Methylenetetrahydrofolate Reductase Research Articles

JAK2 V617F Mutation in Patients with Thrombosis

Background: Thrombosis is a major disorder with serious complications. The JAK2V617F mutation results in constitutive phosphorylation of JAK2 and activation of the cellular proliferation cascade.
 The present study aimed to clarify the prevalence of JAK2V617F mutation in patients with thrombosis.
 Subjects and Methods: This case-control study was conducted on 60 subjects subdivided into 2 groups: 30 healthy subjects as a control group (Group I) and 30 patients diagnosed with thrombosis (Group II). All subjects were subjected to full history taking, and clinical examination and investigated for Molecular detection of JAK2V617F mutation, FV (Factor V Leiden) – PTH (Prothrombin), and MTHFR (Methylene tetrahydro-folate reductase).
 Results: There was a statistically significant difference among the studied groups as regards the JAK2V617F mutation (P value < 0.05, odds ratio = 41.216, 95% C.I. 95% = 2.302 - 738.034, relative risk = 25, 95% C.I. 95% = 1.547– 404.012). This mutation was more significantly associated with venous thrombosis than arterial thrombosis (P = < 0.05).
 Conclusion: This study showed a significant association between JAK2V617F mutation and thrombosis with more significant evidence in the venous than the arterial thrombosis.

Recurrent MiscarriageGreen-top Guideline No. 17.

In this guideline, recurrent miscarriage has been defined as three or more first trimester miscarriages. However, clinicians are encouraged to use their clinical discretion to recommend extensive evaluation after two first trimester miscarriages, if there is a suspicion that the miscarriages are of pathological and not of sporadic nature. Women with recurrent miscarriage should be offered testing for acquired thrombophilia, particularly for lupus anticoagulant and anticardiolipin antibodies, prior to pregnancy. [Grade C] Women with second trimester miscarriage may be offered testing for Factor V Leiden, prothrombin gene mutation and protein S deficiency, ideally within a research context. [Grade C] Inherited thrombophilias have a weak association with recurrent miscarriage. Routine testing for protein C, antithrombin deficiency and methylenetetrahydrofolate reductase mutation is not recommended. [Grade C] Cytogenetic analysis should be offered on pregnancy tissue of the third and subsequent miscarriage(s) and in any second trimester miscarriage. [Grade D] Parental peripheral blood karyotyping should be offered for couples in whom testing of pregnancy tissue reports an unbalanced structural chromosomal abnormality [Grade D] or there is unsuccessful or no pregnancy tissue available for testing. [GPP] Women with recurrent miscarriage should be offered assessment for congenital uterine anomalies, ideally with 3D ultrasound. [Grade B] Women with recurrent miscarriage should be offered thyroid function tests and assessment for thyroid peroxidase (TPO) antibodies. [Grade C] Women with recurrent miscarriage should not be routinely offered immunological screening (such as HLA, cytokine and natural killer cell tests), infection screening or sperm DNA testing outside a research context. [Grade C] Women with recurrent miscarriage should be advised to maintain a BMI between 19 and 25 kg/m2 , smoking cessation, limit alcohol consumption and limit caffeine to less than 200 mg/day. [Grade D] For women diagnosed with antiphospholipid syndrome, aspirin and heparin should be offered from a positive test until at least 34 weeks of gestation, following discussion of potential benefits versus risks. [Grade B] Aspirin and/or heparin should not be given to women with unexplained recurrent miscarriage. [Grade B] There are currently insufficient data to support the routine use of PGT-A for couples with unexplained recurrent miscarriage, while the treatment may carry a significant cost and potential risk. [Grade C] Resection of a uterine septum should be considered for women with recurrent first or second trimester miscarriage, ideally within an appropriate audit or research context. [Grade C] Thyroxine supplementation is not routinely recommended for euthyroid women with TPO who have a history of miscarriage. [Grade A] Progestogen supplementation should be considered in women with recurrent miscarriage who present with bleeding in early pregnancy (for example 400 mg micronised vaginal progesterone twice daily at the time of bleeding until 16 weeks of gestation). [Grade B] Women with unexplained recurrent miscarriage should be offered supportive care, ideally in the setting of a dedicated recurrent miscarriage clinic. [Grade C].

