Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Isolated sulfite oxidase deficiency is a rare but devastating neurologic disease that usually presents in early infancy with seizures and alterations in muscle tone. Only 21 cases have been reported in the literature. We report a case of a newborn infant boy with isolated sulfite oxidase deficiency who presented with generalized seizures on his fourth day of life. Plasma total homocysteine was not detectable. Urinary sulfite, thiosulfate, and S-sulfocysteine levels were elevated. The patient began a low-methionine and low-cysteine diet and was treated with thiamine and dextromethorphan. However, he became increasingly microcephalic and was severely developmentally delayed. Mutation analysis of the sulfite oxidase gene revealed that the patient was homozygous for a novel 4-base pair deletion, and both of his parents were found to be heterozygous carriers of the same deletion. We reviewed the clinical, biochemical, neuroradiologic, and neuropathologic features in all published cases of isolated sulfite oxidase deficiency. Seizures or abnormal movements were prominent features in all cases. Developmental delays were reported in 17 cases. Ectopia lentis was detected in 9 cases. Clinical improvement with dietary therapy was seen in only 2 patients, both of whom presented after the age of 6 months and had relatively mild developmental delays. Plasma or urinary S-sulfocysteine levels were elevated in all cases. Urinary sulfite was detected in all except 1 case. Cerebral atrophy and cystic encephalomalacia were observed with neuroradiologic imaging and were noted in all 3 postmortem reports of isolated sulfite oxidase deficiency. The main alternative in the differential diagnosis of isolated sulfite oxidase deficiency is molybdenum cofactor deficiency.
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PMID:Isolated sulfite oxidase deficiency: a case report with a novel mutation and review of the literature. 1614 Jul 20

Cystathionine beta-synthase (CBS; EC 4.2.1.22) is a key enzyme in the generation of cysteine from methionine. A deficiency of CBS leads to homocystinuria, an inherited human disease characterized by mental retardation, seizures, psychiatric disturbances, skeletal abnormalities, and vascular disorders; however, the underlying mechanisms remain largely unknown. Here, we show the regional and cellular distribution of CBS in the adult and developing mouse brain. In the adult mouse brain, CBS was expressed ubiquitously, but it is expressed most intensely in the cerebellar molecular layer and hippocampal dentate gyrus. Immunohistochemical analysis revealed that CBS is preferentially expressed in cerebellar Bergmann glia and in astrocytes throughout the brain. At early developmental stages, CBS was expressed in neuroepithelial cells in the ventricular zone, but its expression changed to radial glial cells and then to astrocytes during the late embryonic and neonatal periods. CBS was most highly expressed in juvenile brain, and a striking induction was observed in cultured astrocytes in response to EGF, TGF-alpha, cAMP, and dexamethasone. Moreover, CBS was significantly accumulated in reactive astrocytes in the hippocampus after kainic acid-induced seizures, and cerebellar morphological abnormalities were observed in CBS-deficient mice. Taken together, these results suggest that CBS plays a crucial role in the development and maintenance of the CNS and that radial glia/astrocyte dysfunction might be involved in the complex neuropathological features associated with abnormal homocysteine metabolism.
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PMID:Cystathionine beta-synthase, a key enzyme for homocysteine metabolism, is preferentially expressed in the radial glia/astrocyte lineage of developing mouse CNS. 1616 63

