The C677T mutation in the methylenetetrahydrofolate reductase gene contributes to hyperhomocysteinemia in patients taking anticonvulsants

Hyperhomocysteinemia, a possible risk factor for vascular disease can result from folate deficiency due to anticonvulsant therapy. A reaction catalyzed by 5,10-methylenetetrahydrofolate reductase (MTHFR) supplies 5-methyltetrahydrofolate, needed to remethylate homocysteine to methionine. MTHFR gene mutation (C677T) also can lead to hyperhomocysteinemia. We examined interaction between anticonvulsant therapy, C677T homozygosity, serum folate concentration, and plasma total homocysteine (tHcy) concentration in 81 epileptic patients. Patients receiving monotherapy showed no difference in occurrence of hyperhomocysteinemia (tHcy>90th percentile for controls) between homozygotes for C677T and heterozygotes or patients with no mutant MTHFR. No monotherapy patient was folate deficient (<3 ng/ml). Among patients receiving multidrug therapy, hyperhomocysteinemia in homozygotes for C677T occured significantly more often than in heterozygotes or patients with no mutant enzyme (88.9 vs. 21.1%). The same was true for folate deficiency (44.4 vs. 0%). The C677T mutation is closely related to hyperhomocysteinemia and folate deficiency in epileptic patients taking multiple anticonvulsants.     

阿尔茨海默病与叶酸还原酶基因的关联研究

目的　探讨中国人群中阿尔茨海默病 (AD)的发生与 5 ,10 亚甲基四氢叶酸还原酶(methylenetetrahydrofolatereductase ,MTHFR)基因C6 77T错义突变的关系。方法　利用聚合酶链反应 -限制性片段长度多态性 (PCR RFLP)技术 ,检测 75例AD患者和 72例健康老人的MTHFR基因C6 77T位变异 ,并加以对照分析。结果　AD患者MTHFR/C6 77T错义突变的基因频率与健康老人之间无明显差异(基因型P >0 .0 5 ;等位基因P >0 .0 5 ) ,性别分组后亦未见有显著性差异存在。进一步以是否携有等位基因APOE 4分组 ,也未能发现AD患者的APOE 4携带者与MTHFR基因之间的相关性。结论　本研究未能发现MTHFR/C6 77T突变在阿尔茨海默病的发病中的作用。     

Association of C677T polymorphism in the methylenetetrahydrofolate reductase gene (MTHFR gene) with ischemic stroke: a meta-analysis

Abstract

Objective:

Studies on association between methylenetetrahydrofolate reductase gene (MTHFR) C677T gene polymorphism and ischemic stroke have shown conflicting results. We have conducted a meta-analysis to determine the precise association of the C677T polymorphism of MTHFR gene with risk of ischemic stroke.

Materials and methods:

We searched electronic databases Medline, EMBASE, and Google Scholar (last search dated till August 2014). Pooled odds ratios (ORs) with 95% confidence intervals (CIs) from random or fixed-effects models were calculated. The methodological quality of included studies was determined by the quality assessment scale.

Results:

Thirty eight case–control studies fulfilled our inclusion criteria comprising 6310 patients and 8297 controls. The significant associations between MTHFR C677T genetic polymorphism and risk of ischemic stroke were observed in dominant (OR, 1·09; 95% CI, 1·06–1·12, P-value < 0·001) and recessive (OR, 1·31; 95% CI, 1·19–1·44, P-value < 0·001) inheritance models. In an Asian population, significant association between the MTHFR polymorphism and ischemic stroke was observed (dominant model: OR 1·36, 95% CI 1·23–1·49 and under recessive model OR, 1·29; 95% CI, 1·15–1·45). In the Caucasian population borderline, non-significant association was observed under dominant model of inheritance (OR, 1·05; 95% CI, 0·99–1·10) but significant association was observed under the recessive model of inheritance (OR, 1·33; 95% CI, 1·13–1·58).

Conclusion:

The present study results suggest that MTHFR C677T genetic polymorphism is a probable risk of ischemic stroke.     