Associations of serum 25-hydroxyvitamin D with serum folate, cobalanin, and homocysteine concentrations and methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms in healthy adults.

The aim of this study was to investigate the associations of serum 25-hydroxyvitamin D [25(OH)D] with various demographic, anthropometric, and genetic characteristics and biochemical parameters in healthy Greek adults. Demographic (age and sex), anthropometric (body mass index/BMI), and genetic (MTHFR gene polymorphisms) characteristics and biochemical parameters (serum folate, cobalamin/Cbl, and total homocysteine/tHcy concentrations), which had been recorded and measured, among others, in the framework of periodic medical examination (military personnel) or check-up (non-military personnel) of 383 healthy Greek adults (199 men and 184 women) were analyzed. Serum 25(OH)D, tHcy, folate, and Cbl levels were determined using immunoassay methods. The MTHFR C677T and A1298C gene polymorphisms were genotyped using polymerase chain reaction and reverse hybridization. Serum 25(OH)D concentrations were correlated with Cbl levels and MTHFR C677T gene polymorphism, while they had a reverse correlation with serum tHcy levels, age, and BMI. There was no significant correlation between serum 25(OH)D concentrations and sex, serum folate levels, and smoking status. Individuals with the 677TT genotype had statistically significantly lower serum 25(OH)D levels than those with the 677CC or 677CT genotype, while individuals with the 1298CC genotype had statistically significantly higher serum 25(OH)D levels than those with 1298AA or 1298AC genotype. Moreover, the reverse correlation between the serum 25(OH)D and tHcy levels was statistically significant in all six MTHFR genotypes. Serum 25(OH)D levels are associated with age, BMI, serum tHcy, and Cbl levels and MTHFR C677T gene polymorphism. The most significant finding of our study is the observed reverse correlation of serum 25(OH)D levels with serum tHcy levels. Considering that vitamin D deficiency and hyperhomocysteinemia (HHcy) are associated with an increased risk for cardiovascular diseases (CVDs), we suggest that individuals with high serum tHcy levels should be further investigated for, inter alia, their serum 25(OH)D levels.

Effects of folic acid supplementation on chronic atrophic gastritis based on MTHFR C677T polymorphism.

It has been shown the methylenetetrahydrofolate reductase (MTHFR) 677TT (rs 1801133) genotype predicts histopathological alterations in the incisura of patients with chronic atrophic gastritis (CAG). MTHFR is a crucial enzyme in fatty acid (FA) metabolism. This study aimed to evaluate the influence of FA supplementation in CAG patients without Helicobacter pylori infection and the MTHFR C677T (rs 1801133) genotype as a potential CAG predictor. A total of 96 CAG patients, aged 21 to 72 years old, were enrolled in this study. After 6 months of treatment, histopathological outcomes were compared among patients treated with weifuchun (WFC) (1.44 g 3 times per os per day), those treated with WFC and FA (5 mg once daily), and those treated with WFC, FA, and vitamin B12 (VB12) (0.5 mg 3 times per day) based on the Operative Link on Gastritis/Intestinal Metaplasia assessment staging systems. Atrophic lesions in patients treated with WFC and FA improved more than in patients treated only with WFC therapy (78.1% vs 53.3%, P = .04). Atrophic or intestinal metaplasia (IM) lesions in the incisura of patients with the TT genotype were better than those in patients with the CC/CT genotype (P = .02). The treatment of CAG patients with 5 mg of FA supplements daily for 6 months improved their gastric atrophy status, especially for the Operative Link on Gastritis/Intestinal Metaplasia assessment stages I/II. Moreover, our study is the first to reveal that patients with the MTHFR 677TT genotype require more timely and effective FA treatment than those with the CC/CT genotype.

