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)

Cerebral cell volume regulatory mechanisms are activated by sustained disturbances in plasma osmolality. Acute hypernatremia causes a predictable shrinkage of brain cells due to the sudden imposition of a plasma-to-cell osmolal gradient. However, during chronic hypernatremia cerebral cell volume is maintained close to the normal range as a result of the accumulation of electrolytes and organic osmolytes including myo-inositol, taurine, glutamine, glycerophosphorylcholine, and betaine. The increased cytosolic level of these molecules is generally accomplished via increased activity of sodium (Na+)-dependent cotransport systems. The slow dissipation of these additional osmotically active solutes from the cell during treatment of hypernatremia necessitates gradual correction of this electrolyte abnormality. Acute hyponatremia leads to cerebral cell swelling and severe neurological dysfunction. However, prolonged hyponatremia is associated with significant reductions in brain cell electrolyte and organic osmolyte content so that cerebral cell volume is restored to normal. While acute hyponatremia can be treated with the administration of moderate doses of hypertonic saline in order to control seizure activity, chronic hyponatremia should be corrected slowly in order to prevent subsequent neurological deterioration. If the rate of correction exceeds 0.5 mmol/l per hour, or if the total increment in serum [Na+] exceeds 25 mmol/l in the first 48 h of therapy, then there is an increased risk of the development of cerebral demyelinating lesions. Chronic hyperglycemia activates the brain cell volume regulatory adaptations in the same manner as hypernatremia. Therefore, during the treatment of diabetic ketoacidosis, it is imperative to restore normoglycemia gradually in order to prevent the occurrence of cerebral edema.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cell volume regulation: a review of cerebral adaptive mechanisms and implications for clinical treatment of osmolal disturbances: II. 153 29

Betaine (N,N,N-trimethylglycine) and N,N-dimethylglycine have been reported to have anticonvulsant properties in animals. The purpose of the present study was to determine whether these compounds can antagonize strychnine-induced seizures when administered intraperitoneally and to compare their effects with those of sarcosine (N-methylglycine) and glycine. Betaine, N,N-dimethylglycine and sarcosine were equipotent in decreasing the incidence of seizures and death, causing a 38 to 72 percent decrease in the incidence of seizures and death at a dosage of 5 mmole/kg. Glycine had no effect. Thus anticonvulsant activity is conferred to glycine by a single N-methylation.
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PMID:Prevention of strychnine-induced seizures and death by the N-methylated glycine derivatives betaine, dimethylglycine and sarcosine. 258 Dec 77

Intrathecal administration of 25 micrograms strychnine induced consistent sensory and motor behavioral events in rats. Sensory events included scratching and biting the lower half of the body, spontaneous vocalizations and skin hyperalgesia, evidenced by vocalization and reflex scratching in response to stimulation with a 5.5 g von Frey fiber. This mild stimulus failed to elicit vocalizations in the preinjection condition. Strychnine induced two types of motor seizures: (1) falling over with tail whipping and (2) convulsions. The effect of equimolar doses of glycine (G) and some related amino acids: beta-alanine (A), taurine (T) and betaine (B) on the strychnine syndrome was tested by administering them (intrathecal route) along with strychnine. T and G but not B significantly decreased most of the sensory events triggered by strychnine. All amino acids significantly decreased the incidence and duration of convulsions; T and B abolished them. A decreased vocalizations and skin hyperalgesia but synergized with strychnine to facilitate scratching and self biting. These results are consistent with findings that G, A and T displace strychnine from its binding sites in the CNS.
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PMID:Prevention of the convulsant and hyperalgesic action of strychnine by intrathecal glycine and related amino acids. 335 33

The ability of betaine to block homocysteine, pentylenetetrazol, and electroshock induced seizures in mice has previously been observed. In this study, betaine administered IP and intraventricularly to rats blocked pentylenetetrazol-induced seizures, but IP betaine did not block audiogenic seizures. Intraventricular betaine was about 1000-fold more potent than IP betaine in blocking PTZ-induced seizures. Glycine, a component of the betaine molecule, was ineffective. It is concluded that betaine has an appreciable but selective effect in controlling experimental seizures in rats. This effect is mediated directly by the brain, and is not due to metabolism of betaine to glycine.
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PMID:Effects of betaine on seizures in the rat. 399 72

