scholarly journals Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate

2020 ◽  
Vol 9 (9) ◽  
pp. 2836
Author(s):  
Maša Vidmar Golja ◽  
Alenka Šmid ◽  
Nataša Karas Kuželički ◽  
Jurij Trontelj ◽  
Ksenija Geršak ◽  
...  
Keyword(s):  
Methylenetetrahydrofolate Reductase ◽  
Fold Increase ◽  
Mthfr Gene ◽  
Folate Supplementation ◽  
Disease States ◽  
Metabolic Defects ◽  
Key Enzyme ◽  
Cell Processes ◽  
Activity Groups ◽  
Mthfr Deficiency

Adequate levels of folates are essential for homeostasis of the organism, prevention of congenital malformations, and the salvage of predisposed disease states. They depend on genetic predisposition, and therefore, a pharmacogenetic approach to individualized supplementation or therapeutic intervention is necessary for an optimal outcome. The role of folates in vital cell processes was investigated by translational pharmacogenetics employing lymphoblastoid cell lines (LCLs). Depriving cells of folates led to reversible S-phase arrest. Since 5,10-methylenetetrahydrofolate reductase (MTHFR) is the key enzyme in the biosynthesis of an active folate form, we evaluated the relevance of polymorphisms in the MTHFR gene on intracellular levels of bioactive metabolite, the 5-methyltetrahydrofolate (5-Me-THF). LCLs (n = 35) were divided into low- and normal-MTHFR activity groups based on their genotype. They were cultured in the presence of folic acid (FA) or 5-Me-THF. Based on the cells’ metabolic activity and intracellular 5-Me-THF levels, we conclude supplementation of FA is sufficient to maintain adequate folate level in the normal MTHFR activity group, while low MTHFR activity cells require 5-Me-THF to overcome the metabolic defects caused by polymorphisms in their MTHFR genes. This finding was supported by the determination of intracellular levels of 5-Me-THF in cell lysates by LC-MS/MS. FA supplementation resulted in a 2.5-fold increase in 5-Me-THF in cells with normal MTHFR activity, but there was no increase after FA supplementation in low MTHFR activity cells. However, when LCLs were exposed to 5-Me-THF, a 10-fold increase in intracellular levels of this metabolite was determined. These findings indicate that patients undergoing folate supplementation to counteract anti-folate therapies, or patients with increased folate demand, would benefit from pharmacogenetics-based therapy choices.

scholarly journals Case Report: Homozygous C677T MTHFR Gene Mutation in Male with Hypogonadism

2020 ◽  
Vol 2020 ◽  
pp. 1-3
Author(s):  
Rami Salameh ◽  
Mumtaheena Miah ◽  
Catherine Anastasopoulou
Keyword(s):  
Erectile Dysfunction ◽  
Gene Mutation ◽  
Methylenetetrahydrofolate Reductase ◽  
Hypogonadotropic Hypogonadism ◽  
Mthfr Gene ◽  
Testosterone Replacement Therapy ◽  
Male Hypogonadism ◽  
Increased Risk ◽  
Key Enzyme ◽  
Infertility Patients

We report a 44-year-old male, who was diagnosed with hypogonadotropic hypogonadism after complaining of erectile dysfunction, depression, and fatigue. He was started on testosterone replacement therapy. He persistently complained of fatigue despite increasing the dose of testosterone over two years and having therapeutic testosterone levels. He was found to have homozygous C677T methylenetetrahydrofolate reductase (MTHFR) gene mutation. After treatment with folate and B12, his symptoms resolve completely. MTHFR is a key enzyme in the folate pathway, and it plays an essential role in homocysteine metabolism. Homozygous C677T individuals have decreased activity of MTHFR enzyme with increased homocysteine levels, which is associated with increased risk of thrombosis. An association has been reported between C677T variant and male infertility. Patients identified to have hyperhomocysteinemia should be treated with B-complex vitamin supplements. Our case emphasizes other possible etiologies for fatigue and erectile dysfunction in a male with hypogonadism on testosterone therapy. Also, it shows possible association between MTHFR gene mutation and male hypogonadism.

