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)

Hyperhomocysteinaemia is associated with an increased risk of arterial vascular disease and thrombosis in adults. Our aim was to study the association of hyperhomocysteinaemia and stroke in children. Since some patients who had suffered a stroke developed seizures and received treatment with anti-epileptic (antifolate) drugs, we also examined the possible interaction between anti-epileptic drugs and hyperhomocysteinaemia. Plasma total homocysteine was measured in 68 children with stroke (23 of the 68 were taking anti-epileptic drugs) and 100 children undergoing anti-epileptic treatment but without history of stroke, and we compared the values with our reference values for similar ages (n = 195). Total homocysteine was determined by high profile liquid chromatography with fluorescence detection. Hyperhomocysteinaemia was defined as a homocysteine concentration above the 95th percentile for the reference values. Significant differences were found in total homocysteine values of children with stroke and those taking anti-epileptic drugs compared with our reference values for similar ages, except for the adolescent group. Total homocysteine values above the 95th percentile for the reference values were found in 36% of patients with stroke and 28% of children on anti-epileptic treatment. Total homocysteine concentrations in the 23 patients with both stroke and anti-epileptic drug treatment were similar to those of untreated patients with stroke in all age groups. In summary, systematic screening for hyperhomocysteinaemia should be included in the protocol to investigate the aetiology of stroke, even in paediatrics. Anti-epileptic treatment in children with stroke may be responsible for the mild hyperhomocysteinaemia observed in some of them. A dietary supplement of folate may be of benefit in children with stroke and in patients taking anti-epileptic drugs.
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PMID:Evaluation of hyperhomocysteinaemia in children with stroke. 1046 66

A diagnosis of methylenetetrahydrofolate reductase (MTHFR) deficiency was made in four sibs at different ages. The first three, including a pair of twins, had retarded psychomotor development, poor social contact, and seizures. Biologically, hyperhomocysteinemia and hypomethioninemia were found associated with low folate levels in serum and red cells, especially undetectable methyltetrahydrofolate in red cells. In the fourth child, prenatal diagnosis was not conclusive because of moderate decrease of enzymatic activity in chorionic villi and trophoblast. The girl was also affected, as shown by hyperhomocysteinemia and low folate levels found several days after birth. A 677C-->T (Ala-->Val) mutation was found in a homozygous state in the four children and in the father. Additionally, a second homozygous mutation, 1081C-->T, changing an arginine to cysteine also was identified in all of the children, whereas the distantly consanguineous parents were heterozygous. This amino acid substitution affecting an arginine residue in a sequence located at the end of catalytic domain seems critical for the function of the enzyme. The difficulty of prenatal diagnosis is discussed given the variability found in enzymatic activity and in the clinical phenotypes.
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PMID:Methylenetetrahydrofolate reductase deficiency in four siblings: a clinical, biochemical, and molecular study of the family. 1076

Neuropsychiatric involvement in systemic lupus erythematosus (NPSLE) is considered as one of the major manifestations of the disease. Epilepsy has been documented in about 10% of patients with systemic lupus erythematosus (SLE). It is well known that vascular damage in SLE occurs because of multiple mechanisms including hypercoagulation. It has been recently reported that in SLE patients raised levels of homocysteine are associated with arterial thrombosis. Hyperhomocysteinaemia is a condition due to both genetic and non-genetic factors. The most common genetic defect in homocysteine metabolism is a decreased activity of a common 5,10-methylenetetrahydrofolate reductase (MTHFR) variant (677C -->T, a thermolabile form). In this paper we describe the epileptic manifestations in six out of 55 SLE patients. Seizures were the SLE onset symptom for three patients, appeared during the active disease in two cases, and occurred during a period of clinical remission in one patient. In all cases we documented the association of epilepsy with the MTHFR mutation: the homozygosity form was present in one case (16.7%), and heterozygosity in five cases (83.3%). Nevertheless, levels of homocysteine in plasma were in the normal range. Moreover, we found a decrease in the level of S protein values in one case, a high titre positivity of anticardiolipin antibodies (aCL) (IgG and IgM) in three patients and low titre positivity (IgG) in one patient, and lupus anticoagulant (LAC) positivity in four cases. In conclusion, we believe that the abnormalities of coagulation present in our patients could be related to epileptogenesis or to an alteration of the seizure threshold.
Seizure 2002 Jun
PMID:The 677C --> T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in epileptic patients affected by systemic lupus erythematosus. 1202 72

