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 Severe Arterial Thrombophilia Associated With a Homozygous MTHFR Gene Mutation (A1298C) in a Young Man With Klinefelter Syndrome

2008 ◽  
Vol 14 (3) ◽  
pp. 369-371 ◽  
Author(s):  
Mustafa Ozbek ◽  
M. Akif Öztürk ◽  
Kemal Ureten ◽  
Ozcan Ceneli ◽  
Mehmet Erdogan ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Methylenetetrahydrofolate Reductase ◽  
Sex Chromosome ◽  
Klinefelter Syndrome ◽  
Case Reports ◽  
Mthfr Gene ◽  
Testosterone Replacement Therapy ◽  
Increased Risk ◽  
A1298c Mutation ◽  
Chromosome Disorder

Klinefelter syndrome (KS) is the most common sex chromosome disorder in men. It may be associated with an increased risk for venous thrombosis and thromboembolism, which is partially explained by hypofibrinolysis due to androgen deficiency. Additional genetic or acquired thrombophilic states have been shown in KS patients complicated with venous thrombosis as isolated case reports. Arterial thrombotic events had not been previously reported in KS. In this study, a young man with KS who developed acute arterial thrombosis during testosterone replacement therapy is presented. He was homozygous for the A1298C mutation of the methylenetetrahydrofolate reductase (MTHFR) gene.

scholarly journals Molecular beacons: a new approach for semiautomated mutation analysis

1998 ◽  
Vol 44 (3) ◽  
pp. 482-486 ◽  
Author(s):  
Belinda A J Giesendorf ◽  
Jacqueline A M Vet ◽  
Sanjay Tyagi ◽  
Ewald J M G Mensink ◽  
Frans J M Trijbels ◽  
...  
Keyword(s):  
Mutation Detection ◽  
Methylenetetrahydrofolate Reductase ◽  
Mthfr Gene ◽  
Molecular Beacons ◽  
Oligonucleotide Probes ◽  
Tube System ◽  
New Approach ◽  
Increased Risk ◽  
Closed Tube ◽  
Nucleic Acid Research

Abstract Molecular beacons are oligonucleotide probes that become fluorescent upon hybridization. We designed molecular beacons to detect a point mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, a mutation that has been related to an increased risk for cardiovascular disease and neural tube defects. The application of molecular beacons enables fast, semi- automated, accurate mutation detection. Moreover, the procedure is performed in a closed tube system, thereby avoiding carryover contamination. We believe these probes will find their way into nucleic acid research and diagnostics.

Contribution of the Cystathionine β-Synthase Gene (844ins68) Polymorphism to the Risk of Early-onset Venous and Arterial Occlusive Disease and of Fasting Hyperhomocysteinemia

2000 ◽  
Vol 84 (10) ◽  
pp. 576-582 ◽  
Author(s):  
Raffaella de Franchis ◽  
Isabella Fermo ◽  
Giuseppina Mazzola ◽  
Gianfranco Sebastio ◽  
Giovanni Di Minno ◽  
...  
Keyword(s):  
Early Onset ◽  
Gene Polymorphisms ◽  
Protein C ◽  
Methylenetetrahydrofolate Reductase ◽  
Statistical Significance ◽  
Activated Protein C ◽  
Mthfr Gene ◽  
Occlusive Disease ◽  
Activated Protein C Resistance ◽  
Increased Risk