The 677C --> T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in epileptic patients affected by systemic lupus erythematosus.

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.     

The prevalence of C677T mutation in the methylenetetrahydrofolate reductase gene and its association with venous thrombophilia in Taiwanese Chinese

C677T mutation of the methylenetetrahydrofolate reductase gene remains a controversial risk factor for venous thrombosis in Whites. The prevalence of methylenetetrahydrofolate reductase C677T genotype and its association with vascular thrombosis are not well established in Chinese population. We conducted a case-control study to investigate the prevalence of methylenetetrahydrofolate reductase C677T gene mutation and its association with venous thrombophilia in Taiwanese Chinese. The subjects consisted of 112 venous thrombophilic patients and 125 healthy controls, with similar age (p=0.08) and sex (p=0.58). The prevalent rates of C/T heterozygote were 32.8 and 44.6%; whereas those of T/T homozygote were 6.4 and 8.0% in the controls and patients, respectively. Neither C/T heterozygote (odds ratio, 1.7; 95% confidence interval, 1.0-3.0, p=0.05] nor T/T homozygote (odds ratio, 1.4; 95% confidence interval, 0.5-4.0, p=0.5) was significantly associated with venous thrombosis. Even when only subjects (52 patients and 107 controls) with normal inhibitor protein levels were analyzed, the association of T/T homozygote with venous thrombosis remained insignificant (p=0.06) with an odds ratio (95% confidence interval) of 3.4 (0.99-11.7). We concluded that, in Taiwanese Chinese, methylenetetrahydrofolate reductase C677T mutation is a common genetic mutation, but T/T homozygote is not a significant risk factor for venous thrombophilia.     

Effects of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism on executive function in schizophrenia

BACKGROUND: The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism has been associated with both overall schizophrenia risk and severity of negative symptoms. This study examined whether schizophrenia patients homozygous for the risk allele (T/T) exhibit greater impairment in executive function, and determined the extent to which MTHFR's effects on negative symptoms underlie this relationship. METHODS: 200 outpatients with chronic schizophrenia were evaluated with the Verbal Fluency Test (VFT), Wisconsin Card Sort Test (WCST), and California Verbal Learning Test (CVLT). Performance was stratified by MTHFR C667T genotype. Path analysis determined the extent to which MTHFR effects on negative symptoms mediated the relationship between genotype and cognitive measures. RESULTS: T/T subjects exhibited significantly greater deficits on the VFT and had more difficulty achieving the first category on the WCST. Genotype groups did not differ in CVLT performance. C677T effects on negative symptoms contributed to, but did not fully account for, genotype effects on VFT. Negative symptoms did not mediate WCST performance. CONCLUSIONS: MTHFR C677T genotype contributes to certain executive function deficits in schizophrenia. These deficits remained significant when taking into account mediating effects of negative symptoms. Although the intermediate mechanisms for C677T effects remain uncertain, these results suggest that MTHFR-related cognitive impairment and negative symptoms reflect differing neural substrates.     

Evaluation of the relationship between C677T variants of methylenetetrahydrofolate reductase gene and hyperhomocysteinemia in children receiving antiepileptic drug therapy

Homocysteine (Hcy) is a sulfur-containing amino acid involved in methionine metabolism. Elevated plasma Hcy concentration is a possible risk factor for vascular disease. Folate and vitamin B-12 are vitamins that are necessary for remethylization of Hcy to methionine. The methylenetetrahydrofolate reductase (MTHFR) is the key enzyme in remethylation of Hcy to methionine and supplies the required 5-methyltetrahydrofolate as the methyl donor for this reaction. It is well known that some antiepileptic drugs (AED) can lead to hyperhomocysteinemia by affecting the levels of folate and vitamin B-12. The C677T variant of MTHFR gene can also lead to hyperhomocysteinemia particularly when serum folate level is decreased. In this study, we investigated the levels of serum folate, vitamin B-12 and Hcy in epileptic patients receiving carbamazepine (CBZ) or valproic acid (VPA) as monotherapy, and we also evaluated the probable contribution of the C677T variant of MTHFR gene in hyperhomocysteinemia. A total of 93 patients with idiopathic epilepsy receiving CBZ or VPA as monotherapy were included in this study. CBZ and VPA groups consisted of 29 and 64 patients, respectively. The control group comprised 62 healthy children. We measured serum folate, vitamin B-12 and Hcy levels in each group. We found that mean serum folate level was statistically lower and mean Hcy level was higher in epileptic patients receiving CBZ or VPA when compared with those of controls'. We also determined the C677T variants of MTHFR gene (as normal, heterozygote or homozygote) in epileptic patients. We compared the variant groups for serum folate, vitamin B-12 and Hcy levels and found no significant differences among them. In conclusion, C677T variants of MTHFR gene have no contribution in hyperhomocysteinemia in epileptic patients receiving CBZ or VPA.     

