Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.2.1.22 (cystathionine beta-synthase)
965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Severe hyperhomocysteinemia in its most frequent form, is caused by a homozygous enzymatic deficiency of cystathionine beta-synthase (CBS). A major complication in CBS deficiency is deep venous thrombosis or pulmonary embolism. A recent report by Mandel et al (N Engl J Med 334:763, 1996) postulated factor V Leiden (FVL) to be an absolute prerequisite for the development of thromboembolism in patients with severe hyperhomocysteinemia. We studied 24 patients with homocystinuria caused by homozygous CBS deficiency from 18 unrelated kindreds for FVL and for the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and investigated their possible interaction in the risk of venous thrombosis. Thrombotic complications were diagnosed in six patients, of whom only one was a carrier of FVL. On the contrary, thermolabile MTHFR caused by the 677C-->T mutation, was frequently observed among homocystinuria patients, especially among those with thromboembolic complications: three of six homocystinuria patients who had suffered from a thromboembolic event had thermolabile MTHFR. These data indicate that FVL is not an absolute prerequisite and probably not even a major determinant of venous thrombosis in homocystinuria, but, interestingly, thermolabile MTHFR may constitute a significant risk factor for thromboembolic complications in this inborn error of methionine metabolism.
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PMID:Homozygous cystathionine beta-synthase deficiency, combined with factor V Leiden or thermolabile methylenetetrahydrofolate reductase in the risk of venous thrombosis. 949 Jun 85

Thromboembolic disease results from an hypercoagulable state and multifactorial causes may lead to hypercoagulability. Thrombogenic risk factors can be acquired and/or inherited. For each thrombophilic patient, the main clinical features retained are: the patient age, the familial history, the recurrence of thromboembolic events, an unusual site of thrombosis. Anti-phospholipid antibodies, which are considered as acquired thrombogenic risk factors, can be detected with coagulation tests and/or Elisa methods. The association of antiphospholipid antibodies with thrombosis is defined as the anti-phospholipid syndrome. Last decades, genetic risk factors were identified. First of all, antithrombin, protein C and protein S deficiencies were described. These deficiencies are involved in about 10% of patients who develop thrombosis before the age of 50. In 1993, a new genetic risk factor was discovered: activated protein C resistance which is due to the Q506 mutation in factor V. This defect represents the most prevalent abnormality of inherited thrombophilia, affecting 20 to 40% of thrombophilic patients. Interestingly, hyperhomocysteinemia, known as potentially predisposing to arterial disease, was also recognized as a risk factor for venous occlusive disease. Several genes encoding homocystein metabolism enzymes, such as cystathionine beta-synthase or methylenetetrahydrofolate reductase are concerned. Establishment of a causal association between the presence of a biological abnormality and the occurrence of thrombosis may lead to an adapted prophylaxis whatever the risk situation.
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PMID:[Evaluation of hemostasis in venous thromboembolism pathology]. 975 22

Recent developments in ultrasound technology enable the noninvasive measurement of structural and functional vessel wall changes. Until now, the effect of homocysteine on the arterial wall has remained unclear: reports on intima-media thickness (IMT) yield conflicting results, whereas data on vessel wall stiffness are lacking. Because several cardiovascular risk factors result in an increased IMT or stiffness, different groups at risk for atherosclerotic disease, with special emphasis on hyperhomocysteinemia, were studied. Nineteen patients homozygous and 14 subjects heterozygous for cystathionine beta-synthase (CBS) deficiency, 21 patients with familial hypercholesterolemia (FH), 15 patients with essential hypertension, 20 smokers, and 28 control subjects were studied. The IMT values (both right and left) of the common carotid artery (CCA), bulb (BUL), internal carotid artery (ICA), and common femoral artery (CFA) were measured in millimeters by high-resolution ultrasound (Biosound). The distensibility (DC, in 10(-3). kPa-1) and compliance (CC in mm2. kPa-1) coefficients of the CCA (right and left) and CFA (right) were determined by a wall track system (Pie Medical). The mean IMT of the posterior wall in the CCA was 0.70+/-0.09 mm in healthy controls. For patients with vascular disease, FH, and hypertension and in smokers, the mean CCA IMT was larger, whereas no major differences in IMT were observed in patients either homozygous or heterozygous for CBS deficiency. The DC and CC in the right CCA were 23.5+/-6.9 (10(-3). kPa-1) and 0.9+/-0.3 (mm2. kPa-1) in healthy subjects, slightly lower in patients homozygous for CBS deficiency, and clearly lower in patients with vascular disease, FH, and hypertension. No positive correlation was found between plasma homocysteine level and either IMT, CC, or DC. Because smoking was a confounder in each risk group, a stepwise regression analysis was carried out to assess the contribution of each risk factor on IMT and arterial wall stiffness. Age explained most of the variation in IMT of the CCA (coefficient of determination R2 of 0.34), whereas R2 values for serum low density lipoprotein cholesterol, smoking (pack-years), and systolic blood pressure were 0.08, 0.07, and 0.06, respectively. Homocysteine did not contribute to variation in IMT in both the CCA and CFA. Age and smoking contributed to the variation in IMT in the CFA. The variation in DC and CC in the right CCA and right CFA could in part be explained by age, low density lipoprotein cholesterol, and blood pressure. Plasma homocysteine concentration explained only a small proportion of the variation in DC in the CCA (R2=0.02) and in CC in the CFA (R2=0.04). In this study, no relationship was found between homocysteine level and the thickness of the arterial wall, with only a marginal influence on stiffness.
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PMID:Carotid and femoral artery wall thickness and stiffness in patients at risk for cardiovascular disease, with special emphasis on hyperhomocysteinemia. 984 90