Severe hyperhomocysteinemia (50-200 microM) often presents itself with acute neuronal dysfunction including seizures and psychosis. Its moderate form (15-50 microM) is associated with cognitive impairment and dementia. We investigated the neuropharmacological effects of homocysteine and its oxidized forms, homocysteinesulfinic acid (HCSA) and homocysteic acid (HCA), on neuronal network function utilizing dissociated cortical neurons from embryonic Wistar rats on microelectrode arrays. All substances inhibited dose-dependently and reversibly spontaneous neuronal network activity within seconds: L-HCSA and L-HCA blocked spontaneous spike rate (SSR) significantly at very low concentrations, with an IC50 of 1.9 and 1.3 microM, respectively; whereas the dose-response curve of D,L-homocysteine revealed an IC50 of 401 microM. These effects were antagonized by 2-amino-5-phosphonovaleric acid (APV) pointing to the NMDA receptor as mediator of this fast and reversible inhibition of network activity. We conclude that a neuronal dysfunction observed in hyperhomocysteinemia is likely due to HCSA and HCA since effective concentrations of homocysteine are not reached in patients.
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PMID:Implications for hyperhomocysteinemia: not homocysteine but its oxidized forms strongly inhibit neuronal network activity. 1475 42

There is growing evidence that chronic alcoholism is associated with a derangement in the sulfur amino acid metabolism. Excitatory aminoacids such as glutamate, aspartate, and homocysteine have been shown to be increased in patients with chronic alcoholism who underwent alcohol withdrawal. Furthermore, sustained hyperhomocysteinemia occurred in chronic alcoholics with active drinking pattern. Excitotoxicity can be induced by increased hormocysteine levels via rebound activation of NMDA receptor-mediated glutamatergic neurotransmission upon the removal of ethanol-evoked inhibition. Therefore, hyperhomocysteinemia may be responsible for the higher incidence of complications during alcohol withdrawal (e.g.stroke,convulsions). In addition, an association between brain atrophy and increased levels of homocysteine in chronic alcoholism was shown. This may have important implications for the pathogenesis of brain atrophy in alcoholics. Taking into account that high plasma homocysteine levels are helpful in the prediction of alcohol withdrawal seizures, early anti-convulsive therapy could prevent this severe complication. Supplementation of folate, a cofactor of the homocysteine metabolism, lowers raised homocysteine levels and therefore could be established as a new therapeutic strategy in alcohol withdrawal treatment. The results of various studies highlight the need for further research to prove whether alcoholics benefit from a reduced homocysteine level with respect to both, alcohol-related disorders and alcohol withdrawal symptoms.
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PMID:[Folate against hyperhomocysteinemia. A new approach for the prevention and therapy of alcoholism-associated disorders?]. 1525 82

Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is characterized by varying degrees of developmental delay, motor and gait abnormalities, seizures, and thrombosis. Biochemical abnormalities include homocystinuria and hyperhomocysteinemia. Clinical severity correlates with MTHFR activity in cultured fibroblasts; activity can also be assayed in cultured amniocytes and chorionic villus cells (CVC). Forty-four private mutations have been identified, limiting the use of direct mutation detection for prenatal diagnosis. However, intragenic polymorphisms have been identified, making prenatal diagnosis by linkage analysis a possible option, even without knowledge of deleterious mutations. Prenatal diagnosis for severe MTHFR deficiency has been available by biochemical methodologies, but molecular genetic approaches have not yet been reported. We performed prenatal diagnosis for severe MTHFR deficiency in 11 at-risk pregnancies in seven families. A combined approach of linkage analysis and enzymatic assays was used in six pregnancies; linkage analysis alone was performed in one pregnancy. Linkage analysis for the 677C > T or 1298A > C polymorphisms predicted that all seven fetuses were unaffected. For six of these seven fetuses, enzymatic activities were also measured and demonstrated concordant results. Of the 10 pregnancies in which enzymatic assays were performed, activities in cultured amniocytes predicted six unaffected fetuses (1.4-7.1 nmol CHO/mg prot/h (U)) and one affected fetus (0.24 U [control 3.1-9.6 U]). Three pregnancies assessed via CVCs demonstrated two unaffected fetuses (3.6 and 7.7 U) and 1 affected fetus (0 U [control 4.5-7.8 U]). These values were compared to those of the probands (range = 0.02-0.7 U (control 2.4-11.7 U)) in cultured fibroblasts. Our findings suggest that linkage analysis for severe MTHFR deficiency can be a practical approach for prenatal diagnosis.
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PMID:Prenatal diagnosis for severe methylenetetrahydrofolate reductase deficiency by linkage analysis and enzymatic assay. 1589 55

Redox stress activates the endothelium and upregulates matrix metalloproteinases (MMPs), which degrade the matrix and lead to blood-endothelial barrier leakage. Interestingly, elevated levels of plasma homocysteine (Hcy) are associated with vascular dementia, seizure, stroke, and Alzheimer disease. Hcy competes with the gamma-aminobutyric acid (GABA)-A/B receptors and behave like an excitatory neurotransmitter. GABA stimulates the inhibitory neurotransmitter GABA-A/B receptor and decreases arterial blood pressure. However, the neural mechanisms of microvascular remodeling in hyperhomocysteinemia are unclear. This review addresses the idea that Hcy induces microvascular permeability by attenuating the GABA-A/B receptors and increasing redox stress, which activates a disintegrin and metalloproteinase that suppresses tissue inhibitors of metalloproteinase. This process causes disruption of the matrix in the blood-brain barrier. Understanding the mechanism of Hcy-mediated changes in permeability of the blood-brain barrier and extracellular matrix that can alter the neuronal environment in cerebral-vascular dementia is of great importance in developing treatments for this disease.
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PMID:Homocysteine in microvascular endothelial cell barrier permeability. 1604 81