scholarly journals The Relationship Between Methylation Defects and Different Genetic Disorders: Two Case Reports

2016 ◽  
Author(s):  
Emine Aydın ◽  
Ahmet Cevdet Ceylan ◽  
Mehmet Sinan Beksaç
Keyword(s):  
Methylenetetrahydrofolate Reductase ◽  
Chromosomal Abnormalities ◽  
Case Reports ◽  
Genetic Disorders ◽  
Mthfr Gene ◽  
Folate Metabolism ◽  
Key Enzyme ◽  
Gene Switching ◽  
Methylation Defects ◽  
The Relationship

<p>5, 10-methylenetetrahydrofolate reductase (MTHFR) is a coding gene, for a key enzyme in methionine-homocysteine and folate metabolism. This pathway has been associated with gene specific DNA hypo and hypermethylation as a result of gene switching on or off.<br />Methylenetetrahydrofolate reductase C677T and A1298C gene polymorphisms are associated with folate metabolism disorders; such as, it results in an impaired DNA methylation and chromosomal abnormalities, gene deficiencies and structural anomalies. Here, we reported two cases of compound heterozygote and homozygote MTHFR gene mutation association with genetical disorders during the pregnancies.</p>

Methylenetetrahydrofolate reductase polymorphisms as risk factors for retinal venous occlusive disease: A literature review

2021 ◽  
pp. 112067212110006
Author(s):  
Manuel Marques ◽  
Francisco Alves ◽  
Miguel Leitão ◽  
Catarina Rodrigues ◽  
Joana Tavares Ferreira
Keyword(s):  
Risk Factors ◽  
Literature Review ◽  
Methylenetetrahydrofolate Reductase ◽  
Mthfr C677t ◽  
Mthfr Gene ◽  
Mthfr Polymorphisms ◽  
Vein Occlusion ◽  
C677t Mutation ◽  
Retinal Vascular Disease

The role of polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene in retinal vein occlusion (RVO) is a theme of discussion since the first reports of RVO in patients with MTHFR C677T mutation and without classic acquired risk factors for retinal vascular disease. The association between MTHFR polymorphisms and RVO has been studied over the last 20 years producing conflicting results. This review aims to summarize the literature concerning the role MTHFR polymorphisms as risk factors for RVO.

scholarly journals COVID‐19 spreading across world correlates with C677T allele of the methylenetetrahydrofolate reductase (MTHFR) gene prevalence

2021 ◽  
Author(s):  
Giovanni Ponti ◽  
Lorenza Pastorino ◽  
Marco Manfredini ◽  
Tomris Ozben ◽  
Gabriella Oliva ◽  
...  
Keyword(s):  
Methylenetetrahydrofolate Reductase ◽  
Mthfr Gene

Correlation between Methylenetetrahydrofolate Reductase Polymorphisms and Hepatocellular Carcinoma: A Meta-Analysis

2019 ◽  
Vol 74 (3) ◽  
pp. 251-256 ◽  
Author(s):  
Hailong Su ◽  
Guo Zhang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Gene Polymorphisms ◽  
Methylenetetrahydrofolate Reductase ◽  
Meta Analysis ◽  
Random Effect ◽  
Recessive Model ◽  
Mthfr Gene ◽  
Systematic Research ◽  
The Relationship ◽  
Random Effect Models

