Methylenetetrahydrofolate Reductase Research Articles

Εffects of MTR and AS3MT variants on antipsychotic response: prospective evidence from a naturalistic study in Greece.

Relevance. Nitrous oxide-oxygen sedation has been widely used in Russia since the early 2000s. It is widely regarded as an effective method for managing the behavior of uncooperative patients. However, despite generally positive assessments of its safety and efficacy, there remains a lack of research into the potential negative consequences and risks associated with its use, both for patients and healthcare personnel. Objective. To provide structured information that will help dentists working with nitrous oxide sedation minimize its potential toxicity for all personnel involved. Materials and methods. Publications from both international and Russian databases over the past 30 years were reviewed for key terms related to the effects of nitrous oxide on dental personnel. The initial selection process involved screening titles and abstracts, followed by a full-text review of the remaining articles. From the 145 sources identified, 33 of the most relevant studies were selected. Results. Nitrous oxide has been used in dentistry for over 150 years, but its significant toxicity raises concerns about its safety. The primary harmful mechanism is the irreversible oxidation of vitamin B 12 , which disrupts essential processes such as DNA synthesis, myelin formation, homocysteine metabolism, and folic acid metabolism. High-risk groups include dental personnel (due to chronic exposure), individuals with B 12 /folate deficiency, those with congenital MTHFR gene mutations, people with chronic diseases (such as autoimmune disorders and diabetes), pregnant women, and others. Acute effects for dental personnel include dizziness, nausea, and impaired cognitive and motor functions. Chronic effects can be neurological (paresthesia, ataxia, demyelination of peripheral nerves), hematological (anemia, leukopenia), cardiovascular (thromboembolism, hypertension), reproductive (reduced fertility, pregnancy complications), and immune-related. Despite control measures such as ventilation, nitrous oxide monitoring, and respirators, the risk remains due to system leaks and insufficient awareness. Regular check-ups for personnel, twice a year, are critical are critical, including tests for homocysteine and methylmalonic acid, complete blood count, and neurological evaluations when symptoms arise. Dentists must be informed about the occupational risks of nitrous oxide. Conclusion. Proper use of nitrous oxide sedation minimizes these risks. Dentists' proficiency in behavior management techniques, local anesthesia, and personal responsibility for following safety protocols are crucial for ensuring the safety of dental personnel.

Both primary and secondary hemostasis consist of finely regulated pathways, forming a blood clot to stop bleeding. These orchestrated mechanisms involve multiple plasma- and platelet/endothelial-derived receptors, factors, enzymes, and proteins, such as the von Willebrand factor (vWF), fibrinogen, and thrombin. Over-activation or improper resolution of the coagulation cascade leads to severe pathological disorders, arterial and venous. Despite the fact that the genetic etiology of thrombophilia has gained the main research interest, there is growing evidence that the disturbed redox network of key hemostatic pathways signals thrombus formation. Oxidized LDL in dyslipidemias and many endogenous and exogenous compounds act as pro-oxidant stimuli that lead to post-translational modifications of proteins, such as sulfenylation, nitrosation, disulfide formation, glutathionylation, etc. Oxidation of cysteine and methionine residues of vWF, fibrinogen, and thrombomodulin has been detected at thrombotic episodes. Increased homocysteine levels due to, but not restricted to, methylenetetrahydrofolate reductase gene (MTHFR) mutations have been incriminated as a causative factor for oxidative stress, leading to a pro-thrombotic phenotype. Alterations in the vascular architecture, impaired vascular relaxation through decreased bioavailability of NO, accumulation of Nε-homocysteinylated proteins, ER stress, and endothelial cells’ apoptosis are among the pro-oxidant mechanisms of homocysteine. This review article focuses on describing key concepts on the oxidant-based molecular pathways that contribute to thrombotic episodes, with emphasis on the endogenous compound, homocysteine, aiming to promote further molecular, clinical, and pharmacological research in this field.

Genetically reduced MTHFR activity confers protection against multiple sclerosis.