Асоціація поліморфізмів генів GSTP1(A313G), MTHFR (С677T) та IL-10 (C819T) із ризиком виникнення гліобластоми

гліобластома одна з найбільш поширених злоякісних пухлин головного мозку з вкрай низькою виживаністю. Незважаючи на досягнення у вивченні молекулярного патогенезу та біології пухлин мозку, причини виникнення гліобластоми залишаються нез’ясованими. Дослідження останніх років вказують, що зміни у генах, які беруть участь у проліферації, диференціації та апоптозі клітин, можуть впливати на ризик виникнення онкологічних захворювань. Тож метою роботи було дослідити поліморфізми генів GSTP1(A313G), MTHFR (С677Т) та IL-10 (C819T) у хворих на гліобластому та проаналізувати їх зв’язок із ризиком розвитку цієї патології. Біологічним матеріалом для аналізу поліморфізмів генів GSTP1, MTHFR та IL-10 слугувала периферична кров хворих на гліобластому та практично здорових людей. Дослідження поліморфізмів генів проводилось за допомогою методу алель-специфічної ПЛР із використанням власних пар детекторів TaqMan MGB на основі флуоресцентних барвників, що призначені для виявлення однонуклеотидних замін. Встановлено, що частота мутантного алеля G гена GSTP1 у хворих становила 53,6% проти 32% у групі практично здорових людей. Розподіл генотипів гена GSTP1 у групі хворих відповідав закону генетичної рівноваги Харді-Вайнберга та статистично відрізнялась від показника у групі практично здорових людей і становив 0,538 проти 0,320 (χ2 = 13,10, р = 0,003). Визначено, що ризик виникнення гліобластоми є в 4,88 разів вищим у осіб, що є гомозиготними носіями мутантного алелю гена GSTP1 (генотип G313G) у порівнянні з іншими поліморфними варіантами. В результаті наших досліджень, було встановлено, що частота мутантного алеля С гена IL-10 у хворих становила 48,8%, що значно перевищує відповідний показник у групі практично здорових людей – 25%. Встановлено, що розподіл генотипів гена IL-10 у групі хворих відповідав закону генетичної рівноваги Харді-Вайнберга, частота мутантного алеля С гена IL-10 статистично відрізнялась від показника у групі практично здорових людей та становила 0,488 проти 0,250 (χ2 = 18,32, р = 0,00002). Встановлено, що існує асоціація між поліморфізмом гена IL-10 (C819T) та ризиком виникнення гліобластоми, у гомозиготних носіїв із генотипом Т819Т, ризик захворіти збільшується у 6,40 рази. Також нами було встановлено, що частота мутантного алелю Т гена MTHFR у хворих становила 35,0% проти 28,1% у групі практично здорових людей. Розподіл генотипів гена MTHFR у групі хворих відповідав закону генетичної рівноваги Харді-Вайнберга, а розподіл частот поліморфних варіантів ген показав відсутність статистично достовірних відмінностей між групою хворих та групою практично здорових людей (χ2 = 1,43 р = 0,23). Не було встановлено асоціації між поліморфізмом гена MTHFR (С677Т) і ризиком виникнення гліобластоми.

Genetic origins of recurrent miscarriage: A review of the literature

Currently, recurrent miscarriage is considered a polygenic multifactorial disease, that is, a condition in which the predisposition to miscarriage is related to various genetic factors. The realization of these factors depends largely on the environment. This paper analyzes the current world literature on the effect of single-nucleotide polymorphisms of genes associated with recurrent miscarriage. The literature review summarized data from recent meta-analyses regarding the association between recurrent miscarriage and genetic polymorphisms leading to endothelial dysfunction (vascular endothelial growth factor A gene and endothelial NO synthase genes), hereditary thrombophilia (Leiden mutation and polymorphisms in the methylene tetrahydrofolate reductase gene), immunological disorders (cytokine genes, including interleukin-1 beta, interleukin-6, and tumor necrosis factor alpha), altered receptor interactions in the endometrium (progesterone receptor and ESR1 and ESR2 estrogen receptor genes), and imbalance between lipoproteins of different densities (apolipoprotein E gene). The study of genetic predisposition to miscarriage is necessary to identify high-risk cases, initiate timely and careful monitoring, and develop personalized preventive techniques.

Genetic Variants, Neurocognitive Outcomes, and Functional Neuroimaging in Survivors of Childhood Acute Lymphoblastic Leukemia.