The clbC form of methylmalonic acidaemia is a rare and poorly understood condition which results from impaired biosynthesis of methylcobalamin and adenosylcobalamin. The consequent functional deficiencies of methylmalonyl-CoA mutase and methionine synthase produce both methylmalonic aciduria and homocystinuria. Systemic symptoms and neurological decompensation comprise the clinical phenotype. In an effort to clarify the phenotype and prognosis, we obtained clinical information on 50 patients with methylmalonic acidaemia whose cells had been assigned to the cblC complementation group. We identified two distinct phenotypes; they differed in age of onset, presence of systemic symptoms, type of neurological symptoms, and outcome after diagnosis and treatment. Forty-four patients presented in the first year of life. Feeding difficulties, neurological dysfunction (hypotonia, seizures, developmental delay), and ophthalmological and haematological abnormalities characterized their clinical picture. About one-quarter of those patients died. Survival was associated with neurological impairment; only one infant was neurologically intact at follow-up. Onset in childhood, in contrast, was associated with less severe haematological abnormalities, largely involving the red cell series. Extrapyramidal signs, dementia, delirium or psychosis characterized the neurological findings. Survival, with mild to moderate disability in some, was typical in patients with later onset. Treatment in both groups included hydroxycobalamin, betaine and carnitine; complete normalization of biochemical parameters was rare.
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PMID:Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC). 926 89

Methylenetetrahydrofolate reductase deficiency is the most common inborn error of folate metabolism and should be suspected when homocystinuria is combined with hypomethioninemia. The main clinical findings are neurologic signs such as severe developmental delay, marked hypotonia, seizures, microcephaly, apnea, and coma. Most patients present in early life. The infantile form is severe, with rapid deterioration leading to death usually within 1 year. Treatment with betaine has been shown to be efficient in lowering homocysteine concentrations and returning methionine to normal, but the clinical response is variable. We report two brothers with methylenetetrahydrofolate reductase deficiency: the first was undiagnosed and died at 8 months of age from neurologic deterioration and apnea, while his brother, who was treated with betaine from the age of 4 months, is now 3 years old and has developmental delay.
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PMID:Methylenetetrahydrofolate reductase deficiency: importance of early diagnosis. 1096 93

Prospects for definitive therapeutic intervention for Rett syndrome (RS) have been elevated by the discovery of mutations in the methyl-CpG-binding protein 2 gene (MECP2) in more than 80% of females meeting clinical criteria for this disorder. As such, a review of previous clinical trials, descriptions of the status of clinical management for the prominent medical problems of RS, and a preview of an ongoing clinical trial conducted jointly at the Baylor College of Medicine and the University of Alabama at Birmingham are presented. The conduct of controlled clinical trials requires adherence to diagnostic criteria for RS; stratification by age, stage, and presence of MECP2 mutations; and use of clearly defined outcome measures. Previous clinical trials in RS have been conducted with L-carnitine, the ketogenic diet, and the opiate antagonist, naltrexone. The L-carnitine and naltrexone trials were double blind, placebo-controlled and us ed the motor behavioral analysis described in this review. All failed to provide evidence of dramatic improvements in the clinical features of RS. Specific recommendations are presented for clinical management of growth failure, breathing irregularities, seizures, ambulation, scoliosis, gastrointestinal function, self abuse, and habilitation/education although systematic evaluations of each in the context of RS have not been conducted. The only ongoing trial involves dietary supplementation with folate and betaine and is based on the finding that gene expression of some alleles of the agouti gene could be altered by dietary methyl supplementation. The availability of animal models expressing mutations in MECP2 should enhance the evaluation of innovative therapies for RS.
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PMID:Clinical trials and treatment prospects. 1211 36

