Thermolabile Variant Research Articles

Structural analysis of the TPI-Manchester, a thermolabile variant of human triosephosphate isomerase

Human triosephosphate isomerase G122R, also known as TPI-Manchester, is a thermolabile variant detected in a screening of more than 3400 individuals from a population in Ann Arbor, Michigan. Here, the crystallographic structure of G122R was solved to determine the molecular basis of its thermal stability. Structural analysis revealed an increase in the flexibility of residues at the dimer interface, even though R122 is about 20 Å away, suggesting that long-range electrostatic interactions may play a key role in the mutation effect.

Congenital septal defects in Karachi, Pakistan: an update of mutational screening by high-resolution melting (HRM) analysis of MTHFR C677T

BackgroundCongenital heart defects (CHDs) are the heart structural malformations present at birth. Septal defects account for 40% of CHD, including atrial, ventricular and atrioventricular septal defects. In Pakistan, the prevalence of CHD is 3.4 in 1000, and a study estimated that 60,000 babies are born with CHD annually. Methylenetetrahydrofolate reductase (MTHFR), a chief enzyme, involved in the folate metabolism. The missense mutation, C677T (rs1801133), exists in MTHFR gene, results in a MTHFR thermolabile variant having low enzymatic activity. The study is aim to identify the MTHFR C677T variant association with septal defects.MethodsSamples of 194 CHD patients (age X¯\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\overline{X }\\hspace{0.17em}$$\\end{document}= 5.8 ± 5.1) and 50 normal echo controls (age X¯\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\overline{X }\\hspace{0.17em}$$\\end{document}= 6.0 ± 4.9), confirmed by pediatric consultant, were collected. Extracted DNA, quantified by agarose gel electrophoresis and nanodrop, was screened for SNP by high-resolution melting (HRM). Further, HRM results were confirmed using restriction analysis and sequencing. HRM was simply and precisely genotyped the samples within 3 h at low cost.ResultsGenotypic data suggested that heterozygous mutant (CT) was frequent in congenital septal defect patients (0.26) which was higher than controls (0.143), p > 0.05. Mutant (TT) genotype was not found in this study.Conclusionsrs1801133 has lack of significant association with congenital septal defects. The absence of TT genotype in this study suggesting the role of natural selection in targeted population. HRM is an easy, fast and next generation of PCR, which may be used for applied genomics.

Ischaemic stroke with multi-focal venous and arterial thrombosis due to hyperhomocysteinemia: anabolic androgenic steroid use and MTHFR c.667 C > T variant – a case report

BackgroundSeverely elevated serum homocysteine is a rare cause of ischaemic stroke and extra-cranial arterial and venous thrombosis. Several factors can lead to mild elevation of homocysteine including dietary folate and B12 deficiency, and genetic variants of the methylenetetrahydrofolate reductase (MTHFR) enzyme. The use of Anabolic androgenic steroid (AAS) is under-reported, but increasingly linked to ischaemic stroke and can raise homocysteine levels.Case ReportWe present a case of a man in his 40s with a large left middle cerebral artery (MCA) territory ischaemic stroke and combined multifocal, extracranial venous, and arterial thrombosis. His past medical history was significant for Crohn’s disease and covert use of AAS. A young stroke screen was negative except for a severely elevated total homocysteine concentration, folate and B12 deficiencies. Further tests revealed he was homozygous for the methylenetetrahydrofolate reductase enzyme thermolabile variant (MTHFR c.667 C > T). The etiology of this stroke was a hypercoagulable state induced by raised plasma homocysteine. Raised homocysteine in this case was likely multifactorial and related to chronic AAS use in combination with the homozygous MTHFR c.677 C > T thermolabile variant, folate deficiency and, vitamin B12 deficiency.ConclusionIn summary, hyperhomocysteinemia is an important potential cause of ischaemic stroke and may result from genetic, dietary, and social factors. Anabolic androgenic steroid use is an important risk factor for clinicians to consider, particularly in cases of young stroke with elevated serum homocysteine. Testing for MFTHR variants in stroke patients with raised homocysteine may be useful to guide secondary stroke prevention through adequate vitamin supplementation. Further studies looking into primary and secondary stroke prevention in the high-risk MTHFR variant cohort are necessary.