MTHFR C677T mutation in central retinal vein occlusion: a case-control study in Chinese population

Our previous study found that hyperhomocysteinemia was strongly associated with central retinal vein occlusion (CRVO) in the Chinese population. The aim of this study is to determine whether MTHFR C677T mutation is an independent risk factor for CRVO in the Chinese population. A matched case-control study was conducted between July 2004 and May 2005. The study cohort consisted of 64 individuals that had been diagnosed with CRVO and 64 healthy controls (matched for age, gender, hypertension, smoking, and drinking habits). None of the cases or controls had a history of diabetes, glaucoma, medication or any other vascular events that might influence plasma homocysteine levels. A cross-sectional analysis among the 64 cases was performed to compare the prevalence of MTHFR C677T mutation among subjects with and without ischemia and subjects aged above 45 and below 45 years. MTHFR C677T mutation was determined by the template-directed dye-terminator incorporation with fluorescence polarization (TDI-FP) method. The result showed that the prevalence of the MTHFR 677 TT genotype did not significantly differ between patients and controls. However, 10 (34.5%) MTHFR C677 TT genotype was found in the ischemic group but only 4 (14.3%) in the nonischemic group (p=0.026). And we found that 6 MTHFR C677 TT genotype patients who have hyperhomocysteinemia in the ischemic group but only 2 in the nonischemic group (p=0.016).It suggests that MTHFR C677T mutation is associated with hyperhomocysteinemia in the ischemic CRVO in the Chinese population. It may contribute to hyperhomocysteinemia and associate with the development of CRVO.     

Role of methylenetetrahydrofolate reductase gene (MTHFR) 677C>T polymorphism in pediatric cerebrovascular disorders

Homozygosity for the methylenetetrahydrofolate reductase (MTHFR) 677C>T mutation (MTHFR TT) has been linked to an increased risk for stroke, coronary artery disease, and migraine headaches. The authors analyzed the potential link between MTHFR 677C>T homozygosity and childhood stroke. A true association might facilitate screening, recurrence risk stratification, and treatment in patients with cerebrovascular disease. They performed a retrospective chart review of children tested for the MTHFR 677C>/T mutation; 533 patients underwent MTHFR testing, and 8% were homozygous for the MTHFR 677C>T mutation. There was no difference in the cohort compared with the prevalence in the general population. This suggests that the MTHFR 677 C>T polymorphism played a minimal role or no role in stroke risk. However, the data suggest that the MTHFR TT genotype may influence migraine susceptibility in children because there was a higher proportion of migraine patients (28.6%) with the MTHFR TT homozygous genotype.     