Genetic predispositions may modulate risk for developing neurocognitive late effects in childhood acute lymphoblastic leukemia (ALL) survivors. Long-term ALL survivors (n = 212; 14.3[4.77] years, mean[SD]; 49% female) treated with chemotherapy completed neurocognitive testing and task-based functional neuroimaging (fMRI). Based on previous work from our team, genetic variants related to the folate pathway, glucocorticoid regulation, drug metabolism, oxidative stress, and attention were included as predictors of neurocognitive performance, using multivariable models adjusted for age, race, and sex. Subsequent analyses evaluated the impact of these variants on task-based fMRI. Statistical tests were two-sided. Survivors exhibited higher rates of impaired attention(20.8%), motor skills(42.2%), visuo-spatial memory(49.3-58.3%), processing speed(20.1%), and executive function(24.3-26.1%) relative to population norms (10%; p's < 0.001). Genetic variants implicated in attention deficit phenotypes predicted impaired attention span (synaptosome associated protein 25 [SNAP25rs3746544], F(2,172)=4.07, p = 0.019) and motor skills (monoamine oxidase A, [MAOArs1137070], F(2,125)=5.25, p = 0.007). Visuo-spatial memory and processing speed varied as a function of genetic variants in the folate pathway (methylenetetrahydrofolate reductase [MTHFRrs1801133], F(2,165)=3.48, p = 0.033; methylenetetrahydrofolate dehydrogenase 1 [MTHFD1rs2236225], F(2,135)=3.8, p = 0.025; respectively). Executive function performance was modulated by genetic variants in the folate pathway (MTHFD1rs2236225, F(2,158)=3.95, p = 0.021; MTHFD1rs1950902, F(2,154)=5.55, p = 0.005) and glucocorticoid regulation (vitamin D receptor [VDRrs154410], F(2,158)=3.29, p = 0.039; FKBP prolyl isomerase 5 [FKBP5rs1360780], F(2,154)=5.6, p = 0.005). Additionally, MTHFD1rs2236225 and FKBP5rs1360780 were associated with altered brain function during attention and working memory (p < 0.05; FWE corrected). Results extend previous findings of genetic risk of neurocognitive impairment following ALL therapy and highlight the importance of examining genetic modulators in relation to neurocognitive deficits.

Pharmacogenetic Sex-Specific Effects of Methotrexate Response in Patients with Rheumatoid Arthritis.

Methotrexate (MTX) is a commonly used drug for the treatment of rheumatoid arthritis (RA), but its effectiveness can vary greatly among patients. Pharmacogenetics, the study of how genetic variations can affect drug response, has the potential to improve the personalized treatment of RA by identifying genetic markers that can predict a patient's response to MTX. However, the field of MTX pharmacogenetics is still in its early stages and there is a lack of consistency among studies. This study aimed to identify genetic markers associated with MTX efficacy and toxicity in a large sample of RA patients, and to investigate the role of clinical covariates and sex-specific effects. Our results have identified an association of ITPA rs1127354 and ABCB1 rs1045642 with response to MTX, polymorphisms of FPGS rs1544105, GGH rs1800909, and MTHFR genes with disease remission, GGH rs1800909 and MTHFR rs1801131 polymorphisms with all adverse events, and ADA rs244076 and MTHFR rs1801131 and rs1801133, However, clinical covariates were more important factors to consider when building predictive models. These findings highlight the potential of pharmacogenetics to improve personalized treatment of RA, but also emphasize the need for further research to fully understand the complex mechanisms involved.

INFLUENCE OF THE METHYLENE TETRAHYDROFOLATE REDUCTASE (MTHFR) GENE POLYMORPHISMS ON SERUM FOLATE, COBALANIN AND HOMOCYSTEINE LEVELS IN HEALTHY GREEK ADULTS