Accident vasculaire cérébral ischémique du nouveau-né : quels facteurs biologiques de risque thrombotique rechercher et quelles conséquences en pratique ?

All biological risk factors that have been previously identified to increase the risk of thrombosis in adults, have also been studied in neonates with arterial Ischemic Stroke (NAIS), but most studies were retrospective and included relatively low numbers of affected children. We therefore could not suggest recommendations with a strong level of evidence and only expert proposals potentially useful for clinical practice will be presented in this text. Despite these limitations, the extensive analysis of published data supported that factor V Leiden (FVL) and increased levels of Lp(a) could be significant risk factors for NAIS. Importantly, these 2 risk factors cannot be considered as having provoked NAIS, and moreover, they do not influence the prognosis and the immediate treatment. However, since the FVL may have an impact for the prescription of a thromboprophylaxis when the neonate will become adult, to look for its presence in affected patients may be justified. For clinical practice, the following propositions can be applied: 1. Routine testing for thrombophilia (AT, PC PS deficiency, FV Leiden or FII20210A) or for detecting other biological risk factors such as antiphospholipid antibodies, high FVIII, homocystein or Lp(a) levels, MTHFR thermolabile variant, should not be considered in neonates with NAIS. 2. Testing for FV Leiden can be performed in case of documented family history of venous thromboembolic disease. 3. Testing neonates for the presence of antiphospholipid antibodies (APA) is mandatory in case of clinical events suggesting antiphospholipid syndrome in the mother (vascular thrombosis, and/or pregnancy morbidity). 4. Routine testing for thrombophilia is not proposed in both parents in case of early death of the neonate, apart from APA in the mother.

Accidents vasculaires cérébraux ischémiques artériels néonatals : synthèse des recommandations

Neonatal arterial ischemic stroke (NAIS) is a rare event that occurs in approximately one in 5000term or close-to-term infants. Most affected infants will present with seizures. Although a well-recognized clinical entity, many questions remain regarding diagnosis, risk factors, treatment, and follow-up modalities. In the absence of a known pathophysiological mechanism and lack of evidence-based guidelines, only supportive care is currently provided. To address these issues, a French national committee set up by the French Neonatal Society (Société française de néonatologie) and the national referral center (Centre national de référence) for arterial ischemic stroke in children drew up guidelines based on an HAS (Haute Autorité de santé [HAS]; French national authority for health) methodology. The main findings and recommendations established by the study group are: (1) among the risk factors, male sex, primiparity, caesarean section, perinatal hypoxia, and fetal/neonatal infection (mainly bacterial meningitis) seem to be the most frequent. As for guidelines, the study group recommends the following: (1) the transfer of neonates with suspected NAIS to a neonatal intensive care unit with available equipment to establish a reliable diagnosis with MRI imaging and neurophysiological monitoring, preferably by continuous video EEG; (2) acute treatment of suspected infection or other life-threatening processes should be addressed immediately by the primary medical team. Persistent seizures should be treated with a loading dose of phenobarbital 20mg/kg i.v.; (3) MRI of the brain is considered optimal for the diagnosis of NAIS. Diffusion-weighted imaging with apparent diffusion coefficient is considered the most sensitive measure for identifying infarct in the neonatal brain. The location and extent of the lesions are best assessed between 2and 4days after the onset of stroke; (4) routine testing for thrombophilia (AT, PC PS deficiency, FV Leiden or FII20210A) or for detecting other biological risk factors such as antiphospholipid antibodies, high FVIII, homocysteinemia, the Lp(a) test, the MTHFR thermolabile variant should not be considered in neonates with NAIS. Testing for FV Leiden can be performed only in case of a documented family history of venous thromboembolic disease. Testing neonates for the presence of antiphospholipid antibodies should be considered only in case of clinical events arguing in favor of antiphospholipid syndrome in the mother; (5) unlike childhood arterial ischemic stroke, NAIS has a low 5-year recurrence rate (approximately 1%), except in those children with congenital heart disease or multiple genetic thrombophilia. Therefore, initiation of anticoagulation or antithrombotic agents, including heparin products, is not recommended in the newborn without identifiable risk factors; (6) the study group recommends that in case of delayed motor milestones or early handedness, multidisciplinary rehabilitation is recommended as early as possible. Newborns should have physical therapy evaluation and ongoing outpatient follow-up. Given the risk of later-onset cognitive, language, and behavioral disabilities, neuropsychological testing in preschool and at school age is highly recommended.

