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)

Serine proteases in the adult CNS contribute both to activity-dependent structural changes accompanying learning and to the regulation of excitotoxic cell death. Brain serine protease 1 (BSP1)/neuropsin is a trypsin-like serine protease exclusively expressed, within the CNS, in the hippocampus and associated limbic structures. To explore the role of this enzyme, we have used gene targeting to disrupt this gene in mice. Mutant mice were viable and overtly normal; they displayed normal hippocampal long-term synaptic potentiation (LTP) and exhibited no deficits in spatial navigation (water maze). Nevertheless, electrophysiological studies revealed that the hippocampus of mice lacking this specifically expressed protease possessed an increased susceptibility for hyperexcitability (polyspiking) in response to repetitive afferent stimulation. Furthermore, seizure activity on kainic acid administration was markedly increased in mutant mice and was accompanied by heightened immediate early gene (c-fos) expression throughout the brain. In view of the regional selectivity of BSP1/neuropsin brain expression, the observed phenotype may selectively reflect limbic function, further implicating the hippocampus and amygdala in controlling cortical activation. Within the hippocampus, our data suggest that BSP1/neuropsin, unlike other serine proteases, has little effect on physiological synaptic remodeling and instead plays a role in limiting neuronal hyperexcitability induced by epileptogenic insult.
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PMID:Loss of hippocampal serine protease BSP1/neuropsin predisposes to global seizure activity. 1154 9

Clinical experience with the treatment of 3-phosphoglycerate dehydrogenase deficiency, a rare inherited disorder of serine synthesis, is scarce. We report on two sisters with phenotypic heterogeneity and a favourable response to combined serine and glycine supplementation. The elder sibling was found to be normocephalic at birth and showed moderate delay of white matter myelinisation, while her seizures arrested spontaneously even without treatment. In the younger sister with the classical phenotype, feeding difficulties with recurrent gastro-oesophageal reflux prompted us to treat her temporarily with high-dose serine (1400 mg/kg/day). An arrest of head growth then occurred but could be reversed by reducing the serine supply. In both children serine therapy was associated with decreased concentrations of methionine, isoleucine, and ornithine in the cerebrospinal fluid, attributed to competitive inhibition of neutral amino acid transport across the blood-brain barrier. In contrast to reports in the literature, these findings demonstrate that congenital microcephaly, intractable seizures, and dysmyelinisation are not invariably present in patients with 3-phosphoglycerate dehydrogenase deficiency. An adverse effect of high-dose serine therapy on head growth and on the transport of neutral amino acids across the blood-brain barrier should be considered and requires adjustment of treatment.
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PMID:Phenotypic heterogeneity and adverse effects of serine treatment in 3-phosphoglycerate dehydrogenase deficiency: report on two siblings. 1157 99

A deficiency of 3-phosphoglycerate dehydrogenase (PHGDH) is a disorder of serine biosynthesis identified in children with congenital microcephaly, seizures, and severe psychomotor retardation. We report here the identification of the 1468G-->A (V490M) mutation of this gene in two siblings of an Ashkenazi Jewish family, providing further evidence that the V490M mutation is a common, panethnic cause of this deficiency. Using a novel, DNA-based diagnostic test, the mutation was not detected in 400 non-Jewish controls; one heterozygote was found among 400 persons of Ashkenazi Jewish ethnicity. Extensive biochemical studies were undertaken to characterize the effect of this mutation on enzyme activity, turnover, and stability. The V490M PHGDH yielded less than 35% of the activity observed for the wild-type enzyme when overexpressed by transient transfection or when comparing the endogenous activity in fibroblast cells from the patients with controls. Immunoblotting studies showed a comparable reduction in the level of immunoreactive PHGDH in cells expressing the mutant enzyme. Pulse-chase experiments with metabolically labeled PHGDH indicated that this resulted from an increased rate of degradation of the mutant enzyme following its synthesis. Thermolability analyses of mutant and wild-type enzyme activity revealed no significant differences. While others have proposed that the V490M mutation decreases the V(max) of the enzyme, we conclude that this mutation impairs the folding and/or assembly of PHGDH but has minimal effects on the activity or stability of that portion of the V490M mutant that reaches a mature conformation.
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PMID:V490M, a common mutation in 3-phosphoglycerate dehydrogenase deficiency, causes enzyme deficiency by decreasing the yield of mature enzyme. 1175 22