Background and Objectives: Thrombophilia is a prothrombotic disorder that increases the risk of blood clotting and can pose serious health problems. It is considered a condition of gene–gene or gene–environment interactions. Variation in the prevalence of thrombophilia mutations and their interaction among populations necessitates localized genetic assessments. However, population-based genetic data remains limited for developing effective preventive strategies. Materials and Methods: This cross-sectional observational study was conducted over five years (2020–2024) at a tertiary university hospital in Northern Greece. A total of 2961 individuals aged 18–85 years (mean: 50.5) were registered based on family or medical history of venous thromboembolism (VTE) or clinical symptoms of VTE. The final analysis included 2078 participants comprising 1143 males (55%) and 935 females (45%), who met all the inclusion criteria. Inclusion criteria were absence of acute illness or malignancy, informed consent, and an adequate DNA quantity for genotyping, whereas excluded criteria included incomplete laboratory data, active inflammatory or malignant disease, and cognitive or psychiatric conditions. Peripheral blood samples were collected in 2 mL K3-EDTA tubes, and genomic DNA was analyzed using real-time polymerase chain reaction (PCR) with melting curve analysis and hybridization probes (LightMix® in vitro diagnostics, TIB MolBiol, Berlin, Germany). Five thrombophilia-related polymorphisms, Factor V Leiden (F5 G1691A), prothrombin (F2 G20210A), methylenetetrahydrofolate reductase (MTHFR C677T and MTHFR A1298C), and Plasminogen Activator Inhibitor-1 (PAI-1) 4G/5G, were examined for allele and genotype frequencies, Hardy–Weinberg equilibrium testing, pairwise linkage disequilibrium (D′ and r2), and power analysis. For subjects tested for Factor V Leiden (n = 1476), the activated protein C resistance (APC) ratio was additionally evaluated using the ACL TOP 750 analyzer. Results: Allele frequencies were 7.3% for FV Leiden and 3.7% for FII. The PAI-1 allele was distributed at 44%, while the MTHFR (C677T and A1298C) alleles were each present at 33%. Significant linkage disequilibrium was identified between MTHFR (C677T and A1298C) and between MTHFR A1298C and PAI-1. No evolutionary pressure or demographic bias was found in the Hardy–Weinberg equilibrium. The APC ratio demonstrated a high sensitivity (99.2%) and specificity (96.6%), indicating that it may serve as a reliable screening method. Conclusions: Our findings highlight informative patterns in the genetic predisposition to thrombophilia, which may help develop rule-based strategies for implementing thromboprophylaxis guidelines and personalized medical interventions.

Acute portal vein thrombosis in an elderly man with homozygous mutations of plasminogen activator inhibitor-1 and methylenetetrahydrofolate reductase genes

Introduction . Type 2 diabetes mellitus occupies a leading position in the structure of non-infectious diseases in the world. The development of severe vascular complications of the disease, including diabetic foot syndrome, requires complex treatment and is an economically costly process accompanied by high disability and mortality of patients. Objective . To evaluate the association of polymorphic markers A1298C of the MTHFR gene with changes in the microcirculatory bed during the development of diabetic foot. Materials and methods . At the 1st stage of the study, the distribution of genotypes of the A1298C polymorphism of the MTHFR gene was studied in 198 patients with uncomplicated type 2 diabetes mellitus and 199 patients with diabetic foot. At the 2nd stage of the study, 30 patients with a comparable percentage distribution of the frequencies of the studied polymorphism as at the 1st stage were selected from the general groups of patients, and their microcirculation was examined using laser Doppler flowmetry. At the 3rd stage of the study, microcirculation parameters were analyzed depending on the carriage of the genotype of the A1298C polymorphism of the MTHFR gene. Results. In patients with diabetic foot syndrome, who are carriers of the A/A and A/C genotypes, a decrease in the temporal variability of perfusion by 2 and 1.2 times was revealed at a remote point. Locally, in patients with the studied complication of type 2 diabetes mellitus and genotypes C/C, A/C, a deterioration in the general condition of the microcirculatory bed by 2 and 2.2 times was noted. A decrease in the variability of microcirculation at a point on the 1st toe in diabetic foot syndrome with carriage of the A/A and A/C genotypes by 2 and 1.8 times was recorded. Conclusion . Carriage of different genotype variants of the A1298C polymorphism of the MTHFR gene is associated with different pathways for the implementation of mechanisms of microcirculatory bed impairment.