Maternal and neonatal MTHFR-C677T mutation: A case report

Homozygosis for the thermolabile variant (C677T) of the methylene-tetrahydropholate reductase (MTHFR) gene has been related to a high incidence of neural tube defects, pre-eclampsia, retardation in fetal growth and hyperhomocysteinemia. The latter represents a known risk factor for thrombosis. We report the case of a newborn with severe cerebral damage and neonatal epilepsy that needed treatment with antiepileptic drugs. The mother was to be found homozygote for the C677T variant of the MTHFR gene and the child was to be found heterozygote for the same mutation. We underline the possible correlation between the fetal-perinatal adverse events and the mother’s genetic metabolic risks.

Homocysteine, methylenetetrahydrofolate reductase C677T polymorphism, and risk of retinal vein occlusion: an updated meta-analysis.

BackgroundTo evaluate the role of plasma total homocysteine (tHcy) and homozygosity for the thermolabile variant of the methylenetetrahydrofolate reductase (MTHFR) C677T genotype in the risk of retinal vein occlusion (RVO).MethodsRelevant studies were selected through an extensive search of PubMed, EMBASE, and the Web of Science databases. Summary weighted mean differences (WMDs) or odds ratios (ORs) and 95% confidence intervals (CI) were calculated with a random-effects model.ResultsForty-two studies with 6445 participants were included in this updated systematic review and meta-analysis. The mean plasma tHcy level in the RVO patients was significantly higher than in the controls (WMD =2.13 μmol/L; 95% CI: 1.29 to 2.98, P < 0.001), but there was evidence of between-study heterogeneity (P < 0.001). No significant association between MTHFR C677T genotype and RVO was found under all genetic models.ConclusionThere was some evidence that plasma tHcy is associated with an increased risk of RVO. There was no evidence to suggest an association between homozygosity for the MTHFR C677T genotype and RVO.

Factor V Leiden and MTHFR mutations as a combined risk factor for hypercoagulability in referred Patients population from Western India

Background Factor V Leiden mutation is a recognized most prevalent genetic risk factor for venous thromboembolic disease. Factor V mutations, are known to potentiate the effect of MTHFR on deep vein thrombosis. The thermo labile variant of the MTHFR gene (C677T) increases the plasma homocysteine levels and hyperhomocysteneimia is a known risk factor of deep vein thrombosis. Results of studies concerning interaction of Hyperhomocysteneimia and thromobophilic risk factors like Factor V are contradictory. Some studies have shown an increased risk (10-50 times) of deep vein thrombosis because of MTHFR and FVL mutations combined, yet other studies fail to conclude similarly. We attempt to address this paradox in our study referred for DVT, Hyperhomocysteneimia and pulmonary embolism and assess the importance of the synergistic effects of FVL and MTHFR mutations.

Fulminant Encephalopathy with Marked Brain Edema and Bilateral Thalamic Lesions

We encountered two children with acute encephalopathy associated with unique clinical manifestations. Both the patients had status epilepticus at onset and neuroimaging studies revealed marked brain edema and bilateral thalamic lesions. Although they were treated with steroids and immunoglobulin, their outcomes were very poor. A thermolabile variant of carnitine palmitoyltransferase II and an elevated interleukin-6 level in cerebrospinal fluid were observed in one patient each. The constellation of clinical and neuroimaging findings in our patients is apparently not consistent with any established subtype of acute encephalopathy/encephalitis.