The time course and critical determinants of mitochondrial dysfunction and oxidative stress following limbic status epilepticus (SE) were investigated in hippocampal sub-regions of an electrical stimulation model in rats, at time points 4-44h after status. Mitochondrial and cytosolic enzyme activities were measured spectrophotometrically, and reduced glutathione (GSH) concentrations by HPLC, and compared to results from sham controls. The earliest change in any sub-region was a fall in GSH, appearing as early as 4h in CA3 (-13%, p<0.05), and persisting at all time points. This was followed by a transient fall in complex I activity (CA3, 16h, -13%, p<0.05), and later changes in aconitase (CA1,-18% and CA3, -22% at 44h, p<0.05). The activity of the cytosolic enzyme glyceraldehyde-3-phosphate-dehydrogenase was unaffected at all time points. It is known that GSH levels are dependent both on redox status, and on the availability of the precursor cysteine, in turn dependent on the cysteine/glutamate antiporter, for which extracellular glutamate concentrations are rate limiting. Both mechanisms are likely to contribute indirectly to GSH depletion following seizures. That a relative deficiency in GSH precedes later changes in the activities of complex I and aconitase in vulnerable hippocampal sub-regions, occurring within a clinically relevant therapeutic time window, suggests that strategies to boost GSH levels and/or otherwise reduce oxidative stress following seizures, deserve further study, both in terms of preventing the biochemical consequences of SE and the neuronal dysfunction and clinical consequences.
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PMID:Depletion of reduced glutathione precedes inactivation of mitochondrial enzymes following limbic status epilepticus in the rat hippocampus. 1629 Mar 21

Under pathophysiological conditions, cellular amino acids can be profusely released from cells into the cerebral interstitial space. Because several class-C G protein coupled receptors (GPCRs) display a broad natural ligand spectrum, being sensitive to more than one endogenous ligand, we wondered whether the related metabotropic glutamate (mGlu) receptors could be modulated by various types of L-amino acids, allowing them to sense large increase in extracellular amino acid concentration. Here, the agonist, antagonist and allosteric effects of the twenty classical L-amino acids were evaluated on the eight mGlu receptor subtypes. We show that, in addition to glutamate (Glu), cysteine, aspartate and asparagine also lead to the activation of mGlu3, 4 and 5. Interestingly, our data demonstrate that the effect of these three amino acids did not result from a direct activation of the receptors, but from an indirect action involving Glu-transporters/exchangers. These data first demonstrate that mGlu receptors, unlike other class-C GPCRs, display an extremely high selectivity towards one ligand. Moreover, our results also show that Glu transport systems allow mGlu receptors to sense large increase in the extracellular concentration of some amino acids. Such a system will certainly lead to a large increase in some mGlu receptor activity under pathological conditions, such as seizure, ischemia or other brain injuries.
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PMID:Among the twenty classical L-amino acids, only glutamate directly activates metabotropic glutamate receptors. 1631 Feb 27

Uptake of the neurotransmitter glutamate is effected primarily by transporters expressed on astrocytes, and downregulation of these transporters leads to seizures and neuronal death. Neurons also express a glutamate transporter, termed excitatory amino acid carrier-1 (EAAC1), but the physiological function of this transporter remains uncertain. Here we report that genetically EAAC1-null (Slc1a1(-/-)) mice have reduced neuronal glutathione levels and, with aging, develop brain atrophy and behavioral changes. EAAC1 can also rapidly transport cysteine, an obligate precursor for neuronal glutathione synthesis. Neurons in the hippocampal slices of EAAC1(-/-) mice were found to have reduced glutathione content, increased oxidant levels and increased susceptibility to oxidant injury. These changes were reversed by treating the EAAC1(-/-) mice with N-acetylcysteine, a membrane-permeable cysteine precursor. These findings suggest that EAAC1 is the primary route for neuronal cysteine uptake and that EAAC1 deficiency thereby leads to impaired neuronal glutathione metabolism, oxidative stress and age-dependent neurodegeneration.
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PMID:Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse. 1631 88

The aim of this study was to determine seizure-induced oxidative stress by measuring hippocampal glutathione (GSH) and glutathione disulfide (GSSG) levels in tissue and mitochondria. Kainate-induced status epilepticus (SE) in rats resulted in a time-dependent decrease of GSH/GSSG ratios in both hippocampal tissue and mitochondria. However, changes in GSH/GSSG ratios were more dramatic in the mitochondrial fractions compared to hippocampal tissue. This was accompanied by a mild increase in glutathione peroxidase activity and a decrease in glutathione reductase activity in hippocampal tissue and mitochondria, respectively. Since coenzyme A (CoASH) and its disulfide with GSH (CoASSG) are primarily compartmentalized within mitochondria, their measurement in tissue was undertaken to overcome problems associated with GSH/GSSG measurement following subcellular fractionation. Hippocampal tissue CoASH/CoASSG ratios were decreased following kainate-induced SE, the time course and magnitude of change paralleling mitochondrial GSH/GSSG levels. Cysteine, a rate-limiting precursor of glutathione was decreased following kainate administration in both hippocampal tissue and mitochondrial fractions. Together these changes in altered redox status provide further evidence for seizure-induced mitochondrial oxidative stress.
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PMID:Seizure-induced changes in mitochondrial redox status. 1641 13