亚甲基四氢叶酸还原酶基因C677T多态性与先兆型偏头痛相关性的Meta分析

目的探讨亚甲基四氢叶酸还原酶(MTHFR)基因C677T多态性与先兆型偏头痛(MA)的相关性。方法检索1994年1月~2013年3月MEDLINE、EBSCO、EMBASE数据库及PubMed,以及中国医院知识仓库中文期刊全文库、中国生物医学文献数据库、维普、万方等中文数据库中关于MTHFR基因C677T多态性与MA相关性的文献,按纳入、排除标准选择文献,并采用RevMan 5软件进行Meta分析。结果共纳入18项病例对照研究,其中MA患者4276例,对照者27979例。各研究间具有很强的异质性(P0.05,I2=72%),采用随机效应模型分析。Meta分析显示,MTHFR基因TT基因型发生MA的风险明显高于CT+CC基因型(OR=1.33,95%CI:1.02~1.75,P0.01)。剔除不符合H-W遗传平衡定律的3篇文献后,总的分析结果依然稳定(OR=1.39,95%CI:1.02~1.88,P0.01)。在MA人群中所做种族分层分析结果显示,在地中海人种TT基因型增加了MA的发病风险,而在其他高加索人(包括北欧人种和印度雅利安人种)、芬兰人、土耳其人及日本人的研究并未显示出这种相关性。结论 MTHFR基因C677T多态性与MA相关,其TT基因型个体MA发病的风险增加。这在不同种族间存在一定差别。     

Two siblings with a homozygous MTHFR C677T (G80A-RFC1) mutation and stroke

Background  Stroke is a rare disorder in childhood; among its risk factors, C677T mutations in the methylenetetrahydrofolate reductase (MTHFR) gene with secondary hyperhomocysteinemia are considered. Patients and methods  We report on a family in which two brothers had arterial ischemic stroke (AIS). One of these siblings came to our observation at the age of 4 years because of decreased motility of the right arm, mild hypotrophy of the right limbs, and frequent falls: brain magnetic resonance imaging revealed a large left AIS. Family history revealed that his older brother had died at the age of 7 due to AIS. An extensive metabolic investigation revealed a homozygous C677T [G80A-reduced folate carrier 1 (RFC1)] mutation in the MTHFR gene in both the affected siblings and in their healthy older brother and heterozygous mutations in the parents. None of these family members presented hyperhomocysteinemia. Conclusions  To the best of our knowledge, this is the first family with multiple AIS patients harboring homozygous MTHFR gene C677T (G80A-RFC1) mutations without associated hyperhomocysteinemia (the latter factor is usually considered as effector of vascular damage in patients with MTHFR C677T mutations). The pathogenic hypotheses of stroke in this family are considered.     

Comparison of the frequency of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in depressed versus nondepressed patients

Numerous studies have found an association between low serum folate levels and incidence of depression. Folic acid supplementation has been successfully used as an adjunct to treat depression in these patients. However, some individuals have a genetic deficiency in the methylene tetrahydrofolate reductase (MTHFR) gene that limits conversion of folic acid to its biologically active form, L-methylfolate. Several studies have identified a higher frequency of genetic variations in the MTHFR gene in depressed patients than in nondepressed controls. This study evaluated the frequency of the most common genetic variation MTHFR C667T in a group of depressed U.S. Caucasians and compared results with those of a control group of nondepressed U.S. Caucasians. Subjects were recruited from a psychiatric practice, an ambulatory care clinic, and the community. Informed consent and a cheek swab sample were obtained from each subject for analysis using real-time polymerase chain reaction (PCR). Allele and genotype frequencies were compared using Pearson X2 analysis. Complete data were obtained for 156 subjects. No significant differences were found in frequency of the MTHFR C667T T allele (0.415 vs 0.365; p=0.408) or the MTHFR C667T TT genotype (20.7% vs 17.6%; p=0.619) between the depressed and non-depressed controls, respectively. Therefore, use of L-methylfolate without an additional indication of need does not appear to be warranted in this group of U.S. Caucasians. Some patients may benefit from L-methylfolate, but an evidence-based approach, such as MTHFR genotyping, should be used to identify these specific patients. Additional research is also needed to confirm the benefit of L-methylfolate in specific patient populations (e.g., MTHFR TT genotype).     

