 3. Birth cohort analysis showed less risks for those born after 1920. No ALS cases born after 1945. 4. No increase in the incidence of ALS among non-Chamorros transients of Guam and Marianas during W.W.II. 5. Long-term resident non-Charmorro and half-Chamorros on Guam are also affected. 6. Charmorro migrants to U.S. Mainland are affected after long absence from Guam. 7. Incubation period for both ways is estimated to be 18 approximately 20 years. 8. Other forms of dementias like Alzheimer disease (AD) and vascular dementias are on the rise and the leading cause of death is cerebro- and cardiovascular diseases. 9. ALS is also declining in past 10 approximately 15 years in Kii peninsula, and West New Guinea. Changing Ecology of Guam: 1. One third of Island land was used for construction of huge military bases after W.W.II. 2. Urbanization of villages including concrete houses, deep well water supply, sewage, and electrification. 3. Tourism boom: high-rise hotels, development of 7 golf courses and other recreational facilities resulted in loss of flora and erosions of soil. Socioeconomic Changes: 1. Shift in population demography; Efflux of Chamorros and influx of aliens; Chamorros less than 50% by 1990. 2. Tourists passed 1 million in 1994. 3. Automobiles 1 car/1.5 person. 4. Westernization: After W.W.II, almost free access to Military Commissary for imported food and appliances. 5. Life style: from food collection to wage-based society. Genetic Studies: 1. Familial aggregations, but no clear-cut Mendelian inheritance. 2. Segregation analysis: no absolute genetic or environmental cause but additive gene component may play a role in genetic susceptibility and basis for geographical clustering. 3. Absence of Apo-E or Mu/Zn SOD genes. 4. Recent discovery of mtDNA Complex I deficiency in Parkinsonism-dementia cases suggests mitochondrial DNA abnormality. Comparative Environmental Studies: 1. Environmental studies in three hyperendemic areas in the Western Pacific--Kii, Marianas, and west New Guinea, where strikingly high incidences of ALS is known to occur, found the identical geochemical environment--low Ca, Mg, and Zn and high A1, Mn, Fe, Si, in the garden soil and drinking water. 2. Exogenous etiologic factors that are absent from primitive culture of Auyu and Jackai tribes in West New Guinea were eliminated. 3. Cycad neurotoxicity has been excluded. 4. Suspected exogenous agents that are common in these 3 hyperendemic areas are (a) locally grown vegetables, starchy roots, and reef fish; (b) surface water containing soluble organic minerals from red laterites; (c) rain water that is chemically pure and lack of essential minerals. Pathogenic Speculation: Chronic dietary deficiency since birth in Ca, Mg and Zn induced excessive absorption of divalent cations which accelerates oxidant-mediated neuronal degenerations in a genetically susceptible population. The process is probably carried through interactions between cytoskeletal abnormality of the neuron, aging process, abnormal proteins, and mitochondrial dysfunction.
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PMID:[Disappearance of ALS from Guam: implications for exogenous causes]. 875 60

This report concerns retrospective immunohistochemical and immunoelectron microscopic studies on superoxide dismutase-1 (SOD1) in intracytoplasmic hyaline inclusions (IHIs) of the anterior horn cells of three patients with familial amyotrophic lateral sclerosis (ALS) with posterior column involvement. All of the patients were members of the American "C" family. Almost all of the IHIs, present in the soma and cordlike swollen neurites of some affected neurons of the three patients, were intensely stained by an antibody to human SOD1. By contrast, the cytoplasm of anterior horn cells of the ALS patients and of ten control individuals reacted only weakly with the antibody or not at all. Immunoelectron microscopy revealed that the granule-associated thick linear structures that composed the IHIs were intensely labeled by the antibody to SOD1. The IHIs were also positively stained by antibodies to ubiquitin and phosphorylated neurofilament protein, with the distribution of immunoreactivity resembling that seen with the anti-SOD1 antibody. The DNA analysis disclosed a single-site GCC to GTC substitution at codon 4 (Ala4 --> Val) in the SOD1 gene from the brain samples of the patients and from the peripheral blood of their family members. Our results suggest that SOD1 is a component of IHIs and may interact with Ubiquitin and neurofilament protein, and point to the possibility that the presence of intense SOD1 immunoreactivity in the IHIs may be of relevance in processes involving structurally altered SOD1 molecules encoded by the mutated gene.
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PMID:Intense superoxide dismutase-1 immunoreactivity in intracytoplasmic hyaline inclusions of familial amyotrophic lateral sclerosis with posterior column involvement. 878 8

