Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0038454 (stroke)
147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a patient who had an ischemic stroke aged 22 years, an inherited type I protein C deficiency and a heterozygous genotype of prothrombin gene 20210A. In view of recent reports of an increased risk for ischemic cerebral vascular disease in patients with the prothrombin 20210A mutation, we suggest that many of the reported cases of ischemic stroke and protein C deficiency may have had additional prothrombotic disorders such as the prothrombin mutation. The current data concerning the magnified risk for stroke in patients with the prothrombin 20210A mutation suggests the need to study all patients with premature stroke for this mutation and the other risk factors for thrombosis. This would include homocysteine, lupus inhibitor, anticardiolipin antibodies, and possibly the natural inhibitors of coagulation. It is possible that patients with the prothrombin 20210A mutation and ischemic cerebral vascular disease would benefit from long-term anticoagulation therapy in a similar way to patients with the antiphospholipid syndrome.
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PMID:Ischemic stroke in a young patient with protein C deficiency and prothrombin gene mutation G20210A. 989 Jul 20

Stroke is the third leading cause of death and the leading cause of chronic disability in the United States. In the past several decades, case series, case-control studies, and prospective cohort studies have successfully identified nonmodifiable risk markers for stroke, such as age, gender, race, ethnicity, heredity and several well-established modifiable risk factors for ischemic stroke. Hypertension, atrial fibrillation, other cardiac diseases, hyperlipidemia, diabetes, cigarette smoking, physical inactivity, carotid stenosis, and transient ischemic attack (TIA) are all potentially treatable conditions that predispose to stroke. Research on other putative stroke risk factors-including antiphospholipid antibodies, elevated homocysteine, alcohol, inflammation, and infection-is ongoing. Controlled trials have shown that stroke risk can be reduced by blood-pressure control, lipid-lowering agents, surgery for carotid stenosis, warfarin for atrial fibrillation, and antiplatelet agents. It is hoped that an improved understanding of stroke risk factors will reduce the future burden of stroke.
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PMID:Stroke risk factors and stroke prevention. 993 14

A common C677T mutation in the gene for the enzyme 5,10-methylenetetrahydrofolate reductase (5,10-MTHFR) has been linked to elevated levels of homocysteine and was therefore suspected to be a candidate genetic risk factor for arterial occlusive disease. Another mutation, factor V Leiden, has been established as a common hereditary risk factor for venous thrombosis, but its role in arterial disease remains controversial. We investigated the prevalence of both the C677T MTHFR mutation and the factor V Leiden mutation in 81 patients with transient ischemic attack (TIA) or minor stroke (MS) and in 81 age- and sex-matched control subjects free from clinically manifest vascular disease. We further compared clinical and laboratory data as well as clinical course of patients carrying the factor V Leiden mutation alone or in combination with the C677T MTHFR mutation and mutation-free patients. The prevalence of the MTHFR mutation did not differ between patients and control subjects with 11.1% homozygous carriers in both groups (OR for homozygous carriers 1.0; 95% CI 0.38-2.66). However, there was a trend towards a higher prevalence of carriers of factor V Leiden in patients (12.3%) than in control subjects (4.9%) (OR 2.75; 95% CI 0.83-9.17;p=0.09). Furthermore, we found some evidence that the combined occurrence of the C677T MTHFR mutation and factor V Leiden might unfavorably affect the clinical course of the disease, but the number of respective patients was small. Larger studies with a greater number of carriers of both the C677T MTHFR mutation and factor V Leiden seem therefore warranted.
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PMID:C677T MTHFR mutation and factor V Leiden mutation in patients with TIA/minor stroke: a case-control study. 995 Feb 59

High levels of homocysteine are associated with atherosclerosis. A thermolabile form of the enzyme methylene tetrahydrofolate reductase (MTHFR) has been proposed as a major cause of a genetic predisposition to hyperhomocysteinaemia and a point mutation at nucleotide 677 of the MTHFR gene causing a thermolabile MTHFR has been described. We looked for this mutation in 271 patients with CT proven cerebrovascular accidents and 173 control subjects. No significant difference in the frequency of the mutant genotype was found between patients with strokes and the control group. Separate analysis of those under 65 and subdividing stroke patients by anatomical location also revealed no significant difference. We conclude, therefore, that in this population the mutation evaluated is not a major contributor to the aetiology of cerebrovascular disease.
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PMID:Methylene tetrahydrofolate reductase C677T genotype and stroke. 995 81