To date about 20 activating mutations in the calcium-sensing receptor (CaR) gene have been identified to cause autosomal dominant hypocalcemia (ADH) or sporadic hypoparathyroidism. We report a novel activating mutation in the CaR gene in a Japanese family with ADH. The proband, a 15-yr-old boy, and 5 other patients in 3 generations were asymptomatic, except for the proband's grandmother who had a history of seizures. They showed mild hypocalcemia (1.68-1.98 mmol/liter) with normal urinary calcium excretion and low normal serum PTH levels. Their serum magnesium concentrations were below normal in 3 adults and within the normal range in 3 teenagers. There was a significant positive correlation (r = 0.90; P < 0.05) between the serum calcium and magnesium concentrations of 6 affected members. Nucleotide sequencing revealed that the proband had a known polymorphism (Gly(990)Arg) and a novel heterozygous mutation substituting phenylalanine for serine at codon 820 (Ser(820)Phe) in the sixth transmembrane helix of the CaR. In other family members, the Ser(820)Phe mutation cosegregated with hypocalcemia. The mutation was not detected in 50 control subjects. The Gly(990)Arg polymorphism was observed in 8 of 9 family members with or without hypocalcemia and in 36 of 50 controls. The sensitivity of the Ser(820)Phe mutant CaR to calcium was assessed using transiently transfected HEK293 cells and measuring the increases in intracellular Ca(2+) concentrations in response to the changes in extracellular Ca(2+). The concentration-response curve of the mutant receptor was left-shifted, and its EC(50) (2.5 mM) was significantly (P < 0.05) lower than that of the wild-type CaR (3.3 mM). We conclude that the Ser(820)Phe mutation in the CaR caused ADH in this family. The positive correlation between serum calcium and magnesium levels observed in this family may support the concept that renal CaR acts as a magnesium sensor as well as a calcium sensor.
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PMID:A family of autosomal dominant hypocalcemia with a positive correlation between serum calcium and magnesium: identification of a novel gain of function mutation (Ser(820)Phe) in the calcium-sensing receptor. 1205 Feb 33

Tissue-type plasminogen activator (tPA) is a highly specific serine proteinase expressed in the CNS during events that require neuronal plasticity. In this study we demonstrate that endogenous tPA mediates the progression of kainic acid-induced (KA-induced) seizures by promoting the synchronization of neuronal activity required for seizure spreading, and that, unlike KA-induced cell death, this activity is plasminogen-independent. Specifically, seizure induction by KA injection into the amygdala induces tPA activity and cell death in both hippocampi, and unilateral treatment of rats with neuroserpin, a natural inhibitor of tPA in the brain, enhances neuronal survival in both hippocampi. Inhibition of tPA within the hippocampus by neuroserpin treatment does not prevent seizure onset but instead markedly delays the progression of seizure activity in both rats and wild-type mice. In tPA-deficient mice, seizure progression is significantly delayed, and neuroserpin treatment does not further delay seizure spreading. In contrast, plasminogen-deficient mice show a pattern of seizure spreading and a response to neuroserpin that is similar to that of wild-type animals. These findings indicate that tPA acts on a substrate other than plasminogen and that the effects of neuroserpin on seizure progression and neuronal cell survival are mediated through the inhibition of tPA.
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PMID:Regulation of seizure spreading by neuroserpin and tissue-type plasminogen activator is plasminogen-independent. 1207 Feb 98

Congenital microcephaly, intractable seizures and severe psychomotor retardation characterize 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency, a disorder of L-serine biosynthesis. The enzyme defect results in low concentrations of serine and to a variable degree of glycine in plasma and cerebrospinal fluid. Short-term beneficial effects have been reported of oral treatment with the deficient amino acids. In this paper, we report the first follow-up data of amino acid therapy in five patients treated for 3-7.5 years. Different treatment regimes were used, but a favourable response to amino acids was observed in all patients. A major reduction in seizure frequency occurred in all patients; two patients became free of seizures. Amino acids were well tolerated and no adverse effects were documented. A progress of psychomotor development was only observed in one patient, diagnosed early and treated with a high dosage of L-serine. A favourable outcome of 3-PGDH deficiency depends on early diagnosis and treatment.
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PMID:Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids. 1211 26