Effect of multivitamins on plasma homocysteine in patients with the 5,10 methylenetetrahydrofolate reductase C677T homozygous state

The role of hyperhomocysteinemia (HHcy) as a cardiovascular risk factor remains a matter of debate, while it correlates with folates, it demonstrates inverse correlation with plasma homocysteine (Hcy) levels and vitamin B12 levels and reduces plasma Hcy levels following supplementation with multivitamins. The purpose of this study was to demonstrate that administering multivitamins at specific doses for 90 days restores normal plasma Hcy levels in women who are homozygous for the thermolabile variant of 5,10 methylenetetrahydrofolate reductase (MTHFR C677T). We enrolled 106 healthy females aged between 30 and 42 years, who were non-smokers, non-vegetarian, normotensive and who had no history of food abuse in the previous months. Only females were enrolled in order to rule out any bias due to the variation in Hcy plasma concentrations between males and females. Patient blood sampling was performed in order to determine plasma Hcy, serum folic acid and vitamin B12 levels. Furthermore, molecular characterization of the C677T polymorphism present in the MTHFR gene, was also performed. The results of this study demonstrated that supplementation with specific multivitamins restores normal plasma Hcy levels, regardless of the MTHFR genotype. Furthermore, it is unnecessary to adminster high doses of folate to reduce plasma Hcy levels, and administering high doses of folate may cause pro-inflammatory and pro-proliferative effects.

Methylenetetrahydrofolate reductase C677T variant in Moroccan patients with inflammatory bowel disease

BackgroundThe association of genetic polymorphisms related to metabolism of homocysteine and folate with inflammatory bowel disease has been evidenced. Several studies have identified genetic variants of MTHFR as significant susceptibility loci for Crohn's disease (CD) and ulcerative colitis (UC). The C677T genetic polymorphism in the MTHFR gene is found to be associated with a thermolabile variant enzyme that shows a reduced activity. Therefore, we investigated whether the C677T variant confers genetic susceptibility to CD or UC and evaluated the genotype–phenotype associations in the Moroccan population. MethodsThe present study included 96 inflammatory bowel disease patients (68 patients with CD and 28 with UC) and 182 healthy controls. DNA samples were genotyped for the MTHFR (C677T) mutation by the PCR-RFLP method. Statistical analyzes were performed using MedCalc software, Chi square test and Fisher test. ResultsThe respective odds ratio for CD, UC and control group were, 1.55 (CI 95%: 0.53–4.53, P=0.52); 0.50 (CI 95%: 0.06–4.15, P=0.52) and 0.50 (CI 95%: 0.06–4.15, P=0.52). Thus, no statistically significant association with the disease was observed in frequency of the TT variant in comparison to healthy controls. Stratification of IBD patients on the basis of CD or UC showed that individuals carrying at least one T allele are not protected against Crohn's disease. Furthermore, clinical features of the disease did not show any significant association. ConclusionIn conclusion, the present study indicates that the genetic risk for IBD is not modulated by MTHFR C677T polymorphism in Moroccan population.

Congenital MTHFR deficiency causing early-onset cerebral stroke in a case homozygous for MTHFR thermolabile variant

Hyperhomocysteinemia is a risk factor for early-onset venous thrombosis. It can be caused by genetic defects in methionine-homocysteine metabolism. The thermolabile variant of methylene-tetrahydrofolate reductase (MTHFR), c.677C>T, is one of the most common genetic condition, which has been associated with mild to moderate hyperhomocysteinemia, and carriers of this variant are at increased risk of an early-onset stroke-like episode. However, congenital MTHFR deficiency is a rare inborn error of folate metabolism, causing marked hyperhomocysteinemia, and its combination with the thermolabile variant is rarely reported. In this report, we describe a young adult with cerebral infarction. The patient was homozygous for the MTHFR thermolabile variant, but markedly elevated hyperhomocysteinemia led us to investigate the whole MTHFR gene, which revealed two novel MTHFR mutations. This is the first report of MTHFR deficiency in a Korean patient, and one of only a few cases reported in East Asian countries. Despite its rarity, our report underlines the importance of its identification in hyperhomocysteinemia for patient prognosis with appropriate management.

Is a High Homocysteine Level Related to Thrombosis?

To the Editor, The study by Egin and Akar [1] entitled, First observation of MTHFR 678C-A (Ala 222 Ala) single nucleotide polymorphism, in the recent issue of the Journal (2012; 29: 204-5) requires questioning its importance to thrombosis in the light of Dayal et al.’s findings in a mouse model [2]. I used to think that high homocysteine level important in thrombosis, whereas currently I question such knowledge. As such, I think the authors must show the functional effect of their observation in blood coagulation and its relationship to the thermolabile variant of MTHFR ?.

Etiology of Perinatal Stroke; A Role for Prothrombotic Coagulation Factors?