Methionine synthase and 5,10-methylenetetrahydrofolate reductase (MTHFR) sequentially catalyze the remethylation of homocysteine to methionine. A point mutation in the encoding region of the methionine synthase gene, which results in substitution of an aspartic acid for a glycine residue (D919G), has been identified in patients of the cblG genetic complementation group; these patients exhibit significantly decreased methionine synthase activity. Nevertheless, the D919G mutation has also been reported to be common in the general population. In this study, we analyzed the distribution of methionine synthase D/G polymorphism in the Japanese population and examined the extent to which it is associated with altered homocysteine metabolism and late-onset vascular diseases. We studied 215 patients with coronary artery disease, 251 patients with histories of ischemic stroke, and 257 control subjects. The methionine synthase genotype was analyzed by polymerase chain reaction followed by HaeIII digestion; allele frequencies for the D919G variant of the enzyme proved to be similar in all 3 subject groups (control subjects, 0.17; coronary artery disease patients, 0. 17; and ischemic stroke patients, 0.19). Furthermore, in patients with ischemic stroke, plasma levels of homocyst(e)ine and folate were similar, irrespective of methionine synthase genotype. Thus, the methionine synthase D919G mutation was found to be common in the Japanese general population, and it appears unlikely that this polymorphism has a major effect on homocysteine metabolism and/or the onset of vascular diseases.
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PMID:Polymorphism of the methionine synthase gene : association with homocysteine metabolism and late-onset vascular diseases in the Japanese population. 997 10

We report a 13-year-old girl with nephropathic cystinosis on chronic peritoneal dialysis who presented with two episodes of stroke. Laboratory evaluation showed severe hyperhomocysteinemia (108 mumol/l). Further testing revealed that she was homozygous for the thermolabile variant of the methylenetetrahydrofolate reductase (MTHFR) gene. Treatment with folic acid and vitamin B12 lowered plasma homocysteine to less than 20 mumol/l. No further episodes of stroke occurred over a follow-up of 12 months. Homocysteine levels should be measured in patients with chronic renal failure, since simple and safe treatment with folic acid and vitamin B12 is effective in lowering the plasma homocysteine level in patients with the thermolabile MTHFR allele.
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PMID:Cerebral vascular complication and hyperhomocysteinemia in a cystinotic uremic child. 1010 Feb 95

Most large observational studies available today establish that moderate hyperhomocysteinemia, either genetically or nutritionally determined, is an independent risk factor for myocardial infarction, stroke, and thromboembolic disease. This is also true for chronic renal failure patients, who exhibit a high prevalence of hyperhomocysteinemia (85-100%), which reaches high plasma concentrations (20-40 microM, while control values range between 8 and 12 microM). After a renal transplant, homocysteine levels decrease, but tend to be higher than normal. The cause of hyperhomocysteinemia in renal failure is still obscure, since recent data have questioned the previous notion that a net homocysteine renal extraction and/or excretion take place in man. No matter the cause of its increase, the sulfur amino acid homocysteine is thought to induce an increment in cardiovascular risk through three basic biochemical mechanisms: (1) homocysteine oxidation, with H2O2 generation; (2) hypomethylation through S-adenosylhomocysteine accumulation, and (3) protein acylation by homocysteine thiolactone. The final result is membrane protein damage, endothelial damage, and endothelial cell growth inhibition, among other effects. Hyperhomocysteinemia, in general, is susceptible of therapeutic intervention with the vitamins involved in its metabolism. Depending on the cause, vitamin B6, vitamin B12, betaine, and/or folic acid can be effectively utilized. Chronic renal failure patients benefit from folic acid in high dosage: 1-2 mg are usually not effective ('relative folate resistance'), while 5-15 mg reduce homocysteine levels to a 'normative' range (<15 microM) in a substantial group of patients. Good results are also obtained in transplant patients, best with a combination of folic and vitamin B6. The results of the interventional trials focusing on the possible reduction in cardiovascular risk after homocysteine-lowering therapy, both in the general population and in end-stage renal disease, are expected soon, as well as the genetic and biochemical studies in suitable models, with the aim to clarify the cause-effect link suggested by the numerous observational and basic science studies.
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PMID:Homocysteine, a new crucial element in the pathogenesis of uremic cardiovascular complications. 1020 68

To examine whether moderate hyperhomocyst(e)inemia is associated with coronary artery disease and the number of diseased coronary vessels in Koreans, we investigated 201 patients with angiographically documented coronary artery disease and 187 healthy subjects without evidence of stroke and coronary artery disease. The mean plasma total homocysteine in patients was higher than in controls (10.3 micromol/L; 95% confidence interval, 7.0-13.6 vs. 8.9 micromol/L; 6.0-11.8) (p=0.005). The prevalence of moderate hyperhomocyst(e)inemia, defined as the top 90th percentile in controls (13.2 micromol/L), was higher in patients than in controls (23.9% vs. 10.2%, p=0.001). Plasma homocyst(e)ine levels were not correlated to age, body mass index, levels of serum cholesterol, creatinine, and uric acid. Based on multiple logistic regression analyses with adjustment for total cholesterol, hypertension, smoking status, diabetes, age, and body mass index, the adjusted odds ratio of moderate hyperhomocyst(e)inemia for coronary artery disease was 1.53 (95% confidence interval: 1.39-1.65, p=0.0001). Moderate hyperhomocyst(e)inemia, diabetes mellitus, and old age were more prevalent in patients with triple-vessel disease than in single- or double-vessel disease (p=0.02). Multiple logistic regression analysis revealed that moderate hyperhomocyst(e)inemia was a significant predictor of triple-vessel disease with odds ratio of 2.78 (95% confidence interval: 1.08-7.10, p=0.02). We conclude that moderate hyperhomocyst(e)inemia is an independent risk factor for coronary artery disease, and also related significantly to the presence of triple-vessel disease.
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PMID:Moderate hyperhomocyst(e)inemia is associated with the presence of coronary artery disease and the severity of coronary atherosclerosis in Koreans. 1021 80