Peroxynitrite, formed from nitric oxide and superoxide, may affect neurofilament assembly and cause neurofilament accumulation in motoneurons. This hypothesis may reconcile the mutations of two genes: superoxide dismutase-1 in some patients with familial amyotrophic lateral sclerosis, and the gene for the heavy neurofilament in some patients with sporadic amyotrophic lateral sclerosis previously reported. We found colocalization of superoxide dismutase-1 and nitric oxide synthase in the foci of neurofilament accumulation as 'conglomerates' in upper motor neurons and 'axonal spheroids' in lower motor neurons. In addition, all the specific molecules related to the reactions, including calmodulin, 3', 5'-cyclic guanosine-monophosphate, citrulline, and nitrotyrosine were found strongly immunopositive in the site of neurofilament accumulation. Our data support the view that the neurofilament aggregates are tightly linked with superoxide dismutase-1 and nitric oxide synthase activities. Both enzymes may focally contribute to peroxynitrite formation at light neurofilament, which is rich in both tyrosine and arginine residues and hence considered as the vulnerable site for nitrotyrosine formation. Nitrotyrosine is known to inhibit phosphorylation and if it impairs phosphorylation of neurofilament subunits, either light or heavy, may alter the slow axonal transport culminating in proximo-distal accumulation of NF and slowly progressive motoneuron death.
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PMID:Colocalization of NOS and SOD1 in neurofilament accumulation within motor neurons of amyotrophic lateral sclerosis: an immunohistochemical study. 881 14

We describe 36 patients (six were apparently sporadic cases and 30 were cases from nine families) with amyotrophic lateral sclerosis (ALS) characterized by a distinct phenotype associated with homozygosity for an Asp90Ala mutation in the CuZn-superoxide dismutase gene. The presenting motor manifestation in all patients was paresis in the legs, with slow progression to the upper extremities and finally to the bulbar muscles. The age of ALS onset varied from 20 to 94 years, with a mean of 44 years. Mean survival time was 13 years for the 11 deceased patients. However, this is probably biased and untypical (low) when compared with the disease duration in the surviving patients, and when considering other medical complications in the deceased patients. The rate of progression was highly variable, even within families. All patients showed signs of involvement of both upper and lower motor neurons. Other neurological features included painful muscle spasms and paraesthesiae in the lower extremities. Two-thirds of patients experienced difficulty with micturition. Electrophysiological studies confirmed the slow progression and spatial distribution of clinical symptoms in the peripheral motor system. Furthermore, [corrected] potentials evoked by transcranial magnetic stimulation (MEP) were compared with those evoked by cervical or lumbosacral electrical stimulation and often revealed marked slowing of transmission in central motor pathways. In Sweden and Finland ALS patients homozygous for the Asp90Ala mutation constitute a phenotypically characteristic subset of motor neuron disease.
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PMID:Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation. A clinical and genealogical study of 36 patients. 881 80

We report clinical characteristics of familial amyotrophic lateral sclerosis (FALS) with 4 different missense point mutations in exons 2, 4, and 5 of the Cu/Zn superoxide dismutase (SOD) gene, that result in amino acid substitutions of histidine46 by arginine (H46R), leucine84 by valine (L84V), isoleucine104 by phenylalanine (I104F), and valine148 by isoleucine (V148I), in 5 Japanese families. Although features of progressive neurogenic muscular atrophy were common in patients of these families, patients of each family showed characteristic clinical features. FALS patients with the H46R mutation showed a benign clinical course and stereotype progression of muscular weakness and atrophy beginning from the legs. In FALS with the L84V mutation, while the clinical course of the disease was similar, the age at onset was younger in men than women. The patients with I104F showed wide ranges of age at onset and duration with ophthalmoparesis and sensory involvement in one patient. Those with the V148I mutation showed younger age at onset and variable first symptoms within the family. Although lower motor sign was evident in all cases, hyperreflexia varied from 0 to 100% among patients with the different mutations, and the Babinski sign was not observed in any case. Bulbar palsy was frequent with I104F, but not with H46R. SOD activity of the red blood cells was severely reduced with I104F and V148I, but was slightly reduced with H46R. These results suggest that familial ALS with different mutations of the Cu/Zn SOD gene each showed clinical characteristics, and that genetic mutations and clinical features are well correlated in familial ALS.
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PMID:Clinical characteristics of familial amyotrophic lateral sclerosis with Cu/Zn superoxide dismutase gene mutations. 881 57