Objective: Methylene tetrahydrofolate reductase (MTHFR) is a key enzyme of homocysteine metabolism participating in the folate cycle. It is well known that hyperhomocysteinemia is associated with an increased risk for cardiovascular disease. The aim of this study was to investigate the association of MTHFR C677T and MTHFR A1298C gene polymorphisms with serum folate, cobalamin (Cbl) and homocysteine (Hcy) concentrations in healthy Greek adults. Design and method: The MTHFR C677T and A1298C gene polymorphisms were genotyped in 383 healthy Greek adults (199 men; mean age±SD: 37.3±8.2 years) using polymerase chain reaction and reverse hybridization. Serum folate, Cbl and total Hcy (tHcy) levels were determined using immunoassays methods. Results: Among the 383 individuals, 73 (19.1%) were normal (CC), 202 (52.7%) were heterozygous (CT) and 108 (28.2%) were homozygous (TT) regarding the MTHFR C677T gene polymorphism, while 263 (68.7%) were normal (AA), 105 (27.4%) were heterozygous (AC) and 15 (3.9%) were homozygous (CC) regarding the MTHFR A1298C gene polymorphism. The overall C and T allele frequency for the MTHFR C677T gene polymorphism was 45.4% and 54.6%, respectively, while the overall A and C allele frequency for the MTHFR A1298C gene polymorphism was 82.3% and 17.6%, respectively. The individuals with 677TT genotype had significantly lower serum folate and significantly higher serum tHcy levels than individuals with 677 CC or CT genotypes. On the contrary, the A1298C gene polymorphism had no significantly influence on serum folate and tHcy levels. Conclusions: Serum folate and tHcy levels are influenced by the existence of the MTHFR C677T gene polymorphism (mainly 677TT genotype). Individuals with low serum folate levels and/or high serum tHcy levels should be further investigated for a possible existence of MTHFR C677T and not A1298C gene polymorphisms, with aim to determine the suitable treatment.

MTHFR polymorphisms and neurotoxicity and overall survival after methotrexate-based therapy in primary CNS lymphoma.

2079 Background: The folate-antagonist methotrexate (HD-MTX) is an integral to induction chemotherapy for primary CNS lymphoma (PCNSL); however, it can be associated with toxicities, including injury to cerebral white matter known as leukoencephalopathy. Methylenetetrahydrofolate Reductase (MTHFR) is involved in intracellular folate metabolism, and MTHFR polymorphisms may affect CNS-specific side effects of HD-MTX. Here, we evaluated the possible association of MTHFR polymorphisms an HD-MTX related CNS toxicity. Methods: We retrospectively searched our institutional database at the Massachusetts General Hospital for newly diagnosed PCNSL patients treated with HD-MTX (without use of radiotherapy or intrathecal chemotherapy). MTHFR polymorphisms were correlated with evolution of leukoencephalopathy over a time period of five years and patient outcomes. ROC curves were generated to estimate the diagnostic ability of specific MTHFR genotypes. Survival was calculated using Kaplan-Meier survival analysis and log-rank test. The significance level was set at p ≤ 0.05. Results: Among 68 PCNSL patients, MTHFR polymorphisms were found in 60 individuals (88.2%; 677C&gt;T: 29 patients, 1298A&gt;C: 18 patients, combined 677C&gt;T &amp; 1298A&gt;C: 13 patients). Neither MTX clearance nor disease response to HD-MTX was affected by specific genotypes, and complete response was achieved in 72.1% of patients by induction with HD-MTX-based therapy. However, the 1298A&gt;C genotype was associated with increased frequency and severity of leukoencephalopathy over time (χ2 = 7.43). Such genotype predicted treatment-induced leukoencephalopathy with a sensitivity of 71.0%% and a specificity of 62.2% (ROC: p = 0.019). While progression-free survival did not differ in genotype-based subgroups, overall survival was significantly lower when the 1298A&gt;C genotype was present. Conclusions: The MTHFR 1298A&gt;C genotype may serve to identify PCNSL patients at elevated risk for HD-MTX-induced leukoencephalopathy. This was associated with reduced overall survival, potentially due to decreased functional status in patients less suitable for aggressive subsequent therapies.

Association of C677T and A1298C genetic polymorphisms in MTHFR gene with fetal growth restriction, small for gestational age and low birth weight: A meta-analysis

Impaired fetal growth has a wide range of short-term and long-term effects on physical and mental health. Fetal Growth Restriction (FGR), Small for Gestational Age (SGA) and Low Birth Weight (LBW) are three diagnoses of impaired fetal growth/size, but differences between them are not fully understood. This meta-analysis aimed to investigate the association of two genetic variants C677T and A1298C in methylenetetrahydrofolate reductase (MTHFR) gene with the risk of impaired fetal growth and then confirm this association with specific diagnosis. According to PRISMA protocols, 24 articles were included after searching the following databases: PubMed, Google Scholar, Science Direct, Web of Science, Cochrane Library and Cyber-Lenics. Meta-analysis was conducted in dominant, recessive, and allelic models of inheritance. According to our data, MTHFR C677T is associated with higher risk of impaired fetal growth and especially with FGR susceptibility (OR = 1.93, 95% CI 1.27–2.95, P = 0.002). On the other hand, MTHFR A1298C can be suggested as a risk factor of SGA (OR = 1.61, 95% CI 1.16–2.24, P = 0.005). However, it has no significant association with FGR or LBW. Our findings help to better understand MTHFR impact on fetal growth and distinguish FGR and SGA as separated cases of fetal growth abnormality.