The effect of C677T mutation of methylene tetrahydrofolate reductase gene and plasma folate level on hyperhomocysteinemia in patients with meningomyelocele

To evaluate the relationship between genotypes of methylene tetrahydrofolate reductase (MTHFR), and plasma folate and homocysteine (Hcy) levels in meningomyelocele, 21 Korean patients, 47 of their family members, and 43 healthy controls were recruited. The presence of C677T mutation in the MTHFR gene and plasma concentrations of folate/Hcy were investigated. The genotype frequency of C677T mutation was not higher in study groups (patients and family members). The plasma folate concentration showed no difference either between the study and the control groups or among MTHFR-genotypic groups. The plasma Hcy concentration in homozygotes in the study group was higher than that in the control group, and higher than that in heterozygotes when plasma folate levels were low (P=0.006). Although neither MTHFR genotype nor plasma folate/Hcy level plays a definite part on its own, they seem to have an additive effect on the occurrence of meningomyelocele. Our results support folate supplementation for the prevention of hyperhomo- cysteinemia and meningomyelocele. Received: 11 November 1999 Revised: 3 April 2000     

Plasma homocysteine and the methylenetetrahydrofolate reductase C677T gene variant: lack of association with schizophrenia.

Disturbances in methyl-carbon metabolism, which result in hyperhomocysteinemia, have been associated with schizophrenia. Homozygosity for the T677 allele of the methylenetetrahydrofolate reductase (MTHFR) gene, which encodes for a thermolabile enzyme associated with hyperhomocysteinemia, has been found to be increased in schizophrenic patients. We have investigated whether plasma homocysteine concentration and the frequency of C677T MTHFR variant were increased in schizophrenic inpatients of a psychiatric hospital (n=210) compared with controls (n=218). There were no significant differences in plasma homocysteine concentrations between the schizophrenia and the control group. The distributions of T allele and TT genotype frequencies were similar in both groups (40% and 15%). These results show that impaired homocysteine metabolism is unlikely in schizophrenia.     

Association of the 677C-->T mutation on the methylenetetrahydrofolate reductase gene in Turkish patients with neural tube defects

We report the analysis of the 677C-->T mutation on the 5, 10-methylenetetrahydrofolate reductase gene in Turkish controls and cases of neural tube defects. Mutation analysis of 91 patients with neural tube defects, 72 mothers, 63 fathers, and 93 healthy controls has been made by polymerase chain reaction and allele specific restriction digestion with Hinf I. We did not find a significant difference in the 677C-->T allele and genotype distribution among the patients with neural tube defects, their parents, and the control group. This result suggests that another mutation in the folate-related enzyme genes could be responsible for neural tube defects in Turkey. None of the mothers of patients with neural tube defects was advised to use folic acid as recommended to prevent neural tube defects. An immediate attempt to establish an education program for healthcare providers and women of childbearing age is crucial in Turkey. Furthermore, fortification of foods with folate would be a better approach.     

Association of the C677T and A1298C polymorphisms in the 5,10 methylenetetrahydrofolate reductase gene in patients with migraine risk

Although controversial, diminished activity of 5,10 methylenetetrahydrofolate reductase (MTHFR), a regulatory enzyme of homocysteine metabolism, may predispose to migraine in Turkish people. In a case-control study, we determined the prevalence of two common MTHFR polymorphisms,C677T and A1298C, in 102 migraine patients (23 migraine with aura, 70 migraine without aura and nine with tension-type headache) and compared it to that of 136 healthy controls. The frequencies of the T allele of MTHFR677 and the C allele of MTHFR1298 were significantly higher in the total migraine population (33.82%, 33.82%) than in controls (25.38% and 24.26%), respectively.The genotypes T677T and C1298C were the only genotypes significantly associated with migraine (OR=5.702; 95% CI=1.184-27.457; P=0.015) and (OR=8.933; 95% CI=1.953-40.869; P=0.001), respectively). Individuals with migraine with aura with C1298C and C677C/C1298C genotypes were even more profoundly associated with migraine risk than others (OR=14.105; 95% CI=2.417-82.320; P=0.0001) and (OR=10.050; 95% CI=1.580-63.907; P=0.003), respectively. However individuals with migraine without aura with T677T and C1298C genotypes showed the same susceptibility (OR=7.444; 95% CI=1.503-36.863); P=0.005). Patients with C1298C and C677C/C1298C genotypes may also predispose to tension-type headache (OR=8.375; 95% CI=0.685-102.458); P=0.049).