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)

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

The balance of evidence from observational studies suggests that elevated levels of homocysteine 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 caused by factors associated with hyperhomocysteinaemia, including renal impairment, an atherogenic diet and cigarette smoking. Homozygosity for a defective thermolabile variant of methylene-tetrahydrofolate reductase, a common genetic polymorphism which results in hyperhomocysteinaemia, has not been consistently linked with stroke or other vascular diseases. Additional prospective studies are required, with sufficient power to characterise the form of the association between homocysteine concentrations and stroke risk, whether linear or threshold, and to study interactions between homocysteine, other dietary markers and established stroke risk factors such as smoking and hypertension. Ultimately, the case for a causal role for elevated levels of homocysteine in vascular disease, including stroke, will depend on data from randomised controlled trials of homocysteine-lowering interventions. Given the high prevalence of hyperhomocysteinaemia 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 and risk of stroke. 1050 Dec 75

The positive correlation existing between hyperhomocyst(e)inemia [HH(e)] and vascular disease has firmly been established through data derived from numerous epidemiological and experimental observations. Clinical data corroborate that homocysteine (Hcy) is an independent risk factor for coronary, cerebral and peripheral arterial occlusive disease or peripheral venous thrombosis. Hcy is a sulfhydryl-containing amino acid that is formed by the demethylation of methionine. It is normally catalyzed to cystathionine by cystathionine beta-synthase a pyridoxal phosphate-dependent enzyme. Hcy is also remethylated to methionine by 5-methyltetrahydrofolate-Hcy methyltransferase (methionine synthase), a vitamin B12 dependent enzyme and by betaine-Hcy methyltransferase. Nutritional status such as vitamin B12, or vitamin B6, or folate deficiencies and genetic defects such as cystathionine beta-synthase or methylene-tetrahydrofolate reductase may contribute to increasing plasma homocysteine levels. The pathogenesis of Hcy-induced vascular damage may be multifactorial, including direct Hcy damage to the endothelium, stimulation of proliferation of smooth muscle cells, enhanced low-density lipoprotein peroxidation, increase of platelet aggregation, and effects on the coagulation system. Besides adverse effects on the endothelium and vessel wall, Hcy exert a toxic action on neuronal cells trough the stimulation of N-methyl-D-aspartate (NMDA) receptors. Under these conditions, neuronal damage derives from excessive calcium influx and reactive oxygen generation. This mechanism may contribute to the cognitive changes and markedly increased risk of cerebrovascular disease in children and young adults with homocystunuria. Moreover, during stroke, in hiperhomocysteinemic patients, disruption of the blood-brain barrier results in exposure of the brain to near plasma levels of Hcy. The brain is exposed to 15-50 microM H(e). Thus, the neurotoxicity of Hcy acting through the overstimulation of NMDA receptors could contribute to neuronal damage in homocystinuria and HH(e). Since HH(e) is associated with certain neurodegeneratives diseases, in the present review, the molecular mechanisms involved in neurotoxicity due to Hcy are discussed.
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PMID:[Hyperhomocysteinemia: atherothrombosis and neurotoxicity]. 1079 37

Heterozygosity and/or homozygosity for mutations at the genes of the enzymes involved in homocysteine metabolism may confer an increased risk for thrombosis by causing hyperhomocysteinemia. Although the mutations related to homocysteine metabolism possibly increase the risk of stroke, the data are conflicting and there are very few reports linking these defects to acute stroke in children. We aimed to study the role of these mutations in Turkish children with ischemic stroke. Forty-six patients having cerebral infarct were clinically diagnosed, and the infarction verified with magnetic resonance imaging of the brain was included in the study. All patients were below the age of 18 (10 months to 18 years). Sixty-eight controls, consecutively selected among healthy unrelated subjects from the same geographic area of Turkey without personal and family history of thrombosis, stroke or Behest's disease, were included. Genotyping for the common mutations was carried out by the methods described previously. There was no difference between the pediatric stroke patients and controls for the distribution of methylene tetrahydrofolate reductase (MTHFR) 677 C-T, MTHFR 1298 A-C, methylene tetrahydrofolate dehydrogenase (MTHFD) 1958 G-A and methionine synthase reductase (MTRR) 66 A-G alleles. There was no risk for double gene alterations (MTHFR 677 C-T vs. 1298 A-C) after individuals with FV 1691 A mutation is excluded. Twelve of the 46 patients were found to carry FV 1691 A mutation (26.0%), one being homozygote. The cerebral infarct risk for FV 1691 A was found to be 6.4 (CI 95% 1.7-23.0). Eight of the 46 patients were found to carry PT 20210 A mutation (16.6%). Two of the FV 1691 A heterozygous patients carried PT 20210 A mutation at the same time (4.2%). As a conclusion, we can say that FV 1691 A and PT 20210 A mutations are important and must be included to the routine analysis of pediatric stroke patients.
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PMID:Common mutations at the homocysteine metabolism pathway and pediatric stroke. 1132 21