Background/Objectives: Pharmacogenetic variability plays a crucial role in determining both the efficacy and toxicity of chemotherapy for gastrointestinal cancers. However, data on allele frequencies and their clinical relevance in Russian populations remain scarce. Methods: We conducted a prospective observational study of 412 patients with gastrointestinal malignancies between 2020 and 2023. Pharmacogenetic testing was performed prior to the initiation of chemotherapy using real-time allele-specific PCR and microarray hybridization technology. Polymorphisms in the DPYD, UGT1A1, CYP2C8, CYP3A5, GSTP1, ERCC1, XPC, CDA, MTHFR, TYMS, and SLC31A1 genes were analyzed. Results: The frequency of most variants was consistent with those reported in European populations, reflecting the ethnic proximity of the studied cohort. Several clinically relevant variants were identified: DPYD rs2297595 occurred more frequently than in European cohorts, and UGT1A1 rs8175347 was observed at a higher prevalence, underscoring the potential risk of irinotecan-related neutropenia and diarrhea. CYP2C8 rs10509681 was present at frequencies comparable to European populations and is associated with an increased risk of taxane-induced peripheral neuropathy. Other markers (GSTP1, ERCC1, CDA, SLC31A1, MTHFR, TYMS) demonstrated variable associations with chemotherapy efficacy and toxicity, consistent with findings from previous international studies. Conclusions: This study provides the first comprehensive description of pharmacogenetic polymorphisms in a Russian cohort of patients with gastrointestinal cancers. Our findings confirm the clinical importance of DPYD and UGT1A1 testing and highlight additional variants of potential interest.

Disclosure: K. Komisarenko: None.Background: T2DM is a multifactorial metabolic disease with significant genetic contributions. Polymorphisms in folate metabolism genes, particularly MTHFR C677T and A1298C, are associated with impaired homocysteine clearance, endothelial dysfunction, and neurotransmitter imbalance. Post-COVID metabolic stress may amplify these effects, especially in individuals with T2DM, but the combined influence of clinical and genetic factors remains poorly defined. Objective: To evaluate the association of MTHFR C677T and A1298C polymorphisms with plasma levels of serotonin, ST-2, and homocysteine in post-COVID T2DM and to develop multivariate regression models for predicting biomarker variations based on genetic and clinical profiles. Methods: This study included 250 adults with previously diagnosed T2DM who had recovered from confirmed SARS-CoV-2 infection. Demographic and clinical data, including BMI, hypertension status, and COVID-19 treatment modalities, were collected. MTHFR genotyping was performed using PCR-RFLP. Plasma levels of homocysteine were quantified via LC-MS/MS, while serotonin and ST-2 were measured using ELISA. Predictive models were constructed through multiple linear regression. Statistical significance was set at p < 0.05. Results: Patients carrying the 677T or 1298C alleles had significantly higher homocysteine (+3 µmol/L; p < 0.01) and lower serotonin levels (p < 0.05) than wild-type individuals. Elevated BMI and hypertension were additional predictors of unfavorable biomarker changes. Age was negatively associated with ST-2 levels, while a history of pulmonary insufficiency predicted increased ST-2 (p < 0.05). Dexamethasone treatment during COVID-19 was linked to increased serotonin, and oxygen therapy to reduced ST-2. All models were statistically significant (ANOVA p < 0.001) with strong explanatory power (R² = 0.87-0.91). Conclusions:MTHFR gene variants, in conjunction with clinical variables such as BMI and hypertension, influence key biochemical markers in post-COVID T2DM. Integrating genetic and metabolic profiling may inform individualized strategies for folate supplementation and cardiometabolic control. These findings support the practical implementation of genetic screening and biomarker monitoring in post-COVID endocrine care to reduce vascular, neuropsychiatric, and inflammatory complications in high-risk diabetic patients.Presentation: Saturday, July 12, 2025