SummaryThe frequency of the heterozygous 844ins68 mutation of the cystathionine β-synthase (CBS) gene and of its association with the homozygous C677T transition of the methylenetetrahydrofolate reductase (MTHFR) gene, plasma fasting tHcy, folate and vitamin B12 levels were evaluated in 309 consecutive patients with objectively diagnosed early-onset venous (n = 200) or arterial thromboembolic disease (n = 109) recruited over 25 months in Milan (North Italy) and Naples (South Italy). The above gene polymorphisms were also evaluated in a population of 787 unmatched controls, 204 of whom – similar to patients for age- and sex-distribution – had fasting tHcy, vitamins and activated protein C resistance measured in their plasma.Moderate fasting hyperhomocysteinemia was detected in 15.5% of patients and in 5.9% of 204 controls (Mantel-Haenszel OR after stratification for type of occlusive disease and gender: 2.88; 1.48–5.32). The frequencies of the 677TT mutation of the MTHFR gene and of the heterozygous 844ins68 insertion of the CBS gene were not significantly different in the patient (19.4% and 6.9%) and the control population (16.5% and 7.8%), but the association of the two gene polymorphisms – found in 3.9% of patients and in 1.1% of controls – was significantly associated with an increased risk of venous or arterial occlusive diseases (RR = 3.63; 1.48–8.91). The MTHFR 677TT mutation (RR: 6.92; 3.86–12.4) and its association with the 844ins68 insertion (RR: 21.9; 8.35–57.4), but not the isolated insertion (RR: 0.71), were more frequent in patients and controls with fasting hyperhomocysteinemia than in normohomocysteinemic subjects, irrespective of the type of occlusive disease (venous or arterial). When adjusted for determinants of hyperhomocysteinemia in the patient and the control populations (generalized linear model), fasting tHcy levels were significantly higher in subjects with association of the two gene abnormalities (24.2 ± 3.8 µmol/L) than in subjects with the MTHFR 677TT mutation only (14.0 ± 5.8 µmol/L, p = 0.004). Activated protein C resistance was significantly more prevalent in venous patients (9.9%) than in controls (3.9%, OR = 2.69; 1.08–6.88). Six of 21 venous patients with APCresistance also had hyperhomocysteinemia (RR = 5.04; 0.68–37.6), but isolated fasting hyperhomocysteinemia retained statistical significance for the association with venous occlusive disease (RR = 2.84; 1.34–6.01).Heterozygosity for the 844ins68 mutation of the CBS gene is not per se a risk factor for premature arterial and/or venous occlusive diseases. However, when detected in combination with thermolabile MTHFR, it increases by almost 4-fold the risk of occlusive diseases (arterial and/or venous), by increasing the risk and the degree of fasting hyperhomocysteinemia.

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.

Significance of MTHFR gene mutation with normal homocysteine level in vascular events

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e20520-e20520
Author(s):  
V. K. Gadiyaram ◽  
M. A. Khan ◽  
T. Hogan ◽  
R. Altaha ◽  
E. Crowell ◽  
...  
Keyword(s):  
Risk Factors ◽  
Gene Mutation ◽  
Gene Polymorphisms ◽  
Homocysteine Level ◽  
Fetal Loss ◽  
Gene Mutations ◽  
Mthfr Gene ◽  
Vascular Events ◽  
Laboratory Test Results ◽  
Increased Risk

e20520 Background: Hyperhomocysteinemia, due to a combination of genetic and environmental factors, is considered to be a risk factor for vascular disease. Two common variations of the MTHFR gene (C677T and A1298C) result in amino acid substitutions and enhanced thermolability of the enzyme. Individuals with MTHFR gene mutations appear to have raised plasma level of homocysteine which may lead to increased risk of vascular events. However, significance of MTHFR gene mutations with normal homocysteine levels is unknown. Objective: To assess the relation of MTHFR gene mutations with normal homocysteine level and risk of Vascular events (deep venous thrombosis (DVT), pulmonary embolism (PE), Ischemic Heart disease (IHD), cerebrovascular accidents (CVA),recurrent fetal loss). Methods: We reviewed the records of 90 patients referred to our benign hematology clinic for thrombophilia evaluation between 2006 and 2008. All available medical history for risk factors and laboratory test results, obtained from first vascular event through time of consultation, including genetic testing, were reviewed. Anti-cardiolipin antibody, MTHFR genotyping and Protein C and Protein S assays were performed at Warde Medical Laboratory, Ann Arbor, MI. Results: 61 patients with documented vascular events were tested for MTHFR gene mutations. Forty one of these patients also had homocysteine levels available. Thirty-eight of these 41 (92 %) patients had an MTHFR gene mutation with normal homocysteine levels. Eighteen (47%) of these 38 patients had only an MTHFR gene mutation with normal homocysteine level and no other congenital or acquired risk factors for vascular events identified. Conclusions: In our clinic population, many patients with documented vascular events had MTHFR gene polymorphisms with normal homocysteine levels with no other thrombophilia risk factors identified, raising the question of whether MTHFR gene polymorphisms alone, without hyperhomocysteinemia, may somehow contribute to thrombophilia. [Table: see text] No significant financial relationships to disclose.

scholarly journals Methylenetetrahydrofolate (MTHFR), the One-Carbon Cycle, and Cardiovascular Risks

Nutrients ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 4562
Author(s):  
Shanel Raghubeer ◽  
Tandi E. Matsha
Keyword(s):  
Carbon Cycle ◽  
Methylenetetrahydrofolate Reductase ◽  
Mthfr Gene ◽  
C677t Polymorphism ◽  
Cardiovascular Risks ◽  
Mthfr Polymorphism ◽  
Dna And Rna ◽  
Inflammatory Conditions ◽  
Increased Risk ◽  
The One