Point mutations occurring within the Cu/Zn superoxide dismutase (SOD1) gene have been implicated in the etiology of some cases of familial amyotrophic lateral sclerosis (FALS). In order to better understand the functional consequences of these mutations, we have introduced FALS mutations into the mouse SOD1 gene and studied the expression of the mutant templates in stably transformed cell lines. Pulse-chase analyses of lysates derived from cell lines stably expressing the Cu/Zn SOD isoforms indicate that the FALS mutant Cu/Zn SOD proteins are turned over more rapidly than wild-type SOD. Protease inhibitors specific for the major intracellular proteolytic activities were used to characterize the degradative pathways involved in the turnover of mutant Cu/Zn SOD. Inhibition of the chymotrypsin-like activity of the proteasome (also known as multicatalytic proteinase or ubiquitin, ATP-dependent proteinase) by a synthetic dipeptide aldehyde led to a significant increase in levels of the mutant Cu/Zn SOD implicating this proteolytic pathway in the turnover of the FALS mutant SOD proteins.
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PMID:Proteasome inhibition enhances the stability of mouse Cu/Zn superoxide dismutase with mutations linked to familial amyotrophic lateral sclerosis. 883 67

The cause of selective degeneration of motor neurons in the ventral horn of the spinal cord associated with amyotrophic lateral sclerosis (ALS) has still not been elucidated. Recently, so-called oxidative stress has been suggested to be a significant factor in the pathogenesis of this disease. We measured the antioxidant actions of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and cytochrome c oxidase (CO) of the human spinal cord in patients with ALS in comparison with those in control patients. Total SOD activity in spinal cord transections from patients with sporadic ALS was not significantly different from the controls in ventral, lateral, or dorsal regions, although enzymic activity was relatively higher in the ventral compared with the dorsal region. GSH-Px activity in the spinal cord of ALS patients was not very different from that in the control tissue. In contrast, CO activity was significantly reduced in all three regions of the spinal cord in patients with ALS, although the reduction was more marked in the ventral region. These results suggest that reactive oxygen species may attack the mitochondrial respiratory chain, leading eventually to the degeneration of vulnerable motor neurons in the spinal cord, even though no obvious changes in the activity of antioxidant enzymes are detectable.
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PMID:Decreased cytochrome c oxidase activity but unchanged superoxide dismutase and glutathione peroxidase activities in the spinal cords of patients with amyotrophic lateral sclerosis. 884 88

The mutation gly93-->ala of Cu,Zn superoxide dismutase (SOD) is found in patients with familial amyotrophic lateral sclerosis and causes motor neuron disease when expressed in transgenic mice. The progression of clinical and pathological disease was studied in a line of mice designated G1H. Clinical disease started at 91 +/- 14 days of age with fine shaking of the limbs, followed by paralysis and death by 136 +/- 7 days of age. Pathological changes begin by 37 days of age with vacuoles derived from swollen mitochondria accumulating in motor neurons. At the onset of clinical disease (90 days), significant death of somatic motor neurons innervating limb muscles has occurred; mice at end-stage disease (136 days) show up to 50% loss of cervical and lumbar motor neurons. However, neither thoracic nor cranial motor neurons show appreciable loss despite vacuolar changes. Autonomic motor neurons also are not affected. Mice that express wild-type human Cu,Zn SOD remain free of disease, indicating that mutations cause neuron loss by a gain-of-function. Thus, the age-dependent penetrance of motor neuron disease in this transgenic model is due to the gradual accumulation of pathological damage in select populations of cholinergic neurons.
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PMID:Age-dependent penetrance of disease in a transgenic mouse model of familial amyotrophic lateral sclerosis. 884 4


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