Background/Objectives: Type 2 diabetes mellitus (T2DM) represents a major global health problem, and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism has been repeatedly linked to T2DM susceptibility. However, no prior study has investigated this association in the Iraqi Kurdish population. This study aimed to examine the relationship between MTHFR C677T polymorphisms and T2DM in a sample of Iraqi Kurdish patients, and to evaluate its effects on metabolic parameters, lipid profiles, and the incidence of diabetic complications. Methods: This population-based cross-sectional study included 280 participants, comprising 140 patients with T2DM and 140 healthy controls. Biochemical, clinical, and demographic data, including liver and renal function and lipid profiles, were collected. Real-Time polymerase chain reaction (PCR) was used to genotype MTHFR C677T. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to compare groups and assess associations. Results: Compared with controls, T2DM patients had higher blood pressure (BP), waist circumference (WC), body mass index (BMI), and glycated hemoglobin (HbA1c) ( P &lt; 0.001). The CT genotype frequency was 38.57% in T2DM vs. 16.42% in controls (OR = 4.45, 95% CI: 2.49–7.97), and the TT genotype frequency was 20.00% in T2DM vs. 5.00% in controls (OR = 7.59, 95% CI: 3.12–18.42). The TT genotype was associated with lower high-density lipoprotein cholesterol (HDL-C) (42.37 ± 6.68 mg/dL; P &lt; 0.001) and higher homocysteine (Hcy) levels (22.08 ± 5.74 µmol/L). T2DM patients also had elevated albumin-to-creatinine ratio (ACR) (190.80 ± 214.84 mg/g creatinine) and reduced estimated glomerular filtration rate (eGFR) (86.91 ± 22.19 mL/min/1.73 m 2 ) (both P &lt; 0.001), especially in the TT genotype group. Conclusions: The MTHFR C677T polymorphism is strongly associated with T2DM in Iraqi Kurdish patients, with the T allele linked to adverse metabolic profiles and a higher risk of complications. These findings highlight the potential clinical value of incorporating genetic screening into early risk assessment and personalized management strategies in high-risk populations.

Elevated plasma homocysteine (tHcy) is a modifiable risk factor for stroke and cardiovascular disease, influenced by genetic and lifestyle factors. Resistance-based training may reduce tHcy, but the impact of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism remains unclear. This study examined the effects of a 26-week combined aerobic and resistance training program on stroke-related risk factors and tHcy levels in patients with chronic ischemic stroke, stratified by MTHFR genotype. Forty-six patients (mean age: 57.7 ± 8.9 years) completed supervised training three times per week. Assessments before and after the intervention included anthropometry, cardiorespiratory fitness, biochemical markers, and tHcy. Dietary intake was monitored and remained stable. Significant improvements were observed in body weight, fat mass, waist-to-hip ratio, VO2max, and 6 min walk distance. tHcy decreased significantly overall (p &lt; 0.01), with reductions confined to the CC genotype group (p &lt; 0.01). BMI declined in CC and CT groups (p &lt; 0.01 and p &lt; 0.05), while fat-free mass, triglycerides, fasting glucose, and blood pressure showed no changes, likely due to pharmacological control. These findings suggest that combined training improves body composition and functional capacity, while genotype-specific reductions in tHcy highlight the potential of personalized rehabilitation strategies integrating genetic and nutritional considerations in stroke care.