A subgroup of children with arterial ischemic stroke in the pre- or perinatal period present with delayed diagnosis. We identified 22 children who met the following criteria: (1) normal neonatal neurological history, (2) hemiparesis and/or seizures first recognized after two months of age, and (3) computed tomography or magnetic resonance imaging showing remote cerebral infarct. Laboratory evaluations included protein C, protein S, antithrombin, activated protein C resistance screen (APCR), Factor V Leiden (FVL), prothrombin gene defect, methylene tetrahydrofolate reductase variant (MTHFR), anticardiolipin antibody (ACLA), and lupus anticoagulant. Not all children received all tests. Age at last visit ranged from 8 months to 16.5 years (median 4 years). Twelve were boys. Fourteen had left hemisphere infarcts. Median age at presentation was 6 months. Eighteen had gestational complications. Fourteen children had at least transient coagulation abnormalities (ACLA = 11, ACLA + APCR = 1, APCR = 2 with FVL + MTHFR = 1); six of these children had family histories suggestive of thrombosis. Cardiac echocardiogram was unremarkable in the 15 tested. Outcomes included persistent hemiparesis in 22; speech, behavior, or learning problems in 12; and persistent seizures in five, with no evidence of further stroke in any patient. The persistence and importance of coagulation abnormalities in this group need further study.
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PMID:Presumed pre- or perinatal arterial ischemic stroke: risk factors and outcomes. 1150 98

We describe a 36-year-old man with familial protein S deficiency and homozygosity to the methylene tetrahydrofolate reductase (MTHFR) thermolabile variant who had a stroke followed by an episode of idiopathic osteonecrosis that was successfully managed by surgical core decompression. The patient's symptomatic thrombophilia, as well as that of several of his first-degree relatives who also had thrombotic events, raises the possibility that the thrombophilia was a contributing factor to the development of his osteonecrosis.
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PMID:Idiopathic osteonecrosis in an adult with familial protein S deficiency and hyperhomocysteinemia. 1168 42

The vitamins folic acid, B12 and B6 and B2 are the source of coenzymes which participate in one carbon metabolism. In this metabolism, a carbon unit from serine or glycine is transferred to tetrahydrofolate (THF) to form methylene-THF. This is either used as such for the synthesis of thymidine, which is incorporated into DNA, oxidized to formyl-THF which is used for the synthesis of purines, which are building blocks of RNA and DNA, or it is reduced to methyl-THF which used to methylate homocysteine to form methionine, a reaction which is catalyzed by a B12-containing methyltransferase. Much of the methionine which is formed is converted to S-adenosylmethionine (SAM), a universal donor of methyl groups, including DNA, RNA, hormones, neurotransmitters, membrane lipids, proteins and others. Because of these functions, interest in recent years has been growing particularly in the area of aging and the possibility that certain diseases that afflict the aging population, loss of cognitive function, Alzheimer's disease, cardiovascular disease, cancer and others, may be in part explained by inadequate intake or inadequate status of these vitamins. Homocysteine, a product of methionine metabolism as well as a precursor of methionine synthesis, was shown recently to be a risk factor for cardiovascular disease, stroke and thrombosis when its concentration in plasma is slightly elevated. There are now data which show association between elevated plasma homocysteine levels and loss of neurocognitive function and Alzheimer's disease. These associations could be due to a neurotoxic effect of homocysteine or to decreased availability of SAM which results in hypomethylation in the brain tissue. Hypomethylation is also thought to exacerbate depressive tendency in people, and for (colorectal) cancer DNA hypomethylation is thought to be the link between the observed relationship between inadequate folate status and cancer. There are many factors that contribute to the fact that the status of these vitamins in the elderly is inadequate. These factors are in part physiological such as the achlorhydria which affects vitamin B12 absorption and in part socioeconomic and habitual. We need more studies to confirm that these vitamins have important functions in the etiology of these diseases. We also need to establish if these diseases can be prevented or diminished by proper nutrition starting at a younger age.
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PMID:Folate, vitamin B12 and vitamin B6 and one carbon metabolism. 1181 80