alpha-Conotoxins possess a conserved four-cysteine framework and disulfide linkages (C(1)(-)(3), C(2)(-)(4)) that fold toward the globular conformation with absolute fidelity. Despite the presence of a similar conserved set of cysteine framework, chi/lambda-conotoxins adopt an alternate disulfide-pairing (C(1)(-)(4), C(2)(-)(3)) and its consequent ribbon conformation, exhibiting distinct biological activities from alpha-conotoxins. chi/lambda-Conotoxin CMrVIA (VCCGYKLCHOC-COOH) isolated from the venom of Conus marmoreus natively exists in the ribbon conformation and induces seizures in mice at a potency that is of three orders higher than the non-native globular form. We have chemically synthesized two isoforms of CMrVIA conotoxin in the ribbon and globular conformation and determined their structures by (1)H NMR spectroscopy. The ribbon (PDB ID 2B5P) and globular conformations (PBD ID 2B5Q) were calculated to have paired-wise backbone RMSDs of 0.48 +/- 0.1 and 0.58 +/- 0.1 A respectively. Unlike the native globular alpha-conotoxins, the globular canonical form of CMrVIA chi/lambda-conotoxin exhibited heterogeneity in its solution structure as noted by the presence of minor conformers and poorer RMSD of structure calculation. Paired-wise backbone comparison between the native ribbon and the non-native globular form of CMrVIA conotoxin revealed an RMSD of 4.73 A, emphasizing their distinct conformational differences. These structural data are essential for the understanding of the structure-function activity of chi/lambda-conotoxins, as well as unraveling the folding propensities of these short peptide toxins.
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PMID:Solution structures of two structural isoforms of CMrVIA chi/lambda-conotoxin. 1690 80

The amino acid homocysteine (Hcy), formed from methionine has profound importance in health and diseases. In normal circumstances, it is converted to cysteine and partly remethylated to methionine with the help of vit B12 and folate. However, when normal metabolism is disturbed, due to deficiency of cystathionine-beta-synthase, which requires vit B6 for activation, Hcy is accumulated in the blood with an increase of methionine, resulting into mental retardation (homocystinuria type I). A decrease of cysteine may cause eye diseases, due to decrease in the synthesis of glutathione (antioxidant). In homocystinurias type II, III and IV, there is accumulation of Hcy, but a decrease of methionine, thus, there is no mental retardation. Homocysteinemia is found in Marfan syndrome, some cases of type I diabetes and is also linked to smoking and has genetic basis too. In hyperhomocysteinemias (HHcys), clinical manifestations are mental retardation and seizures (type I only), ectopia lentis, secondary glaucoma, optic atrophy, retinal detachment, skeletal abnormalities, osteoporosis, vascular changes, neurological dysfunction and psychiatric symptoms. Thrombotic and cardiovascular diseases may also be encountered. The harmful effects of homocysteinemias are due to (i) production of oxidants (reactive oxygen species) generated during oxidation of Hcy to homocystine and disulphides in the blood. These could oxidize membrane lipids and proteins. (ii) Hcy can react with proteins with their thiols and form disulphides (thiolation), (iii) it can also be converted to highly reactive thiolactone which could react with the proteins forming -NH-CO- adducts, thus affecting the body proteins and enzymes. Homocystinuria type I is very rare (1 in 12 lakhs only) and is treated with supplementation of vit B6 and cystine. Others are more common and are treated with folate, vit B12 and in selected cases as in methionine synthase deficiency, methionine, avoiding excess. In this review, the role of elevated Hcy levels in cardiovascular, ocular, neurologial and other diseases and the possible therapeutic measures, in addition to the molecular mechanisms involved in deleterious manifestations of homocysteinemia, have been discussed.
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PMID:Biochemistry of homocysteine in health and diseases. 1713 33