Thrombophilia is influenced by genetic variants, such as Factor V Leiden (FVL) and the prothrombin G20210A mutation. In clinical settings, assessing numerous genetic factors can lead to diagnostic errors and unnecessary treatments. This meta-analysis examines gene variants associated with thrombosis in the Iranian population, where their role in thrombotic disorders remains underexplored. A systematic literature search was performed across PubMed, Scopus, and Web of Science, targeting case-control studies published up to July 2025. Studies were included if they evaluated thrombophilia-related polymorphisms in Iranian patients with various thrombotic conditions, such as recurrent pregnancy loss (RPL), venous thromboembolism (VTE), or deep vein thrombosis (DVT). Advanced statistical analyses, including random-effects models, fixed-effects models, and Bayesian meta-analysis, were used to compute odds ratios (ORs) and 95% confidence intervals (CIs). From 36 studies encompassing over 14 000 participants, significant associations emerged. For RPL, FVL G1691A heterozygote (OR: 1.998, 95% CI: 1.02-3.88), methylenetetrahydrofolate reductase (MTHFR) C677T heterozygote (OR: 1.77, 95% CI: 1.31-2.39), MTHFR A1298C heterozygote (OR: 3.10, 95% CI: 1.33-7.20) and homozygote (OR: 1.69, 95% CI: 1.05-2.70), prothrombin G20210A heterozygote (OR: 2.435, 95% CI: 1.09-5.39) and homozygote (OR: 0.487, 95% CI: 0.40-0.58), plasminogen activator inhibitor-1 (PAI-1) polymorphisms, factor V (FV) A4070G, FV 5279A/G, factor XIII (FXIII) Val34Leu, and integrin subunit beta-3 (ITGB3)1565T/C were linked to elevated RPL risk. Additionally, FVL G1691A heterozygote (OR: 5.25, 95% CI: 2.39-11.54) was associated with higher VTE risk, while MTHFR C677T heterozygote (OR: 1.404, 95% CI: 1.030-1.914) increased DVT risk. These ethnicity-specific findings highlight critical genetic risk factors for thrombotic disorders in Iranians, potentially guiding precise diagnostics and personalized interventions.

BackgroundMethylenetetrahydrofolate reductase (MTHFR) is a key enzyme in homocysteine metabolism. Its 677C>T and 1298A>C polymorphisms can reduce enzyme activity, potentially elevating homocysteine levels. H-type hypertension (hypertension with homocysteine ≥10 μmol/L) is an important risk factor for ischemic stroke, and its synergistic effect exacerbates vascular damage. However, the association between these MTHFR polymorphisms and elevated homocysteine levels in patients with hypertension complicated by ischemic stroke remains unclear. This study aimed to investigate the association between MTHFR gene polymorphisms and H-type hypertension in patients with ischemic stroke.MethodsA total of 215 patients with ischemic stroke and hypertension admitted to the Department of Neurology at the Taian City Central Hospital from June 2021 to December 2022 were enrolled. General clinical data and biochemical indicators were collected. MTHFR genotyping was performed using a universal sequencing kit and a TL998A fluorescence detector. Linkage disequilibrium was analyzed via SHEsis software. Statistical analyses were conducted using SPSS 25.0. P < 0.05 indicates that the difference is statistically significant.ResultsAmong patients with ischemic stroke combined with hypertension in this region, the proportion of H-type hypertension was 89.3%. The proportion of males in the H-type hypertension group was significantly higher than in the non-H-type hypertension group (P < 0.05). The genotype and allele distributions of MTHFR(677C>T) (risk allele: T) differed significantly between groups (P < 0.05): the H-type group had a higher frequency of the TT genotype (47.4% vs. 17.4%) and T allele (67.2% vs. 50.0%). Multivariate logistic regression analysis showed that the MTHFR(677C>T) TT genotype was an independent risk factor for H-type hypertension (P = 0.021, OR = 2.615, 95%CI [1.154–5.926]). For haplotypes with a frequency >3%, there were three haplotypes of MTHFR(677C>T)/(1298A>C). The C-A haplotype was a protective factor for H-type hypertension (P = 0. 028, OR = 0.485, 95%CI [0.252–0.934]), while the T-A haplotype was a risk factor (P = 0.022, OR = 2.029, 95%CI [1.096–3.756]).ConclusionIn patients with ischemic stroke, the MTHFR(677C>T) TT genotype is an independent risk factor for H-type hypertension. For haplotypes with a frequency >3%, the C-A haplotype was a protective factor for H-type hypertension, whereas the T-A haplotype was a risk factor.

