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 report a novel missense point mutation in exon 4 of the Cu/Zn superoxide dismutase (SOD) gene of affected members of a Japanese kindred segregating familial amyotrophic lateral sclerosis (FALS) through at least three successive generations. The mutation, which is predicted to cause the replacement of isoleucine at codon 104 by phenylalanine (I104F), is associated with a significant reduction in Cu/Zn SOD enzyme activity but results in a highly variable clinical phenotype. Age at onset varied from 6 to 55; the initial symptoms occurred in either the lower or upper extremities in different family members. The duration of the disease varied from 3 to 38 years. Two subjects, aged 59 and 34, remained asymptomatic until their death from other causes, although their offspring carrying the same mutation have already developed clinical evidence of the disease. These results suggest that FALS from this novel I104F mutation shows considerable clinical variation.
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PMID:Variable clinical symptoms in familial amyotrophic lateral sclerosis with a novel point mutation in the Cu/Zn superoxide dismutase gene. 750 Nov 56

Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disorder of the motor system in the CNS characterized by motor neuron death in the spinal cord, brain stem and cortex. Readily available tissues such as fibroblasts from ALS patients can serve as simple model systems to study the molecular mechanisms leading to degenerative disorders. We have used Fura-2 fluorescence microscopy and single-cell imaging to study the spatiotemporal dynamics of intracellular free calcium ([Ca2+]i) in primary cultures of fibroblasts from skin biopsies from ALS and normal subjects. Increases in [Ca2+]i were induced by stimulation with bradykinin (100 nM); neurotensin (50 nM); N-formyl-Met-Leu-Phe (chemotactic peptide) (1 microM); [Arg8]-vasopressin (1 microM) and histamine (10 microM). The levels of [Ca2+]i in 80-120 individual cells per agonist were monitored for 15 min. No significant differences were found in the resting levels of [Ca2+]i in control (102 +/- 4 nM) and ALS (98 +/- 6 nM) fibroblasts and in the maximal [Ca2+]i levels after stimulation with N-formyl-Met-Leu-Phe, [Arg8]-vasopressin, and histamine. Significantly lower [Ca2+]i transients were found in fibroblasts from ALS donors compared to controls when stimulated with neurotensin (p < 0.002) and bradykinin (p < 0.005). The percentage of individual cells reacting to a given agonist (40-100%) was similar in both groups. The molecular basis of the impaired calcium homeostasis in fibroblasts from ALS patients is not known, but a generalized membrane defect can be excluded since the [Ca2+]i responses are defective only when bradykinin or neurotensin are used as agonists.
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PMID:Calcium homeostasis in fibroblasts from patients with amyotrophic lateral sclerosis. 785 28

Following the report of an increased mortality among patients with amyotrophic lateral sclerosis given high daily doses of branched-chain aminoacids, we assessed the plasma concentrations of large neutral aminoacids and glutamic acid and the large neutral aminoacid brain influx in 24 amyotrophic lateral sclerosis patients receiving placebo or branched-chain aminoacids (L-leucine 12 g, L-isoleucine 6 g, L-valine 6 g daily), in 15 untreated amyotrophic lateral sclerosis patients and in 15 healthy volunteers. The branched-chain aminoacid plasma concentrations increased three- to six-fold in the treated group compared to the patients receiving placebo or no treatment and to the healthy controls. Plasma glutamic acid concentrations in healthy volunteers were 51.59 +/- 7.53 nmol/ml while in the amyotrophic lateral sclerosis patients receiving no treatment, placebo or branched-chain aminoacids were 92.33 +/- 12.15 nmol/ml, 91.21 +/- 15.86 nmol/ml and 95.08 +/- 17.96 nmol/ml respectively. The glutamic acid concentration was significantly higher (P < 0.01) in amyotrophic lateral sclerosis patients than in healthy individuals. Plasma phenylalanine and tyrosine were lower in the amyotrophic lateral sclerosis patients than in healthy controls, regardless of treatment, whereas tryptophan levels were not significantly different. The branched-chain aminoacid brain influx of the treated group was 110-140% of that measured in the patients receiving placebo and in the healthy controls. The aromatic aminoacid brain influx was lower in the treated group than in the placebo group or healthy controls. An impairment of brain large neutral aminoacid availability might possible contribute to enhancing the progression of symptoms in patients with amyotrophic lateral sclerosis.
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PMID:The imbalance of brain large-chain aminoacid availability in amyotrophic lateral sclerosis patients treated with high doses of branched-chain aminoacids. 857 75

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

We have identified a novel two-base mutation in exon 1 of the Cu/Zn superoxide dismutase (SOD1) gene (TGC to TTT), which resulted in Cys6 to Phe substitution in a Japanese family with amyotrophic lateral sclerosis (ALS). This is the first case of familial ALS-associated two-base change of the SOD1 gene. Similar to several mutations in exon 1 of the SOD1 gene such as Ala4 to Val, Ala4 to Thr and Val14 to Met, affected members of the present family showed a rapid progression of motor dysfunction. Although Ala4, Cys6 and Val7 reside in the middle of the first beta-strand of the SOD1, a family with a mutation of Val7 to Glu associates with slow progression of the disease. These findings suggest that clinical courses are variable with each mutation, even in the same exon.
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PMID:A novel two-base mutation in the Cu/Zn superoxide dismutase gene associated with familial amyotrophic lateral sclerosis in Japan. 890 21