Background: The correlation between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and hepatocellular carcinoma (HCC) remains controversial. Objectives: We performed this study to better assess the relationship between MTHFR gene polymorphisms and the likelihood of HCC. Methods: A systematic research of PubMed, Medline, and Embase was performed to retrieve relevant articles. ORs and 95% CIs were calculated. Results: A total of 15 studies with 8,378 participants were analyzed. In overall analyses, a significant association with the likelihood of HCC was detected for the rs1801131 polymorphism with fixed-effect models (FEMs) in recessive comparison (p = 0.002, OR 0.62, 95% CI 0.43–0.82). However, no positive results were detected for the rs1801133 polymorphism in any comparison. Further subgroup analyses revealed that the rs1801131 polymorphism was significantly associated with the likelihood of HCC in Asians with both FEMs (recessive model: p < 0.0001, OR 0.42, 95% CI 0.29–0.62; allele model: p = 0.004, OR 1.20, 95% CI 1.06–1.35) and random-effect models (recessive model: p = 0.002, OR 0.47, 95% CI 0.29–0.75). Nevertheless, we failed to detect any significant correlation between the rs1801133 polymorphism and HCC. Conclusions: Our findings indicated that the rs1801131 polymorphism may serve as a genetic biomarker of HCC in Asians.

MTHFR 677T-1298C haplotype in acute lymphoblastic leukemia: Impact on methotrexate therapy

2021 ◽  
pp. 107815522110171
Author(s):  
Rim Frikha ◽  
Moez Elloumi ◽  
Tarek Rebai ◽  
Hassen Kamoun
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Methylenetetrahydrofolate Reductase ◽  
Fragment Length Polymorphism ◽  
Lymphoblastic Leukemia ◽  
Allelic Frequency ◽  
Mthfr Gene ◽  
Methotrexate Therapy ◽  
Wild Type ◽  
Functional Variants ◽  
Toxicity Score

Introduction Functional variants of the Methylenetetrahydrofolate reductase ( MTHFR) gene, the C677T and A1298C, have largely investigated in pharmacogenomics of Methotrexate (MTX) in acute lymphoblastic leukemia (ALL), yet the conclusions are inconsistent. In addition; most of these studies do not analyze haplotypes. Here, we investigate the MTHFR 677/1298 genotypes and the 677-1298 haplotype and characterize the MTX response in Northern African ALL patients. Methods Genomic DNA was extracted from whole venous from a total of 28 patients with ALL. Genotyping were carried out with restriction fragment length polymorphism (RFLP). A toxicity score (TS) is calculated for each patient and correlate to the haplotype. Results The allelic frequency of MTHFR 677T-1298C haplotype was 10.7% in ALL patients. According to the toxicity’s score (TS) there was no significant differences between haplotype groups (p = 0.79): TS was higher with wild type of MTHFR (TS = 3.43; SEM ± 0.85) followed by combined genotype (677T-1298C) (TS = 2.67; SEM ± 0.88) and isolated variant (C677T or A1298C) (TS = 2.64; SEM ± 0.92). Conclusion Despite the limitation of this study; our results suggest that the MTHFR 677T-1298C haplotype is common in ALL and may be a promising HD-MTX chemotherapy-related adverse effects biomarker.

scholarly journals Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency

2015 ◽  
Vol 39 (1) ◽  
pp. 115-124 ◽  
Author(s):  
Martina Huemer ◽  
Regina Mulder-Bleile ◽  
Patricie Burda ◽  
D. Sean Froese ◽  
Terttu Suormala ◽  
...  
Keyword(s):  
Methylenetetrahydrofolate Reductase ◽  
Residual Activity ◽  
Clinical Pattern ◽  
Mthfr Deficiency

Ethnic Differences in the Frequency of the C677T Mutation in the Methylenetetrahydrofolate Reductase (MTHFR) Gene in Healthy Israeli Populations

2000 ◽  
Vol 4 (3) ◽  
pp. 309-311 ◽  
Author(s):  
Rivka Dresner Pollak ◽  
Yechiel Friedlander ◽  
Arthur Pollak ◽  
Maria Idelson ◽  
Idit Bejarano-Achache ◽  
...  
Keyword(s):  
Ethnic Differences ◽  
Methylenetetrahydrofolate Reductase ◽  
Mthfr Gene ◽  
C677t Mutation

scholarly journals Is MTHFR polymorphism a risk factor for Alzheimer's disease like APOE?