Moderately elevated plasma homocysteine levels have been established as an independent risk factor for atherosclerosis and its complications, including cerebrovascular disease. A common mutation (C677T) in the gene encoding for the enzyme methylenetetrahydrofolate reductase (MTHFR) has been linked to increased plasma homocysteine levels in homozygous carriers, particularly in the presence of low folate levels. However, the results of most of the previous studies suggest that the C677T MTHFR mutation is not a significant risk factor for arterial disease. This discrepancy might, at least partly, be due to the fact that plasma homocysteine levels are influenced by several other factors, including age, gender, renal function, and vitamin status. We investigated the relation between plasma homocysteine levels, the C677T MTHFR mutation, and these other factors in a population of 96 patients with transient ischemic attacks or minor strokes and in 96 age- and sex-matched healthy control subjects. We further tested the value of a multivariate model for the prediction of plasma homocysteine levels under particular consideration of the MTHFR mutation status. In the patients, plasma homocysteine levels were significantly higher than in the healthy control subjects. With regard to the MTHFR mutation, the distribution of the C/C, C/T, and T/T genotypes was not significantly different between patients and healthy control subjects. Univariate (linear regression) analysis revealed significant (positive) correlations between plasma homocysteine levels on the one hand and age and creatinine on the other, the latter particularly in subjects with creatinine levels in the upper quartile. Significant (negative) correlations were found between plasma homocysteine levels, vitamin B12, and folate levels. However, these relations could much better be expressed by means of a multiplicative regression model. T/T subjects exhibited slightly higher homocysteine levels than C/C and C/T subjects; however, the differences between the 3 genotypes were not significant. Multivariate (stepwise regression) analysis revealed age, vitamin B12 levels, folate levels, and creatinine levels as significant independent variables influencing plasma homocysteine levels, whereas the MTHFR mutation status and gender were removed from the model. Considering all 192 subjects, only 28.8% of the variance of plasma homocysteine levels could be accounted for by the model. However, in homozygous carriers of the MTHFR mutation, the predictive power of the model is very high, explaining 76.1% of the variance of plasma homocysteine levels. According to our results, the C677T mutation does not constitute a major risk factor for transient ischemic attack or minor stroke, even under consideration of other possibly confounding factors that are known to affect plasma homocysteine levels. However, it is possible to predict plasma homocysteine levels in homozygous carriers of the mutation with high accuracy. The knowledge of the MTHFR mutation status may therefore help to identify subjects at high risk for hyperhomocysteinemia.
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PMID:Genetic and nongenetic factors influencing plasma homocysteine levels in patients with ischemic cerebrovascular disease and in healthy control subjects. 1036 Jun 32

The balance of evidence from observational studies suggests that elevated homocysteine levels are associated with increased risk of carotid artery disease and stroke. There is however a paucity of prospective studies. There are also concerns regarding confounding due to factors associated with hyperhomocysteinemia, including renal impairment, an atherogenic diet and cigarette smoking. Homozygosity for a defective thermolabile variant of MTHFR, a common genetic polymorphism which results in hyperhomocysteinemia, has not been consistently linked with stroke or other vascular disease. There is a need for additional prospective studies with data on relevant confounders, sufficient power to characterise the form of the association between homocysteine concentrations and stroke risk, whether linear or threshold, and power to study interactions between homocysteine, other dietary markers and established stroke risk factors such as smoking and hypertension. Similarly, the evidence linking hyperhomocysteinemia with hypertension is limited and inconsistent. Given the biological mechanisms proposed in support of the homocysteine-CVD hypothesis, one would predict a positive association between homocysteine and blood pressure. There is a need to address this hypothesis directly in studies with reliable measurements of both homocysteine and blood pressure. Ultimately, the case for a causal role for elevated homocysteine levels in vascular disease, including hypertension and stroke, will depend on data from randomised controlled trials of homocysteine lowering interventions. Given the high prevalence of hyperhomocysteinemia in apparently well nourished populations and the tendency for homocysteine concentrations to increase with age, modest effects of homocysteine on stroke risk will have profound implications for public health.
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PMID:Homocysteine, hypertension and stroke. 1037 45


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