Objective: Stroke is relatively rare in children and the clinical presentation of perinatal stroke is often subtle. In perinatal stroke, multiple, often coexisting, risk factors are involved, varying from maternal and fetal risk factors during pregnancy and delivery, to infectious causes and cardiac diseases as well as medical interventions and congenital prothrombotic coagulation factors.Methods: To explore the prevalence of different predisposing conditions in perinatal stroke patients we evaluated 96 patients (43 males; 53 females), including subjects with ischemic and hemorrhagic stroke subtypes. Baseline investigations included complete blood count, total cholesterol, triglycerides, lipoprotein (a), prothrombin, activated thromboplastin, plasma fibrinogen level, activity of protein C sensitivity ratio, total plasma homocysteine, lupus anticoagulant, anticardiolipin, and anti-β2 glycoprotein1 antibodies. DNA analysis was performed for the Factor V Leiden mutation, Factor II G20219A variant, and the thermolabile variant of MTHFR.Results: The major genetic risk factor in our series of patients was heterozygosity and homozigosity for the MTHFR C677T mutation (39/96 patients; 40%) in 5 patients was associated with the Factor V Leiden mutation, in 6 with deficiency of activity of protein C. Acquired predisposing conditions were present in 18/96 (18%) patients and included Threatened abortion, oligohydramnios, intra uterine growth retardation, gestosis, chorioamniositis. In 7 patients both genetic and aquired predisposing factors were present.Conclusion: Our results emphasize that prothrombotic coagulation risk factors, especially MTHFR mutation, can predispose to perinatal stroke, alone or in combination with other genetic or acquired factors.

Heterozygote Advantage of the MTHFR C677T Polymorphism on Specific Cognitive Performance in Elderly Chinese Males without Dementia

Aims: Aging is associated with cognitive deterioration, and genetic factors are implicated in individual cognitive differences in the aged. The C677T mutation in the 5,10-methylenetetrahydrofolate reductase gene (MTHFR) yields a common thermolabile variant (T) with reduced enzyme activity and consequent elevation of serum homocysteine concentrations. We designed the present study to investigate whether this functional polymorphism may affect global and specific cognitive functions in older Chinese males without dementia. Methods: The subjects included 356 elderly males without major psychiatric disorders or dementia, who were assessed by the Cognitive Abilities Screening Instruments (CASI) and the Wechsler Digit Span Task tests. Results: A significant association was found between the MTHFR C677T polymorphism and total CASI scores (p = 0.012), particularly in short-term memory (p = 0.002) and concentration/mental manipulation (p = 0.007). Post hoc tests indicated that the C/T heterozygotes achieved better cognitive function test results than C/C or T/T carriers. No association was found between the MTHFR genotype and the Wechsler Digit Span Task tests. Conclusion: These results suggest that a heterozygote advantage exists for the MTHFR C677T polymorphism in specific cognitive functions in elderly Chinese males without dementia.

Thrombophilic screening in young patients (< 40 years) with idiopathic ischemic stroke: A controlled study

Introduction Despite extensive clinical and laboratory investigations, the etiology of ischemic stroke remains unknown in approximately one third of patients. Materials and Methods Thirty-four consecutive patients less than 40 years old (Males 13, Females 21, mean age 26.6 years, range 2-39) with documented ischemic stroke underwent, one year after the acute event, laboratory evaluation of antithrombin, protein C, free and total protein S, activated protein C resistance, fibrinogen, factor VII:C, homocysteine levels and antiphospholipid antibodies (APA). Moreover, prevalence of F5 R506Q, F2 G2021A and homozygosis for thermolabile variant C677T of the methylenetetrahydrofolate reductase ( MTHFR) were also evaluated and compared to the results obtained in 120 normal controls. Results Antithrombin and protein C levels resulted normal in all cases. One patient (2.9%) showed free protein S deficiency and 3 patients (8.8%) had activated protein C resistance. Homocysteine levels above 15 μmol/L were found in one patient (2.9%). APA were found in 21 patients (61.7%) and in only 2 out of 120 (1.66%) controls (OR = 95.31; 95% C.I.: 18.22-667.81). The multivariate analysis selected that the presence of APA was significantly associated with an increased risk of stroke (OR = 156.60; 95% C.I.: 25.99-943.47) in this cohort of patients. The combination between APA and cardiovascular risk factors determined a risk of 29-fold (OR = 29.31; 95% CI: 3.28-261.69). Discussion Our data suggest that the presence of APA is associated with an increased risk of idiopathic ischemic stroke in young patients. Furthermore, also the combination of APA and cardiovascular risk factors is significantly associated with development of idiopathic ischemic stroke.