Certain forms of seizure involve excessive glutamate transmission. We have recently identified a protein, referred to as the inhibitory protein factor (IPF), which potently inhibits glutamate uptake into isolated synaptic vesicles. In an effort to understand the mechanism underlying excessive glutamate transmission associated with seizure, we have analyzed IPF content in various brain regions of the spontaneously epileptic rat, SER (tm/tm, zi/zi), the absence-seizure tremor rat, TM (tm/tm), and the seizure-free control rats zitter ZI (zi/zi) and Wistar tremor control, each at 13 weeks of age. IPF content was found to be markedly reduced in the hippocampus, but not in the other brain regions, of SER, compared to the control and TM rats. TM rats also exhibited reduced IPF content compared to seizure-free controls. These changes appear developmentally regulated; no such alteration was observed in 8-week-old rats, which rarely show seizure. These observations indicate that an aberrant decrease in IPF is associated with certain forms of seizure; this decrease could lead to an abnormal increase in the amount of exocytotically released glutamate through its excessive accumulation in synaptic vesicles.
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PMID:Aberrant reduction of an inhibitory protein factor in a rat epileptic model. 1235 Mar 84

Overactivation of N-methyl-D-aspartate (NMDA) glutamate receptors is closely related to epilepsy and excitotoxicity, and the phosphorylation of these receptors may facilitate glutamate-mediated synaptic transmission. Here we show that in awake rats the microinjection into the hippocampus of okadaic acid, a potent inhibitor of protein phosphatases 1 and 2A, induces in about 20 min intense electroencephalographic and behavioral limbic-type seizures, which are suppressed by the systemic administration of the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine hydrogen maleate and by the intrahippocampal administration of 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, an inhibitor of protein kinases. Two hours after okadaic acid, when the EEG seizures were intense, an increased serine phosphorylation of some hippocampal proteins, including an enhancement of the serine phosphorylation of the NMDA receptor subunit NR2B, was detected by immunoblotting. Twenty-four hours after okadaic acid a marked destruction of hippocampal CA1 region was observed, which was not prevented by the receptor antagonists. These findings suggest that hyperphosphorylation of glutamate receptors in vivo may result in an increased sensitivity to the endogenous transmitter and therefore induce neuronal hyperexcitability and epilepsy.
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PMID:Okadaic acid induces epileptic seizures and hyperphosphorylation of the NR2B subunit of the NMDA receptor in rat hippocampus in vivo. 1242 30

The metabolic and anatomical substrate of most forms of mental retardation is not known. Because the basis of normal brain function is not sufficiently understood, the basis of abnormal function is understood poorly. Even in disorders where the fundamental biochemical defect is known, such as phenylketonuria (PKU) and other enzyme defects, the exact basis for brain dysfunction is uncertain. The outcome for treated PKU, galactosemia, homocystinuria, and lysosomal disorders is not yet optimal. The various forms of nonketotic hyperglycinemia often respond poorly to current therapy. Less familiar disorders, with or without seizures, such as deficient synthesis of serine or creatine and impaired glucose transport into the brain, and disorders with variable malformations, such as Smith-Lemli-Opitz (SLO) syndrome and the congenital disorders of glycosylation (CDGs), may initially be thought to be a nonspecific form of developmental delay. Less familiar disorders, with or without seizures and disorders with variable malformations may initially be thought to be a nonspecific form of developmental delay. Simple tests of urine, blood, and cerebrospinal fluid may lead to a diagnosis, accurate genetic counseling, and better treatment. Metabolic brain imaging (magnetic resonance spectroscopy (MRS)) has also helped to reveal biochemical abnormalities within the brain.
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PMID:Metabolic disorders and mental retardation. 1256 Oct 56

We have previously reported that varying stimulus intensity produces qualitatively different types of synaptic plasticity in area CA1 of hippocampal slices: brief low-intensity (LI) theta-burst (TB) stimuli induce long-term potentiation (LTP), but if the stimulus intensity is increased (to mimic conditions that may exist during seizures), LTP is not induced; instead, high-intensity (HI) TB stimuli erase previously induced LTP ("TB depotentiation"). We now have explored the mechanisms underlying TB depotentiation using extracellular field recordings with pharmacological manipulations. We found that TB depotentiation was blocked by okadaic acid and calyculin A (inhibitors of serine/threonine protein phosphatases PP1 and PP2A), FK506 (a specific blocker of calcineurin, a Ca(2+)/calmodulin (CaM) protein phosphatase), and 8-Br-cAMP (an activator of protein kinase A) with 3-isobutyl-1-methylxanthine (IBMX, a phosphodiesterase inhibitor). These results suggest that protein phosphatase pathways are involved in the TB depotentiation similar to other type of down-regulating synaptic plasticity such as low-frequency stimulation (LFS)-induced long-term depression (LTD) and depotentiation in the rat hippocampus. However, TB depotentiation and LFS depotentiation could have differential functional significance.
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PMID:Protein phosphatases mediate depotentiation induced by high-intensity theta-burst stimulation. 1257 46


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