Recurrent spontaneous abortion (RSA) is one of the most common reproductive complications among women of childbearing age. Several factors-including genetic, anatomical, endocrine, infectious, environmental, and immunological causes-have been implicated in RSA. This study aimed to explore the potential association between RSA and the expression patterns of selected genes involved in critical biological processes related to pregnancy maintenance and miscarriage. The relative expression levels of matrix metallopeptidase 2 (MMP2), matrix metallopeptidase 9 (MMP9), DNA methyltransferase 1 (DNMT1), DNA methyltransferase 3 alpha (DNMT3A), and methylenetetrahydrofolate reductase (MTHFR) were evaluated using peripheral blood samples from 30 women with a history of two or more spontaneous abortions (cases) and 30 age-matched non-pregnant women with no history of miscarriage and at least one successful pregnancy (controls). No significant differences in the mRNA expression levels of the target genes were observed between women with RSA and the control group. Our findings suggest that peripheral blood gene expression profiles of MMP2, MMP9, DNMT1, DNMT3A, and MTHFR may not adequately reflect tissue-specific changes associated with RSA. Further investigations using relevant tissues, such as placental or decidual samples, are warranted to better understand the molecular mechanisms underlying RSA.

Gestational diabetes mellitus (GDM) is a common pregnancy complication with rising incidence and adverse maternal-fetal outcomes. Genetic polymorphisms in folate metabolism genes may influence GDM susceptibility through homocysteine pathway alterations. To investigate the associations between MTHFR (C677T, A1298C) and MTRR (A66G) polymorphisms and GDM risk, including gene‒gene interactions, in Chinese Han pregnant women, this retrospective cohort study analyzed 1312 Chinese Han pregnant women. The MTHFR C677T, A1298C, and MTRR A66G polymorphisms were genotyped using allele-specific PCR. Polymorphism-GDM associations were assessed using logistic regression, adjusting for maternal age, prepregnancy BMI, and folate intake. Gene‒gene interactions were evaluated using multiplicative interaction models. After confounder adjustment, the MTHFR 677TT genotype was associated with GDM (OR 1.89, 95% CI 1.24−2.93) compared to wild-type. The MTRR 66AG and 66GG genotypes were associated with GDM, with ORs of 2.73 (95% CI: 1.93–3.89) and 3.10 (95% CI: 1.72–5.41), respectively. Significant gene‒gene interactions were observed between MTHFR C677T & A1298C (OR 2.22, 95% CI 1.25−4.23 for TT/AA combination) and MTHFR C677T & MTRR A66G (OR 6.06, 95% CI 3.48−14.10 for TT/AG combination), indicating synergistic effects that surpass the expected multiplicative combination of individual polymorphism effects. MTHFR C677T and MTRR A66G polymorphisms independently and interactively increase GDM odds in Chinese Han women, enabling personalized risk prediction and targeted prevention.

Abstract Background Female infertility affects a significant number of women worldwide. It is defined as the inability to achieve pregnancy after one year of regular attempts without the use of contraceptive methods. Among the obstetric complications associated with infertility, recurrent miscarriage stands out, characterized by the occurrence of two or more consecutive miscarriages. The MTHFR gene (methylenetetrahydrofolate reductase) encodes the homonymous enzyme responsible for catalyzing the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the active form of folate, which is essential for cellular metabolism. Polymorphisms in this gene, such as C677T and A1298C, are associated with reduced enzymatic activity, affecting folate metabolism with its recognized impact on the prevention of neural tube defects. Low levels of folic acid, associated with increased homocysteine concentrations, are linked to recurrent miscarriages and other pregnancy complications. The aim of this study was to determine the genotypic frequency of the C677T and A1298C polymorphisms of the MTHFR gene in patients with infertility and recurrent miscarriage. Methods This study analyzed 759 samples from 253 female patients undergoing investigation for reproductive difficulties. Clinical samples were collected and subjected to karyotype analysis (n=253) and detection of two mutations in the MTHFR gene (n=506). Karyotype analysis was performed using G-banding techniques, according to the protocols established by the International System for Human Cytogenomic Nomenclature (ISCN). For MTHFR gene mutation testing, real-time Polymerase Chain Reaction (PCR) was employed. The alleles analyzed included C677T and A1298C, the main variants associated with altered enzymatic function. The inclusion criteria were patients with a history of infertility and recurrent miscarriage, aged between 21 and 50 years, and the availability of complete results for both genetic tests. Results All 253 samples analyzed showed normal results for karyotype analysis. Considering the MTHFR gene polymorphisms, the overall mutation frequency was 53.75% (272/506) for the analyzed alleles. When evaluating the polymorphisms individually, 14.62% of patients had no mutations, 37.15% presented mutation in C677T, and 26.1% in A1298C. Furthermore, 22.13% of patients had mutations in both polymorphisms. The heterozygous mutation was predominant for both polymorphisms, observed in 79.33% for C677T and 87.70% for A1298C. Among the patients with mutations in both polymorphisms, all exhibited heterozygous mutations (100%). Homozygous mutations were found in 20.66% for C677T and 12.29% for A1298C. Regarding age group, the prevalence of mutations was observed in patients between 31 and 40 years old, who represented 64.82% of the cases analyzed. In this age group, the primary reason for the investigation was infertility, accounting for 70.12% of diagnostic hypotheses, while 29.88% of cases were related to recurrent miscarriage. Conclusion The results highlighted the high frequency of the C677T and A1298C polymorphisms of the MTHFR gene in patients with a history of infertility and recurrent miscarriages, reinforcing the relevance of these variants in the context of reproductive health. The prevalence of heterozygous mutations in both polymorphisms, as well as the genetic alterations observed in women aged 31 to 40 years, indicate the need to consider the impact of these genetic factors during clinical evaluation of infertility and pregnancy complications.