Combined methylmalonicaciduria and homocystinuria is a disorder of intracellular cobalamin metabolism that remains a challenge to the physician unfamiliar with the diagnosis. We have followed six patients with combined methylmalonicaciduria and homocystinuria (four males, two females, age 4.2-24 years) for a median of 6.5 years (range 4-9 years). Age at diagnosis was between 18 days and 14 months in early-onset cases (n = 4) and 15 and 19 years in late-onset cases. Predominant clinical features include microcephaly, hydrocephalus, seizures, and white-matter changes on magnetic resonance imaging in early-onset cases. The white-matter changes may be secondary to impaired methylation owing to a lack of readily available methyl groups. Spastic quadriparesis and diplegia are long-term sequelae in late-onset cases. Management consists of hydroxycobalamin intramuscular injections, oral folate, betaine, and carnitine supplementation. Dietary protein restriction may be necessary when metabolic control remains difficult. The implementation of an emergency regimen should alleviate episodes of metabolic decompensation and reduce the rate of hospital admissions.
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PMID:Practical management of combined methylmalonicaciduria and homocystinuria. 1215 May 82

The identification and subsequent development of the GABA transport inhibitor tiagabine has confirmed the important role that GABA transporters play in the control of CNS excitability. Tiagabine was later demonstrated to be a selective inhibitor of the GABA transporter GAT1. Although selective for GAT1, tiagabine lacks cell type selectivity and is an equipotent inhibitor of neuronal and glial GAT1. To date, four GABA transporters have been cloned, i.e., GAT1-4. The finding that some of these display differential cellular and regional expression patterns suggests that drugs targeting GABA transporters other than GAT1 might offer some therapeutic advantage over GAT1 selective inhibitors. Furthermore, it is particularly interesting that several recently defined GABA transport inhibitors have been demonstrated to display a preferential selectivity for the astrocytic GAT1 transporter. That cellular heterogeneity of GAT1 plays a role in the control of CNS function is confirmed by the demonstration that inhibition of astrocytic GABA uptake is highly correlated to anticonvulsant activity. At the present time, a functional role for the other GABA transporters is less well defined. However, recent findings have suggested a role for the mouse GAT2 (homologous to the human betaine transporter) in the control of seizure activity. In these studies, the non-selective GAT1 and mouse GAT2 transport inhibitor EF1502 (N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-(methylamino)-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol) was found to exert a synergistic anticonvulsant action when tested in combination with the GAT1 selective inhibitors tiagabine and LU-32-176B (N-[4,4-bis(4-fluorophenyl)-butyl]-3-hydroxy-4-amino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol). Additional studies will be required to define a role for the other GABA transporters and to further identify the functional importance of their demonstrated cellular and regional heterogeneity. A summary of these and other issues are discussed in this brief review.
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PMID:GABA transporters as drug targets for modulation of GABAergic activity. 1545 99

Mammalian ALDH7A1 is homologous to plant ALDH7B1, an enzyme that protects against various forms of stress, such as salinity, dehydration, and osmotic stress. It is known that mutations in the human ALDH7A1 gene cause pyridoxine-dependent and folic acid-responsive seizures. Herein, we show for the first time that human ALDH7A1 protects against hyperosmotic stress by generating osmolytes and metabolizing toxic aldehydes. Human ALDH7A1 expression in Chinese hamster ovary cells attenuated osmotic stress-induced apoptosis caused by increased extracellular concentrations of sucrose or sodium chloride. Purified recombinant ALDH7A1 efficiently metabolized a number of aldehyde substrates, including the osmolyte precursor, betaine aldehyde, lipid peroxidation-derived aldehydes, and the intermediate lysine degradation product, alpha-aminoadipic semialdehyde. The crystal structure for ALDH7A1 supports the enzyme's substrate specificities. Tissue distribution studies in mice showed the highest expression of ALDH7A1 protein in liver, kidney, and brain, followed by pancreas and testes. ALDH7A1 protein was found in the cytosol, nucleus, and mitochondria, making it unique among the aldehyde dehydrogenase enzymes. Analysis of human and mouse cDNA sequences revealed mitochondrial and cytosolic transcripts that are differentially expressed in a tissue-specific manner in mice. In conclusion, ALDH7A1 is a novel aldehyde dehydrogenase expressed in multiple subcellular compartments that protects against hyperosmotic stress by generating osmolytes and metabolizing toxic aldehydes.
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PMID:Aldehyde dehydrogenase 7A1 (ALDH7A1) is a novel enzyme involved in cellular defense against hyperosmotic stress. 2020 35


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