Increased risk of methotrexate toxicity with MTHFR gene mutation

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.

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

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e20520 ◽

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.

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Association between FVL G1691A, MTHFR C677T and A1298C Polymorphisms with Risk for Retinopathy of PrematurityAssociation between FVL G1691A, MTHFR C677T and A1298C Polymorphisms with Risk for Retinopathy of Prematurity

World Journal of Peri & Neonatology ◽

10.18502/wjpn.v4i1.7540 ◽

2021 ◽

Author(s):

Hamideh Shajari ◽

Mohammadamin Ghadyani ◽

Seyed Hamed Hosseini-Jangjou ◽

Reza Bahrami ◽

Seyed Alireza Dastgheib ◽

...

Keyword(s):

Retinopathy Of Prematurity ◽

Factor V Leiden ◽

Mthfr C677t ◽

Mthfr Gene ◽

Factor V ◽

Background Retinopathy ◽

Increased Risk ◽

Pcr Rflp ◽

Rflp Assay ◽

Preventable Blindness

Background: Retinopathy of prematurity (ROP) is an important cause of preventable blindness in children. The aim of this study was to examine the association of the polymorphisms at Factor V Leiden (FVL) and methylene tetrahydrofolate reductase (MTHFR) gene with risk of ROP. Methods: A total of 106 neonates with ROP and 110 healthy neonates were enrolled. The FVL G1691A and MTHFR C677T and A1298C polymorphisms were genotyped by PCR-RFLP assay. Results: There was a significant association between FVL G1691A polymorphism and an increased risk of ROP. However, the MTHFR C677T and A1298C polymorphisms were not associated with risk of ROP. Conclusion: FVL G1691A polymorphism may be risk factor for development of ROP in neonates. However, there was no significant association between MTHFR C677T and A1298C polymorphisms and risk of ROP. However, it is critical that larger and well-designed studies in different ethnicities are needed to confirm our conclusions.

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Molecular beacons: a new approach for semiautomated mutation analysis

Clinical Chemistry ◽

10.1093/clinchem/44.3.482 ◽

1998 ◽

Vol 44 (3) ◽

pp. 482-486 ◽

Cited By ~ 71

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.

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

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614070 ◽

2000 ◽

Vol 84 (10) ◽

pp. 576-582 ◽

Cited By ~ 38

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.

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Expectations of Surveillance for Non-BRCA Gene Mutation Carriers at Increased Risk for Breast Cancer

Journal of Surgical Research ◽

10.1016/j.jss.2020.06.029 ◽

2020 ◽

Vol 256 ◽

pp. 267-271

Author(s):

Rachel Caskey ◽

Brandon Singletary ◽

Kareen Ayre ◽

Catherine Parker ◽

Helen Krontiras ◽

...

Keyword(s):

Breast Cancer ◽

Gene Mutation ◽

Brca Gene ◽

Mutation Carriers ◽

Increased Risk ◽

Brca Gene Mutation

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Plasma Homocysteine, MTHFR Gene Mutation, and Open-angle Glaucoma

Journal of Glaucoma ◽

10.1097/ijg.0b013e31816f7631 ◽

2009 ◽

Vol 18 (1) ◽

pp. 73-78 ◽

Cited By ~ 25

Author(s):

Colin I. Clement ◽

Ivan Goldberg ◽

Paul R. Healey ◽

Stuart L. Graham

Keyword(s):

Gene Mutation ◽

Open Angle Glaucoma ◽

Mthfr Gene ◽

Plasma Homocysteine ◽

Open Angle

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Differential U2AF1 mutation sites, burden and co-mutation genes can predict prognosis in patients with myelodysplastic syndrome

Scientific Reports ◽

10.1038/s41598-020-74744-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Haiqiong Wang ◽

Yongbo Guo ◽

Zhenkun Dong ◽

Tao Li ◽

Xinsheng Xie ◽

...

Keyword(s):

Survival Rate ◽

Myelodysplastic Syndrome ◽

Gene Mutation ◽

Poor Prognosis ◽

Gene Mutations ◽

Chromosome 8 ◽

Common Mutation ◽

Mutation Load ◽

Mutation Site ◽

Increased Risk

Abstract To investigate the U2AF1 gene mutation site, mutation load and co-mutations genes in patients with myelodysplastic syndrome (MDS) and their effects on prognosis. Gene mutation detection by next-generation sequence and related clinical data of 234 MDS patients were retrospectively collected and analyzed for the relationship between the clinical characteristics, treatment efficacy and prognosis of U2AF1 gene mutation. Among the 234 MDS patients, the U2AF1 gene mutation rate was 21.7% (51 cases), and the median variant allele frequency was 39.5%. Compared with the wild type, the U2AF1 mutant had a higher incidence of chromosome 8 aberration, and was positively correlated with the occurrence of ASXL1, RUNX1, SETBP1 gene mutation, negatively correlated with SF3B1, NPM1 genes mutation (p < 0.05). The most common mutation site of U2AF1 was S34F (32 cases), while U2AF1 Q157P site mutations had a higher incidence of chromosome 7 abnormalities (p = 0.003). The U2AF1 gene mutation more frequently coincided with signal pathway related gene mutations (p = 0.043) with a trend of shortened overall survival. Among patients with U2AF1 gene mutations, those with ASXL1 mutations were prone to develop into acute myeloid leukemia, those with RUNX1 mutations had an increased risk of relapse, and those with TET2 mutations had higher 1-year survival rate. Compared with the patient group of lower mutation load (VAF ≤ 40%), the group with higher mutation load of U2AF1 (VAF > 40%) had a significantly lower 1-year survival rate (46.1% and 80.5%, p = 0.027). The criteria of U2AF1 VAF > 40% is an independent indicator for poor prognosis of MDS patients. VAF > 40% of U2AF1 is an independent factor of short OS in MDS patients. MDS patients with a mutation in the Q157P site of U2AF1 and a higher U2AF1 mutation load suggests poor prognosis, and co-mutated genes in U2AF1 can affect disease progression and prognosis.

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Myocardial Infarction in a Teenage Male With MTHFR Gene Mutation

CHEST Journal ◽

10.1016/j.chest.2016.08.103 ◽

2016 ◽

Vol 150 (4) ◽

pp. 95A

Author(s):

Jeremy Landeo Gutierrez ◽

Subhrajit Lahiri ◽

Branko Cuglievan ◽

Athena Pefkarou

Keyword(s):

Myocardial Infarction ◽

Gene Mutation ◽

Mthfr Gene

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