2005 ◽  
Vol 63 (1) ◽  
pp. 1-6 ◽  
Author(s):  
Liana Lisboa Fernandez ◽  
Rosane Machado Scheibe
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Methylenetetrahydrofolate Reductase ◽  
Venous Blood ◽  
Dna Amplification ◽  
Mthfr Gene ◽  
Chi Square ◽  
Mthfr Polymorphism ◽  
Significant Difference

BACKGROUND: The role of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms as risk factors for the occurence of Alzheimer's disease (AD) is still controversial: OBJECTIVE: To verify the association between MTHFR and apolipoprotein E (APOE) polymorphisms and Alzheimer's disease. METHOD: This work was conducted as a case-control study. Cases included thirty patients with probable AD. Controls were constituted by 29 individuals without dementia according to neuropsychological tests paired to age, sex, race and educational level. DNA was isolated from peripheral leukocytes of anticoagulated venous blood. Genotyping of APOE and MTHFR were performed by DNA amplification and digestion. The frequences of APOE and MTHFR genotypes were submitted by chi-square test corrected by Fisher test; the APOE genotypes, to chi-square linear tendency test and the frequences of MTHFR mutant and AD, by stratificated anlysis adjust by Mantel-Haenszel method. RESULTS: There was significant difference about APOE4 and APOE2 in the groups. (p=0.002) The odds ratio increased exponentially with the increased number of E4 allele (chi2 linear tendency test). No significant difference was detected on MTHFR genotypes in both case and control groups. CONCLUSION: The APOE4 is a risk factor and demonstrated a dose-depenent effect while APOE2 allele conferred a protection to AD. The MTHFR mutation had no correlation with AD.

scholarly journals Should MTHFR 1298 A>C be tested together with MTHFR 677 C>T polymorphism in women with reproductive challenges?

Genetika ◽  
2017 ◽  
Vol 49 (2) ◽  
pp. 377-386
Author(s):  
Jelena Djurovic ◽  
Oliver Stojkovic ◽  
Jelena Todorovic ◽  
Kristina Savic ◽  
Gorana Stamenkovic
Keyword(s):  
Genomic Dna ◽  
Methylenetetrahydrofolate Reductase ◽  
Critical Role ◽  
Mthfr Gene ◽  
Elevated Risk ◽  
Similar Frequency ◽  
Mthfr Polymorphisms ◽  
Healthy Female ◽  
Healthy Control ◽  
Associated Conditions

Methylenetetrahydrofolate reductase (MTHFR) plays a critical role in the folate metabolism. The polymorphism 677C>T of the MTHFR gene, producing thermolabile enzyme with decreased function, is widely studied and associated with many conditions. Additionally, it has been shown that another polymorphism, 1298A>C, also reduces the activity of this enzyme, although to a lesser extent. The aim of this study is to evaluate the clinical informativeness of testing both MTHFR polymorphisms. Genomic DNA, were extracted from peripheral blood of 180 female patients with pregnancy complications and 183 healthy female controls, and genotyped for MTHFR 677C>T and 1298A>C loci, using TaqMan assays. Our study found similar frequency of alleles and genotypes between two groups. Based on MTHFR 677C>T genotype, 11.7% of patients homozygous for this mutation were under the possible risk. When the position 1298 was included in the testing, 22.8% of the patients were heterozygous for both polymorphisms. Additionally, 8.9% of the patients were homozygous only for the MTHFR 1298 mutation. Although,s there was no differences compared to healthy control (p>0.05), 43% of patients were found to have elevated risk which is about four time highers than results with only MTHFR 677C>T genotyping. After obtaining information for the 677 position, testing for the second polymorphism (1298A>C) should be considered, since we have shown that it dramatically increases the rate of detection of patients who are potentially at risk for MTHFR associated conditions.

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