Thrombotic and thromboembolic complications are the main causes of morbidity and mortality in patients with homocystinuria. However, it is unusual for thrombosis and infarction to be the presenting feature leading to investigation for homocystinuria and cerebrovascular lesions in the first year of life. We describe a previously healthy 6-month-old infant who presented with a large middle-cerebral-artery territory infarction and died of massive brain swelling. Homocystinuria due to cystathionine beta-synthase (CBS) deficiency was diagnosed by metabolite analysis and confirmed by enzymatic activity measurement in a postmortem liver biopsy. Homocystinuria should be considered in the differential diagnosis of venous or arterial thrombosis, regardless of age, even in the absence of other common features of the disease. We recommend systematic metabolic screening for hyperhomocysteinemia in any child presenting with vascular lesions or premature thromboembolism.
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PMID:Fatal haemorrhagic infarct in an infant with homocystinuria. 1007

The alterations of the metabolism of methionine determining an accumulation of homocysteine in blood (hyperhomocysteinemia) recognize a multifactorial etiology, hereditary as well as acquired. To date several case-control studies have documented that the condition of hyperhomocysteinemia can be considered an independent risk factor of coronary disease and its noxious effects are dose-dependent. It exerts its effect by different mechanisms both prothrombotic and endothelial. In our study we started from an initial cohort of 2227 subjects (1210 males, 1017 females) aged between 45 and 64 years among which we selected 22 persons with at least 2 first-degree relatives below age 50 who had had either a major cardiovascular event (acute myocardial infarction or sudden death) or angiographically documented cardiac disease. We reconstructed the proper pedigrees obtaining 22 families in whom we identified four main subgroups to carry out analyses and comparisons: case-control, composed respectively of all the subjects who survived a major cardiovascular event or a coronary disease documented angiographically and clinically healthy subjects; affected line and non affected line, composed respectively of members belonging to the family line of the proband and members of collateral family line. Each of the subjects involved in the study underwent a complete history regarding job and sports activities, a standardized physical examination, 12-lead digital ECG according to the European Standard Communication Protocol. A blood sample was taken in fasting conditions to determine total cholesterol, HDL and LDL cholesterol, triglycerides, glycemia, fibrinogen, plasma homocysteine. The results indicate how among the cases there were more subjects with homocysteine higher than the 95 degrees percentile in males alone (p = 0.03), the estimated odds ratio calculated from Fisher's test was 8.34 (95% confidence interval 1.32-52.7). Despite the fact that mean age was significantly lower (p = 0.01) in males of the affected line compared to those of the non affected line, the results show much higher homocysteine values in the affected family line in both males and females: a difference quite evident in the distribution especially as regards the 95 degrees percentile. These results obtained in the subjects belonging to the same families emphasize that familial aggregation, which influences the sharing of the genetic patrimony, socio-cultural environment and food habits can induce a differential risk for homocysteinemia. The study of mutations of genes coding for the key enzymes of the metabolism of homocysteine, methylenetetrahydrofolate reductase and cystathionine beta-synthase, which we prepared, will enable use to evaluate the relative influence feeding habits and genetic factors have in the development of hyperhomocysteinemia.
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PMID:[A hyperhomocysteinemia study in a population with a familial factor for acute myocardial infarct and sudden cardiac death at a young age]. 1018 34

Mild hyperhomocysteinemia is associated to mutations either in cystathionine beta-synthase (CBS) or in 5,10-methylenetetrahydrofolate reductase (MTHFR) genes. In 1995, Sebastio et al. characterized a 68 bp insertion in cis with the most common CBS mutation (T833C) detected in homocystinuric patients. Recently, this double mutation has been detected in Italian and North-American controls. Compared to a group of patients affected by coronary artery disease, North-American controls showed not statistically significant difference. Moreover, Italian controls displayed a microheterogeneity in the mutant allele frequency distribution depending on their geographical origin (North or South of Italy). Aim of our study was to evaluate the prevalence of the double in cis mutation in different populations. We studied 377 healthy subjects belonging to various human groups. Genomic DNA, extracted from peripheral blood samples, was amplified using specific primers; PCR fragments were digested with Bsr I restriction enzyme to detect the double mutation. Our data show a significant heterogeneity among the populations studied, therefore this mutation turned out to be a reliable anthropogenetic marker. The distribution of the double mutation will contribute, with other DNA polymorphisms, to evaluate the genetic admixture of mixed populations such as Afro-Americans.
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PMID:World distribution of the T833C/844INS68 CBS in cis double mutation: a reliable anthropological marker. 1019 Mar 22