The thermolabile variant of 5,10-methylenetetrahydrofolate reductase is a possible risk factor for amyotrophic lateral sclerosis

Hyperhomocysteinemia is a risk factor for neurodegeneration, and binding of copper by homocysteine is a putative underlying mechanism. As mutations of the copper-dependent superoxide dismutase are observed in familial ALS, we tested whether genetic variants with influence on homocysteine metabolism are associated with ALS. We compared the frequency of seven variants of genes involved in homocysteine metabolism in 162 patients with sporadic ALS and 162 controls who did not significantly differ in age (t = 1.27, p = 0.205) and gender (χ(2) = 2.48, p = 0.115) using binary regression analysis. Results showed that the variant MTHFR c.677C>T was significantly associated with ALS, i.e. the T-allele was more frequent among patients. Explorative regression analysis revealed that MTHFR c.677C>T was not associated with spinal ALS, but with bulbar onset: CC/CT/TT in patients 0.33/0.51/0.16 versus 0.50/0.44/0.06 in controls; Wald = 5.73, p = 0.017. In addition, DHFR c.594+59del19bp was not associated with spinal, but with bulbar onset: del,del/del,ins/ins,ins in patients 0.16/0.67/0.18 versus 0.11/0.52/0.37 in controls; Wald = 5.02, p = 0.025. The other variants did not show significant associations. In summary, the variants MTHFR c.677C>T and DHFR c.594+59del19bp are involved in homocysteine metabolism. Homocysteine is neurotoxic and binds copper. Thus, the individual variability of homocysteine metabolism, e.g. due to genetic variants, may contribute to the vulnerability of ALS.

Polymorphisms of 5,10-Methylenetetrahydrofolate Reductase and Cystathionine β-Synthase Genes as a Risk Factor for Neural Tube Defects in Sétif, Algeria

Background: Neural tube defects (NTD) are severe congenital malformations due to a failure in neural tube formation at the beginning of pregnancy. The etiology of NTD is multifactorial, with environmental and genetic determinants. We suggest a study of gene-gene interactions regarding the possible association of NTD with specific mutations of 5,10-methylenetetrahydrofolate reductase (MTHFR) and cystathionine β-synthase (CBS) genes. Patients and Methods: The genetic analysis of the MTHFR C677T polymorphism was performed by real-time polymerase chain reaction (PCR) on a Light Cycler, the CBS genotype was analyzed by PCR in a thermal cycler. Ninety-two mothers who had conceived NTD children and 48 fathers were investigated. A group of 147 adults, including 82 apparently healthy women, was used as control. Results: Among control mothers, 35 (43%) were heterozygous for the C677T variant and 14 (17%) were TT homozygous. Among the cases, 25 (52%) out of 48 mothers and 22 (46%) out of 48 fathers carried the T allele; 9 mothers (19%) and 5 fathers (10%) had the TT genotype. A homozygous C677T mutation was not an NTD risk factor in this preliminary study in an Algerian population; a possible gene-gene interaction between the MTHFR C677T polymorphism and the CBS 844ins68 has also been examined in relation to NTD, but no such association has been shown. There was a statistically significant difference between the heterozygosity genotype frequency of CBS polymorphisms in mothers with a previous child with NTD compared with the mother controls (odds ratio: 3.72; 95% CI: 1.59–8.73). Conclusion: Our results with Algerian NTD mothers did not show a significant association for any group, suggesting that the thermolabile variant C677T in the MTHFR gene is not a risk factor for a mother to have NTD offspring; rather, folic acid supplementation or fortification should become mandatory for all women of reproductive age in Algeria.