AMPA receptor-elicited excitotoxicity is manifested as both a type of programmed cell death termed dark cell degeneration and edematous necrosis, both of which are linked to increased intracellular Ca2+ concentration. The appearance of marked cytoskeletal changes in response to abusive AMPA receptor activation, coupled with increased intracellular Ca2+ concentration suggests activation of various destructive enzymes such as calpains, a family of Ca2+-dependent cysteine proteases. Since calpains and AMPA have been linked to both necrotic cell death and programmed cell death, we sought to determine the role of calpains in mediating both types of AMPA-mediated toxicity in Purkinje neurons of the cerebellum. These studies employed immunohistochemistry for cytoskeletal breakdown products of calpain activity coupled with confocal microscopy and pharmacological interventions with calpain and AMPA receptor antagonists. The present study identifies an early involvement of calpains in mediating AMPA-induced dark cell degeneration, but not edematous necrosis, based upon the effectiveness of AMPA to generate calpain-derived alpha-spectrin cleavage products in cerebellar Purkinje neurons that express dark cell degeneration, and the effectiveness of calpain antagonists, PD150606 and MDL28170, to attenuate AMPA-induced dark cell degeneration. Moreover, the AMPA receptor antagonist CNQX, a proven inhibitor of AMPA-elicited dark cell degeneration, also blocked AMPA-induced increases in alpha-spectrin, further suggesting interplay between abusive AMPA receptor activation, calpain activation and dark cell degeneration. Since AMPA-induced dark cell degeneration possesses morphological changes that resemble those that occur following brain ischemia in vivo, hypoglycemia, or extended seizure episodes, the involvement of calpains as mediators of cell death is potentially far reaching and has widespread therapeutic implications in numerous CNS disorders.
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PMID:Involvement of calpain in AMPA-induced toxicity to rat cerebellar Purkinje neurons. 1718 64

CBS is a vitamin B6-dependent transsulfuration enzyme needed to synthesize cysteine from methionine, catalyzing the condensation of serine with homocysteine to form cystathionine. A deficiency of CBS causes homocystinuria (MIM 236200), one of the most prevalent inborn errors, characterized by mental retardation, seizures, psychiatric disturbances, skeletal abnormalities and vascular disorders. Patients with CBS deficiency exhibit a major biochemical abnormality, hyperhomocysteinemia (HHcy), a condition associated with highly elevated plasma homocysteine levels. HHcy is recognized as a risk factor for several neurological diseases, such as cognitive impairment, dementia and Alzheimer's disease. Although the link between CBS deficiency and homocystinuria was first described over 40 years ago and mental retardation was the first clinical feature of the disease to be classified, very little is known about the role of CBS in the CNS. Here we show the regional and cellular distribution of CBS in the adult and developing mouse brain. In the adult mouse brain, CBS was expressed ubiquitously, but most intensely in the cerebellar molecular layer and hippocampal dentate gyrus. Immunohistochemical analysis revealed that CBS is preferentially expressed in cerebellar Bergmann glia and in astrocytes throughout the brain. At early developmental stages, CBS was expressed in neuroepithelial cells in the ventricular zone, but its expression changed to radial glial cells and then to astrocytes during the late embryonic and neonatal periods. Moreover, CBS was significantly accumulated in reactive astrocytes in the hippocampus after kainic acid-induced seizures, and cerebellar morphological abnormalities were observed in CBS-deficient mice. These results support the role of CBS in the development and maintenance of the CNS, and suggest that radial glia/astrocyte dysfunction might be involved in the complex neuropathological features associated with abnormal homocysteine metabolism.
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PMID:[Disruption of amino acid metabolism in astrocyte and neurological disorders--possible implication of abnormal glia-neuron network in homocystineuria]. 1766 44


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