ANALYSIS OF THE CONTRIBUTION OF GENES HP, ACE, HPSE1, MTHFR AND HFE TO THE DEVELOPMENT OF HEART FAILURE

Objective: Heart Failure (HF) is a clinical syndrome characterised by typical symptoms, associated with a cardiac incapacity of pumping blood. Although there have been improvements in treating HF, this disease still has a high mortality rate. Genes HP, ACE, HPSE1, MTHFR, and HFE are involved in various events and regulatory mechanisms associated with the disease such as the functionality of Haptoglobin, the activity of ACE and Heparanase enzymes and the metabolisms of Folic Acid and Iron. The purpose of this study is to investigate the contribution of the variants Hp1/2 (HP), I/D (ACE), rs4693608 (HPSE1), C677T (MTHFR), H63D and C282Y (HFE) to the development of HF individually or in epistasis. Design and method: Genotype data previously obtained in 143 HF patients and 246 healthy individuals was used to carry out analysis. The analysis of the data was performed with SPSS software. The association between genotypes and alleles was tested by Chi-Square or Fisher tests. Odds Ratios were calculated as well as the corresponding confidence intervals. Results: We have observed a higher risk for developing HF in the presence of: 1) the T allele [OR (IC, 95) = 2,932] and CT genotype [OR (IC, 95) = 3,618] of the C677T polymorphism; 2) epistasis between II and YY genotypes of the I/D and C282Y polymorphisms [OR (IC, 95) = 5,191]; 3) epistasis between II and DD genotypes of the I/D and H63D polymorphisms [OR (IC, 95) = 6,626]; 4) epistasis between the 2 and C alleles of HP gene and C677T polymorphism [OR (IC, 95) = 4,351]; 5) epistasis between the C and A alleles of the C677T and rs4693608 polymorphisms [OR (IC, 95) = 6,804]. A protective effect was observed for the CC genotype of the C677T polymorphism [OR (IC, 95) = 0,341]; between the D allele of the I/D variation and the Y [OR (IC, 95) = 0,233] and D [OR (IC, 95) = 0,279] alleles of the C282Y and H63D polymorphisms, respectively. Conclusions: We have concluded that HP, ACE, HPSE1, MTHFR, and HFE genes contribute to the susceptibility of developing HF individually or in epistasis.

Molecular Dynamics Study of Human MTHFR Wild-Type and A222V Mutant-Type: A Computational Approach

Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme for the homeostasis and metabolism of intracellular folate. However, it is known that one of the commonly found MTHFR gene SNPs (A222V) causes a decrease in activity which decreases folate levels and increases the accumulation of homocysteine in the blood. The purpose of this study was to investigate the molecular dynamics of MTHFR wild-type protein and MTHFR A222V mutant protein in silico. After some preparations, the crystal structure of MTHFR with code 6FCX obtained from the Protein Data Bank was used as the input file for molecular dynamics (MD) simulations. YASARA-Structure was employed for performing 50 ns production run of MD simulations. The deviation of the root-mean-squared deviation value of the backbone atoms (∆RMSDBb) of MTHFR wild-type is consistently less than 2 Å from the beginning of the MD simulations production runs. On the other hand, there is a sudden spike of ∆RMSDBb of MTHFR A222V from 15.01 to 20.00 ns of 2.221 Å. According to the analysis of ∆RMSDBb, MTHFR wild-type protein is considered stable and the MTHFR A222V mutant protein is considered unstable which may lead to various clinical problems for the person possessing this mutation.