BackgroundLow-dose methotrexate (MTX) is a standard treatment for ectopic pregnancy. While generally safe, it can rarely cause life-threatening hematologic toxicity. The mechanisms underlying these severe reactions in patients without traditional risk factors are poorly understood. We report a case of severe pancytopenia and systematically analyze the literature to characterize this rare but critical complication in MTX treatment for ectopic pregnancy.Case PresentationA 24-year-old woman received a single 50 mg/m2 dose of MTX for a persistent ectopic pregnancy while on concurrent benzathine penicillin therapy for syphilis. Within 24 h, she developed nausea, vomiting, and facial edema, rapidly progressing to severe mucositis and life-threatening pancytopenia with absolute neutrophil count nadir of 0.1 × 109/L, platelet nadir of 8 × 109/L and hemoglobin nadir of 76 g/L. Investigations revealed delayed MTX clearance and a heterozygous methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, a known genetic risk factor for MTX toxicity. A diagnosis of MTX toxicity was made, and she fully recovered after intensive supportive care including hydration, urine alkalinization, calcium leucovorin rescue, hematopoietic growth factors, and antibiotics.ConclusionSevere MTX toxicity following low-dose treatment for ectopic pregnancy is a rare but potentially fatal complication, with 3 deaths among 16 reviewed cases. Our analysis suggests a multifactorial etiology involving genetic predisposition and pharmacokinetic interactions. The MTHFR C677T variant compromises folate metabolism, while concurrent medications like benzathine penicillin may impair MTX renal clearance through competitive inhibition of organic anion transporters. Early symptom onset precedes standard monitoring schedules, necessitating enhanced clinical vigilance and consideration of pharmacogenetic factors and drug interactions in clinical practice.

Influence of methylenetetrahydrofolate 677C > T variant in murine models following valproic acid exposure.

Potential sex-specific associations between MTHFR C677T polymorphism and thyroid autoantibodies in spontaneous abortion: A retrospective study in the Lingnan region of China.

Methylene-tetrahydrofolate reductase (MTHFR) is an important enzyme for acetogenic carbon fixation, but the redox mechanism driving this reaction is not clearly understood. Previous enzymology work and energetic accounting on species such as Clostridium autoethanogenum has led to confounding results when placed in the context of in vivo experiments. In this work, we create multiple C. autoethanogenum strains harboring alternative MTHFR enzyme complexes as well as genome-scale metabolic models to better understand how these organisms conserve energy on gas substrates. The inclusion of a Type-III MTHFR unexpectedly allows for higher growth than expected and suggests the possibility of an additional redox balancing cycle employed during autotrophic growth.