Eight of 38 patients (21%) with familial and 5 of 175 patients (3%) with sporadic amyotrophic lateral sclerosis (ALS) had missense mutations in the SOD-1 gene. Two novel mutations were identified. One in exon 4 substituting leucine with phenylalanine (L84F) in a familial patient and the second in exon 3 at substituting glycine with serine (G72S) in an "apparently" sporadic patient. Over 60 point mutations have now been described in all five exons of SOD-1, involving 43 of the 153 residues. Hypotheses about the toxic role of mutant SOD-1 in the pathogenesis of ALS must account for this molecular diversity.
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PMID:Mutations in all five exons of SOD-1 may cause ALS. 950 58

Although the cellular mechanisms of pharmacological actions of gabapentin (Neurontin) remain incompletely described, several hypotheses have been proposed. It is possible that different mechanisms account for anticonvulsant, antinociceptive, anxiolytic and neuroprotective activity in animal models. Gabapentin is an amino acid, with a mechanism that differs from those of other anticonvulsant drugs such as phenytoin, carbamazepine or valproate. Radiotracer studies with [14C]gabapentin suggest that gabapentin is rapidly accessible to brain cell cytosol. Several hypotheses of cellular mechanisms have been proposed to explain the pharmacology of gabapentin: 1. Gabapentin crosses several membrane barriers in the body via a specific amino acid transporter (system L) and competes with leucine, isoleucine, valine and phenylalanine for transport. 2. Gabapentin increases the concentration and probably the rate of synthesis of GABA in brain, which may enhance non-vesicular GABA release during seizures. 3. Gabapentin binds with high affinity to a novel binding site in brain tissues that is associated with an auxiliary subunit of voltage-sensitive Ca2+ channels. Recent electrophysiology results suggest that gabapentin may modulate certain types of Ca2+ current. 4. Gabapentin reduces the release of several monoamine neurotransmitters. 5. Electrophysiology suggests that gabapentin inhibits voltage-activated Na+ channels, but other results contradict these findings. 6. Gabapentin increases serotonin concentrations in human whole blood, which may be relevant to neurobehavioral actions. 7. Gabapentin prevents neuronal death in several models including those designed to mimic amyotrophic lateral sclerosis (ALS). This may occur by inhibition of glutamate synthesis by branched-chain amino acid aminotransferase (BCAA-t).
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PMID:A summary of mechanistic hypotheses of gabapentin pharmacology. 955 85

Microencapsulated genetically engineered cells have the potential to treat a wide range of diseases. For example, in experimental animals, implanted microencapsulated cells have been used to secrete growth hormone to treat dwarfism, neurotrophic factors for amyotrophic lateral sclerosis, beta-endorphin to decrease pain, factor XI for hemophilia B, and nerve growth factors to protect axotomized neurons. For some applications, microencapsulated cells can even be given orally. They can be engineered to remove unwanted molecules from the body as they travel through the intestine, and are finally excreted in the stool without being retained in the body. This application has enormous potential for the removal of urea in kidney failure, ammonia in liver failure and amino acids such as phenylalanine in phenylketonuria and other inborn errors of metabolism.
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PMID:Therapeutic uses of microencapsulated genetically engineered cells. 961 2

We report clinical characteristics of familial amyotrophic lateral sclerosis (FALS) with four different missense point mutations in exons 1, 2, 4, and 5 of the Cu/Zn superoxide dismutase (SOD) gene, that result in amino acid substitutions of cysteine 6 by phenylalanin (C 6 F), histidine 46 by arginine (H46R), leucine 84 by valine (L84V), isoleucine 104 by phenylalanine (I104F), and valine 148 by isoleucine (V148I), in five Japanese families. Although features of progressive neurogenic muscular atrophy was common in patients of these families, patients of each family showed characteristic clinical features. Immunoreactivity for Cu/Zn SOD of the motor neurons was not different between the ALS and controls. In contrast, immunoreactivity for NT was densely detected in motor neurons of ALS while that was not or was only minimally detected in those of controls. Adenovirus-mediated E. coli LacZ gene was transferred and expressed both in the muscle and spinal cord of transgenic mice. These results suggest that familial ALS with different mutations of the Cu/Zn SOD gene showed each clinical characteristics, that nitration of protein-tyrosine residue is upregulated in motor neurons of the spinal cord of ALS, and that there could be a possible future therapy of ALS with exogenous gene transfer.
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PMID:[Molecular mechanism of ALS and a possible gene therapy]. 1037 8

The influence of metal ions (Na(+), Mg(2+) and Cd(2+)) on the thermal unfolding of phenylalanine transfer ribonucleic acid (tRNA(Phe)) was studied by UV spectroscopy-monitored melting experiments. Absorbance data were obtained during the unfolding process in the range 220-340 nm and later analyzed by a multivariate curve resolution approach (MCR-ALS) based on factor analysis. This procedure determines the number of spectroscopically distinct conformations present during the unfolding process and reveals their concentration profiles and pure spectra, without any initial assumption having to be made about the number of steps in the unfolding pathway. From the concentration profiles and pure spectra, information such as T(m) values can be recovered. The results were compared with those obtained previously in spectroscopic and calorimetric unfolding experiments, showing that the multivariate approach recovers information that complements that obtained in traditional spectroscopic melting experiments.
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PMID:Study of the influence of metal ions on tRNA(Phe) thermal unfolding equilibria by UV spectroscopy and multivariate curve resolution. 1193 71


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