The 5-10-methylenetetrahydrofolate reductase (MTHFR) enzyme is vital for cellular homeostasis due to its key functions in the one-carbon cycle, which include methionine and folate metabolism and protein, DNA, and RNA synthesis. The enzyme is responsible for maintaining methionine and homocysteine (Hcy) balance to prevent cellular dysfunction. Polymorphisms in the MTHFR gene, especially C677T, have been associated with various diseases, including cardiovascular diseases (CVDs), cancer, inflammatory conditions, diabetes, and vascular disorders. The C677T MTHFR polymorphism is thought to be the most common cause of elevated Hcy levels, which is considered an independent risk factor for CVD. This polymorphism results in an amino acid change from alanine to valine, which prevents optimal functioning of the enzyme at temperatures above 37 °C. Many studies have been conducted to determine whether there is an association between the C677T polymorphism and increased risk for CVD. There is much evidence in favour of this association, while several studies have concluded that the polymorphism cannot be used to predict CVD development or progression. This review discusses current research regarding the C677T polymorphism and its relationship with CVD, inflammation, diabetes, and epigenetic regulation and compares the evidence provided for and against the association with CVD.

scholarly journals The influence of choline treatment on behavioral and neurochemical autistic-like phenotype in Mthfr-deficient mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Galila Agam ◽  
Zoe Taylor ◽  
Ella Vainer ◽  
Hava M. Golan
Keyword(s):  
Methylenetetrahydrofolate Reductase ◽  
Human Subjects ◽  
Repetitive Behavior ◽  
Treatment Recommendation ◽  
Male Mice ◽  
Protein Levels ◽  
Increased Risk ◽  
Key Enzyme ◽  
Neurochemical Changes ◽  
Deficient Mice

Abstract Imbalanced one carbon metabolism and aberrant autophagy is robustly reported in patients with autism. Polymorphism in the gene methylenetetrahydrofolate reductase (Mthfr), encoding for a key enzyme in this pathway is associated with an increased risk for autistic-spectrum-disorders (ASDs). Autistic-like core and associated behaviors have been described, with contribution of both maternal and offspring Mthfr+/− genotype to the different domains of behavior. Preconception and prenatal supplementation with methyl donor rich diet to human subjects and mice reduced the risk for developing autism and autistic-like behavior, respectively. Here we tested the potential of choline supplementation to Mthfr-deficient mice at young-adulthood to reduce behavioral and neurochemical changes reminiscent of autism characteristics. We show that offspring of Mthfr+/− mothers, whether wildtype or heterozygote, exhibit autistic-like behavior, altered brain p62 protein levels and LC3-II/LC3-I levels ratio, both, autophagy markers. Choline supplementation to adult offspring of Mthfr+/− mothers for 14 days counteracted characteristics related to repetitive behavior and anxiety both in males and in females and improved social behavior solely in male mice. Choline treatment also normalized deviant cortical levels of the autophagy markers measured in male mice. The results demonstrate that choline supplementation even at adulthood, not tested previously, to offspring of Mthfr-deficient mothers, attenuates the autistic-like phenotype. If this proof of concept is replicated it might promote translation of these results to treatment recommendation for children with ASDs bearing similar genetic/metabolic make-up.

scholarly journals METHYLENETETRAHYDROFOLATE REDUCTASE C677T GENE POLYMORPHISM AND PROSTATE CANCER RISK

2018 ◽  
Vol 11 (5) ◽  
pp. 387
Author(s):  
Samah Tellouche-bouhouhou ◽  
Djalila Chellat-rezgoune ◽  
Noureddine Abadi ◽  
Dalila Satta ◽  
Abderrezak Dahdouh
Keyword(s):  
Prostate Cancer ◽  
Methylenetetrahydrofolate Reductase ◽  
Cancer Susceptibility ◽  
Prostate Cancer Risk ◽  
Mthfr C677t ◽  
Mthfr Gene ◽  
Single Nucleotide ◽  
Mthfr C677t Polymorphism ◽  
Increased Risk ◽  
Significant Difference

Objective: The single nucleotide polymorphism C677T of the methylenetetrahydrofolate reductase (MTHFR) gene encodes a thermolabile enzyme. This polymorphism was found to be implicated in cancer susceptibility. In this study, we analyzed the distribution of the MTHFR C677T polymorphism in two cohorts; patients and controls native of East of Algeria to explore the possible association between this polymorphism and prostate cancer susceptibility.Methods: Our examination has been conducted in 98 cases and 98 healthy controls. Genotyping was realized by polymerase chain reaction-restriction fragment length polymorphism method.Results: Compared with CC homozygous, the CT heterozygous was found to have a significantly increased risk of prostate cancer (p=0.04; odds ratio [OR]=2.01, 95% confidence interval [CI]: 1.02–3.95). However, no statistically significant difference was observed concerning the TT homozygous (p=0.74; OR=1.25, 95% CI: 0.51–3.04).Conclusion: Our results indicate that the genotype CT is a risk factor for prostate cancer in East of Algeria.