Homocystein (Hcy) is regarded as a neuroexcitatory substance, which is therefore used as an epileptogenic agent in experimental epileptology. Experiments "in vivo" as well as "in vitro" revealed its relation to NMDA glutamate receptors, and its potential neurotoxicity. From the clinical aspect, hyperhomocysteinemia (HHcy), mostly as a marker of the risk factor in the vascular damage, was often studied in patients treated with antiepileptic drugs (AE). However, the neuroexcitatory influence of mild HHcy (up to 30 micromol/l) was rarely discussed. Out of a group of 123 adult patients on long-term conventional AE we analyzed 8 patients (7 men and one woman) with moderate to severe HHcy (30.7-109.0 micromol/l) retrospectively and 2-5 years after HHcy normalization. All of them suffered from partial and/or secondary generalized seizures accompanied by neuropsychological impairment depending on the aetiology of the disease. The patients were characterized by a concurrence of several factors: (1) All of them received conventional AEs inducing the cytochrome P 450 at the time HHcy was diagnosed. (2) Molecular-genetic tests showed enzymopathic impairment (methylentetrahydrofolate reductase-MTHFR mutation of the gene C677 T) also in all eight, homozygous in 7 cases and heterozygous in 1 case. (3) All patients were found to have a vitamin deficit or marginal values of at least one of the vitamins under study, especially folate and/or vitamin B6 and 812. With reference to clinical and EEG features, the potential neuroexcitatory influence of Hcy is discussed taking into account its effect on pathogenetic factors.
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PMID:Moderate hyperhomocysteinemia in patients treated for epilepsy. 1706 42

Cerebral venous thrombosis (CVT) is an under diagnosed condition for acute or slowly progressive neurological deficit. CVT is less frequent than arterial thrombosis. CVT has a wide spectrum of signs and symptoms, which may evolve suddenly or over the weeks. It is clinically challenging and mimics many neurological conditions such as, meningitis, encephalopathy, benign intracranial hypertension, and stroke. With increasing awareness, CVT cases are now being diagnosed more frequently. Newer imaging procedures have led to easier recognition of venous sinus thrombosis, offering the opportunity for early therapeutic measures. It may be difficult to diagnose it on clinical grounds alone. Headache is the most frequent symptom in patients with CVT, present in about 80% of cases. Most common pattern of presentation is with a benign intracranial hypertension-like syndrome. The prognosis of CVT is worse in elderly subjects. The shorter the history the more likely is the presence of focal signs. Sixth cranial nerve palsy usually manifests as false localizing sign. Subarachnoid haemorrhage (SAH) has been described, as the presenting event with CVT. Patients may have seizures that can be recurrent. Cranial nerve syndromes are seen with venous sinus thrombosis. Psychiatric disturbances are sometimes the presenting symptoms. CVT, an important cause of stroke in puerperium, is frequently observed in India. We have seen 6 patients of CVT out of 490 stroke registry. Of these 6, four were females and two were males. The mean age among females was 27.75 years and among males was 41.5 years. Of the 4 females two were postpartum; one was on oral contraceptive and in one Antiphospholipid antibodies (APLA) were positive. Amongst two males one had hyperhomocysteinemia and one had hyperlipidemia.
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PMID:Cerebral venous thrombosis--clinical presentations. 1718 79

Homocysteine, a sulphur-containing amino acid formed by demethylation of methionine, is involved in numerous processes of methyl group transfer, all playing pivotal roles in the biochemistry of the human body. Increased levels of plasma homocysteine (hyperhomocysteinemia) - which may result from a deficiency of folate, vitamin B6 or B12 or mutations in enzymes regulating the catabolism of homocysteine - are associated with a wide range of clinical manifestations, mostly affecting the central nervous system (e.g., mental retardation, cerebral atrophy and epileptic seizures). Recent evidence suggests that changes in the metabolic fate of homocysteine, leading to hyperhomocysteinemia, may also play a role in the pathophysiology of neurodegenerative disorders, particularly Parkinson's disease (PD). The nervous system might be particularly sensitive to homocysteine, due to the excitotoxic-like properties of the amino acid. However, experimental findings have shown that homocysteine does not seem to posses direct, cytotoxic activity, while the amino acid has proven able to synergize with more specific neurotoxic insults. Hyperhomocysteinemia has been repeatedly reported in PD patients; the increase, however, seems mostly related to the methylated catabolism of l-Dopa, the main pharmacological treatment of PD. Therefore, hyperhomocysteinemia may not be specific to movement disorders or other neurological diseases, the condition being, in fact, rather the result of the combinations of different factors, mainly metabolic, but also genetic and pharmacological, intervening in the neurodegenerative process.
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PMID:Homocysteine and Parkinson's disease: a dangerous liaison? 1733 37


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