Paediatric patients with systemic lupus erythematosus (SLE) and antiphospholipid antibodies (aPL), specifically lupus anticoagulants (LAC) are at high risk of developing thromboembolic events (TE). Our objectives were to determine the prevalence of TE in paediatric SLE patients with LAC and to determine if anticoagulation was effective to decrease morbidity, and prevent recurrent TE. We reviewed data on 149 paediatric SLE patients treated over 10 years. In all, 24 patients (16%) were LAC positive, and 21 TE occurred in 13 of these LAC positive patients (54% incidence of TE in LAC positive patients). The events were cerebral venous thrombosis (9), arterial stroke (3), deep venous thrombosis (4), pulmonary embolism (2), other venous event (1) and other arterial events (2). The median duration between SLE diagnosis and first TE was 15.2 months (range 0-62), and the median age at first TE was 15.1 years (range 11.4-18.4). Long-term anticoagulation was prescribed, and eight patients (62%) were transferred to adult care on lifelong oral warfarin; four (31%) remain under our care on lifelong warfarin, and one patient died of causes unrelated to her TE. No patient has been identified with deficiencies of protein C, protein S or antithrombin III. One patient is heterozygous for Factor V Leiden, and one is heterozygous for both the Prothrombin 20210A mutation and the MTHFR (methylene tetrahydrofolate reductase) mutation. Four patients had recurrent TE (31%), and three were not anticoagulated at the time of their second event. One patient had two recurrences on therapeutic anticoagulation. Thromboembolic events are prevalent in the LAC positive paediatric SLE population, and consideration for lifelong anticoagulation must occur after an initial TE.
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PMID:Thromboembolism in paediatric lupus patients. 1459 22

We present a case of ischaemic stroke in a 23-year-old woman, associated with homozygous methylene tetrahydrofolate reductase (MTHFR)-C677T and hyperhomocysteinaemia. Her other risk factors for stroke were ostium secundum atrial septal defect and use of oral contraceptives. This case illustrates the need to include plasma homocysteine (Hcy) measurement in investigations following stroke. In the presence of hyperhomocysteinaemia, the MTHFR genotype should be determined. If the index case has the polymorphism, then all first-degree relatives should also be investigated by measurement of plasma Hcy and determination of MTHFR genotype.
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PMID:Hyperhomocysteinaemia in a young woman presenting with stroke, associated with methylene tetrahydrofolate reductase C677T homozygosity. 1511 41

An increased incidence of ischemic stroke has been reported in patients with Crohn's disease. Cerebral infarcts are usually considered as a complication of the hypercoagulable state associated with this inflammatory bowel disease (IBD). The association between Crohn's disease, hyperhomocysteinemia and large-artery stroke of the young has rarely been reported. A 39-year-old woman, with prior medical history of Crohn's disease and hypertension, presented with an ischemic stroke of the left internal carotid artery (ICA) territory. Etiological workup disclosed bilateral high-grade ICA stenosis and atheroma of the subclavian and vertebral arteries. Exhaustive search for prothrombotic factors showed inflammation, with an increased level of fibrinogen and factor IX, and a marked hyperhomocysteinemia. Both vitamin B1 and vitamin B6 plasmatic levels were decreased. Heterozygous C677T methylene-tetrahydrofolate reductase gene mutation was present. This observation highlights the combined proatherogenic effect of vitamin B deficiency-induced hyperhomocysteinemia and inflammation leading to large-artery stroke of the young in the setting of Crohn's disease. Our case report stresses the importance of vitamin deficiency screening in patients with IBD in terms of stroke prevention.
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PMID:Large-artery stroke in a young patient with Crohn's disease. Role of vitamin B6 deficiency-induced hyperhomocysteinemia. 1517 25


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