scholarly journals Loci C677T and A1298C of the methylenetetrahydrofolate reductase gene and the risk of neural tube defects in the Kyrgyz population

2019 ◽  
pp. 3-8
Author(s):  
Н.М. Алдашева ◽  
Э.М. Мамбетсадыкова ◽  
Э.Т. Талайбекова ◽  
С.Дж. Боконбаева ◽  
Х.М. Сушанло ◽  
...  
Keyword(s):  
Neural Tube ◽  
Neural Tube Defects ◽  
Methylenetetrahydrofolate Reductase ◽  
Strong Association ◽  
Mthfr Gene ◽  
Control Group ◽  
Increased Risk ◽  
Pcr Rflp ◽  
1298C Allele ◽  
Kyrgyz Population

Цель. Изучить ассоциацию полиморфных локусов С677Т и А1298С гена MTHFR с развитием дефектов нервной трубки (ДНТ) у детей киргизской национальности. Методы. В исследование включены 76 детей и их матери. В основную группу вошли 30 детей с пороками невральной трубки, чаще всего в виде изолированной спиномозговой грыжи или в сочетании с другими врожденными пороками развития, а также их матери. 46 детей без ДНТ и их матери составили контрольную группу. Идентификация генотипов полиморфных локусов С677Т и А1298С гена MTHFR проводилась методом анализа полиморфизма длин рестрикционных фрагментов (ПДРФ). Результаты. При анализе распределения генотипов и аллелей полиморфизма А1298С гена MTHFR выявлено, что среди детей с ДНТ статистически значимо чаще встречались гетерозиготный генотип А1298С (χ²=9,67; р=0,0079) и аллель 1298С (χ²=4,17; р=0,04). При наличии генотипа А1298С риск развития ДНТ повышается в 4,71 раза (OR=4,71; p=0,0079), а при наличии аллеля 1298С - в 2,2 раза (OR=2,20; p=0,04). Полиморфный локус С677Т гена MTHFR самостоятельно не был ассоциирован с ДНТ, однако гетерозиготность по двум полиморфным аллелям ассоциирована с ДНТ (χ²=5,60; p=0,018) и существенно повышает относительный риск развития ДНТ (OR=9,75; p=0,018). Заключение. У детей киргизской национальности полиморфный локус А1298С гена MTHFR ассоциирован с развитием дефекта нервной трубки. Комбинированная гетерозиготность (С677Т/А1298С) по обоим полиморфизмам является дополнительным отягощающим фактором. Aim. The aim of the study was to investigated whether polymorphisms С677Т and А1298С of the MTHFR gene are associated with neural tube defects (NTDs) in the Kyrgyz population. Methods. The study included 76 children and their mothers. The study group included 30 children and their mothers, where the child had a neural tube defect, most commonly in the form of an isolated spina bifida or in combination with congenital anomalies. Control group - 46 children without congenital malformations. С677Т and А1298С polymorphisms analysis in the MTHFR gene were performed by PCR-RFLP method. Results. The frequency of the heterozygous A1298C genotype (χ²=9,67; p=0,0079) and 1298C allele (χ²=4,10; p=0,041) of the MTHFR gene was higher in cases than in controls. Child with heterozygous A1298C genotype had a 4,71- fold (OR=4,71; p=0,0079) higher risk of NTDs when compared with those who had the AA genotype. Child carriers of the 1298C allele had a 2,2-fold higher risk of NTDs (OR=2,20; p=0,041). С677Т/А1298С genotypes are more frequent among cases than controls (χ²=5,00; p=0,025). We showed that the combinations of С677Т/А1298С is strong association with NTDs (χ²=5,60; p=0,018). Subjects carriers of the combinations of С677Т/А1298С genotypes had a significant 9,7-fold higher risk of NTDs (OR=9,75; p=0,018). Conclusion. There is significant association between С677Т and А1298С polymorphism in MTHFR gene and neural tube defects in the Kyrgyz population. An increased risk of neural tube defects associated with heterozygous A1298C genotype, 1298C allele and combinations of С677Т/А1298С in MTHFR gene.

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