Cystathionine beta-synthase (CBS) is an important enzyme for methionine metabolism. A common 844ins68 insertion variant in the CBS gene has been described. This 68-bp duplication of the intron 7-exon 8 boundary within the CBS gene already has been reported to be associated in cis with the T833C mutation. Heterozygosity for CBS deficiency is considered an important cause of hyperhomocysteinemia that strongly relates to cardiovascular disease, as well as homozygosity for another common variant, the C677T mutation of 5,10-methylene tetrahydrofolate reductase. We analysed the prevalence of the 844ins68 variant in the CBS gene in 595 unrelated apparently healthy individuals from nine Italian regions and in 133 patients with coronary artery disease. Our data confirm that the T833C mutation cosegregates in cis with the 844ins68 in all carriers of the insertion. Furthermore, no statistical difference was found in the insertion variant allele frequency between controls and coronary artery disease patients. Our study indicates a microheterogeneity in the distribution of the 844ins68 in the Italian population.
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PMID:Microheterogeneity in the distribution of the 844ins68 in the cystathionine beta-synthase gene in Italy. 1033 41

Homocysteine is a sulfur amino acid whose metabolism stands at the intersection of two pathways: remethylation to methionine, which requires folate and vitamin B12 (or betaine in an alternative reaction); and transsulfuration to cystathionine, which requires pyridoxal-5'-phosphate. The two pathways are coordinated by S-adenosylmethionine, which acts as an allosteric inhibitor of the methylenetetrahydrofolate reductase reaction and as an activator of cystathionine beta-synthase. Hyperhomocysteinemia, a condition that recent epidemiological studies have shown to be associated with increased risk of vascular disease, arises from disrupted homocysteine metabolism. Severe hyperhomocysteinemia is due to rare genetic defects resulting in deficiencies in cystathionine beta synthase, methylenetetrahydrofolate reductase, or in enzymes involved in methyl-B12 synthesis and homocysteine methylation. Mild hyperhomocysteinemia seen in fasting conditions is due to mild impairment in the methylation pathway (i.e. folate or B12 deficiencies or methylenetetrahydrofolate reductase thermolability). Post-methionine-load hyperhomocysteinemia may be due to heterozygous cystathionine beta-synthase defect or B6 deficiency. Early studies with nonphysiological high homocysteine levels showed a variety of deleterious effects on endothelial or smooth muscle cells in culture. More recent studies with human beings and animals with mild hyperhomocysteinemia provided encouraging results in the attempt to understand the mechanism that underlies this relationship between mild elevations of plasma homocysteine and vascular disease. The studies with animal models indicated the possibility that the effect of elevated homocysteine is multifactorial, affecting both the vascular wall structure and the blood coagulation system.
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PMID:Homocysteine metabolism. 1044 23

Background: The continued identfication of new mutations in the cystathionine beta-synthase (CBS) gene is important in correlating the genotype/phenotype of patients with classic homocystinuria and in assessing whether heterozygosity of CBS deficiency is an important cause of mild hyperhomocysteinemia, an independent risk factor for occlusive vascular diseases. Methods and Results: Single-strand polymorphism and direct nucleotide sequencing were used to detect two novel mutations in the CBS gene of three homocystinuric patients from two unrelated families. The first mutation, a G-to-A transistion at nucleotide 1316 in exon 12, results in an amino acid substitution of arginine by glutamine at codon 439. The second mutation is a G-to-A transition at nucleotide 1109 in exon 10 and results in an amino acid substitution of cysteine by tyrosine at codon 370. All three patients are apparently compound heterozygotes, with one of the two novel mutations on one allele and the T(833)C mutation on the other allele. Conclusions: The absence of the G(1316)A and G(1109)A in 216 control alleles demonstrates that these two novel mutations do not represent common polymorphisms, but rather are responsible for the defective CBS enzyme activities encoded by one of the two alleles of the CBS gene in each of the two families.
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PMID:Two Novel Mutations in the Cystathionine beta-synthase Gene of Homocystinuric Patients. 1046

Recent genetic studies have led to the characterization of molecular determinants contributing to the pathogenesis of hyperhomocysteinemia. In this article we summarize the current insights into the molecular genetics of severe, moderate and mild hyperhomocysteinemia. We will consider deficiencies of the trans-sulfuration enzyme cystathionine beta-synthase (gene symbol: CBS), and the disturbances of the remethylation enzymes 5, 10-methylenetetrahydrofolate reductase (gene symbol: MTHFR), methionine synthase (gene symbol: MTR), and the recently identified methionine synthase reductase (gene symbol: MTRR). Furthermore, we will focus on clinically important genetic polymorphisms which are highly prevalent and thus of potential general interest.
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PMID:Molecular genetics of homocysteine metabolism. 1068 51


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