Homocysteine, Methylenetetrahydrofolate Reductase C677T Polymorphism, and Risk of Retinal Vein Occlusion: A Meta-analysis

To assess the role of plasma total homocysteine (tHcy) concentrations and homozygosity for the thermolabile variant of the methylenetetrahydrofolate reductase (MTHFR) C677T gene as risk factors for retinal vascular occlusive disease. Retinal vein occlusion (RVO) is an important cause of vision loss. Early meta-analyses showed that tHcy was associated with an increased risk of RVO, but a significant number of new studies have been published. RVO patients and controls. Data sources included MEDLINE, Web of Science, and PubMed searches and searching reference lists of relevant articles and reviews. Reviewers searched the databases, selected the studies, and then extracted data. Results were pooled quantitatively using meta-analytic methods. tHcy concentrations and MTHFR genotype. There were 25 case-control studies for tHcy (1533 cases and 1708 controls) and 18 case-control studies for MTHFR (1082 cases and 4706 controls). The mean tHcy was on average 2.8 micromol/L (95% confidence interval [CI], 1.8-3.7) greater in the RVO cases compared with controls, but there was evidence of between-study heterogeneity (P<0.001, I(2) = 93%). There was funnel plot asymmetry suggesting publication bias. There was no evidence of association between homozygosity for the MTHFR C677T genotype and RVO (odds ratio [OR] 1.20; 95% CI, 0.84-1.71), but again marked heterogeneity (P = 0.004, I(2) = 53%) was observed. There was some evidence that elevated tHcy was associated with RVO, but not homozygosity for the MTHFR C677T genotype. Both analyses should be interpreted cautiously because of marked heterogeneity between the study estimates and possible effect of publication bias on the tHcy findings. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Combined Thrombophilia and Obstetric Complications

Gestational vascular complications are a major cause of maternal and fetal morbidity. A growing body of evi- dence suggests significant correlation of inherited and acquired thrombophilia with pregnancy loss, pre-eclampsia, ec- lampsia, placental abruption, intrauterine growth restriction (IUGR), and intra uterine fetal death (IUFD). Placental patho- logical findings in women with thrombophilia are characterized by thrombosis and fibrin deposition to a greater degree than in normal pregnancy (1). The term Combined Thrombophilia is used when more than one prothrombotic conditions exist at the same time. As per definition any added prothrombotic diathesis promotes pregnancy to a combined thrombo- philic state (1, 2). Thrombophilic risk factors are common and can be found in 15% to 25% of Caucasian population. The combination of prothrombotic risk factors is not uncommon. Since pregnancy is an acquired hypercoagulable state, women harboring thrombophilia may present with clinical symptoms of vascular complications for the first time during gestation or at the postpartum period (3, 4). Combined thrombophilia also exists when inherited and/or acquired prothrombotic factors are pooled. Every combination carries a different risk of thrombosis. A scoring system, which is composed of four major categories: obstetrical history, previous thromboembolic events, family history and type of thrombophilia, can help us to stratify universally the thrombotic risk during pregnancy and peripartum and administer the appropriate antithrombotic treatment. BACKGROUND Pregnancy is considered to be an acquired hypercoagula- ble state due to increased levels of coagulation factors, de- creased levels of anticoagulants and decreased fibrinolytic activity. The gradual increase in hypercoagulability during normal pregnancy predisposes to venous thromboembolism (VTE), and to gestational vascular complications, including recurrent pregnancy loss, intrauterine- growth restriction (IUGR), eclampsia, pre-eclampsia and placental abruption. These adverse pregnancy outcomes affect up to 15% of ges- tations and are the major cause of maternal and fetal morbid- ity and mortality (3). In one study, at least one thrombophilic defect was found in 96/145 (66%) of woman with recurrent fetal loss compared to 41/145 (28%) in controls (or=5.0, 95/5 ci: 3.0-8.5 p <0.0001) (4). Inherited thrombophilia is common and can be found in 15% to 25% of Caucasian populations. Thus, a combination of thrombophilic risk factors is not rare and can be detected, regarding Israel, in up to 5% of women with pregnancy loss (4, 5). Factor V Leiden is the most common inherited mutation that is associated with increased risk of VTE. Other com- monly inherited thrombophilia type is the prothrombin (FII G20210A) mutation but also the C677T polymorphism in the methylenetetrahydrofolate- reductase gene, which results in a thermolabile variant of the enzyme predisposing to hyper- homocysteinemia. However, the most thrombogenic *Address correspondence to this author at the Thrombosis and Hemostasis