0992 Reversible Pediatric Central Sleep Apnea in Hyperhomocysteinemia and Cerebral Sinus Venous Thrombosis

Abstract Introduction Pediatric central sleep apnea (CSA) rarely initially presents in adolescent age groups, being more commonly diagnosed in infants. CSA may result from a multitude of neurological insults, such as stroke and brain masses. It may also less often present in metabolic and non-ischemic thrombotic disorders. Report of case(s) A 12-year-old female with history of global developmental delay of unclear etiology, chronic headaches, insulin resistance, and early morning tremors was referred for initial evaluation of possible narcolepsy. Severe daytime sleepiness had acutely worsened over the previous month. She was unable to stay awake during school, despite sleeping 13 hours per 24 hours. Central hypersomnia was suspected and polysomnogram with MSLT was scheduled. The patient presented to the Emergency Department 10 days later for worsening headaches and new oral aversion with 12-pound weight loss. Examination showed ataxic gait and dysarthria. Brain MRI revealed non-occlusive cerebral sinus venous thrombosis (CSVT) involving the superior sagittal sinus, right transverse sinus, right sigmoid sinus, right jugular bulb/vein, and cortical veins overlying both cerebral hemispheres with no stroke. Anticoagulation with enoxaparin was initiated and thrombophilia work-up commenced. Polysomnogram demonstrated a central AHI of 49.9/hr with significant periodic breathing and no obstructive sleep apnea. Oxygen titration sleep study failed to significantly improve CSA and BPAP was initiated. Thrombophilia work-up revealed severe hyperhomocysteinemia. Genetic analysis was consistent with autosomal recessive severe methylenetetrahydrofolate reductase (MTHFR) deficiency. The patient was begun on metabolic treatment with betaine, pyridoxine, hydroxocobalamin, and vitamin C, and transitioned to oral rivaroxaban. At 4 months, blood levels had normalized, and MRI demonstrated resolution of CSVT. Family endorsed BPAP compliance and complete resolution of all sleep symptoms. In addition, there was significant improvement in cognition, interpersonal skills, and abstract thought. Follow up polysomnogram 10 months after presentation demonstrated no CSA nor periodic breathing. Conclusion To our knowledge, this is the first report of MTHFR deficiency and CSVT resulting in severe CSA. While it is difficult to ascertain which entity ultimately caused the CSA, MTHFR deficiency can produce significant neurologic impairment through white matter disease and defective myelination, while CSVT can provoke venous hypertension, venous stasis, or hypoxia. Support (if any)

Homocysteine levels, H-Hypertension, and the MTHFR C677T genotypes: A complex interaction

Background and objectivesHigh homocysteine levels are associated with increased risk of hypertension and stroke. Homocysteine is metabolized by the methylenetetrahydrofolate reductase (MTHFR). We aimed to investigate the levels of homocysteine and their association with hypertension, stroke, and antihypertensive medication usage in patients with different MTHFR C677T genotypes. Methods and resultsGenotype frequency of MTHFR polymorphism was performed, and plasma homocysteine levels were measured in 2,640 adult Lebanese patients. Hypertension, history of stroke, and list of medications were documented, among other clinical and demographic parameters. The TT mutant genotype and the T mutant allele of MTHFR were more prevalent in hyperhomocysteinemia (HHcy) and H-hypertensive (H-HTN, defined as hypertension with hyperhomocysteinemia) patients when compared to non-HHcy subjects and non H-HTN patients respectively. Homocysteine levels were significantly higher in hypertensive patients specifically among those on diuretics. A higher level of homocysteine was found in hypertensive patients with the MTHFR T allele compared to patients carrying the C allele. Among the T allele carriers, the average plasma homocysteine level was 13.3 ± 0.193 μmol/L for hypertensive subjects compared to 11.9 ± 0.173 μmol/L (non-hypertensives). Furthermore, homocysteine levels significantly correlated with stroke risk in patients with the T alleles. ConclusionsWe found an association of homocysteine with hypertension, hypertensive medication, and stroke risk among patients with the MTHFR T allele and the TT genotype. The association of diuretics therapy with higher homocysteine levels calls for routine measurements and therapeutic control of homocysteine in patients on diuretic, to improve health-related outcomes.

Gender-specific association of SLC19A1 and MTHFR genetic polymorphism with oxidative stress biomarkers and plasma folate levels in older adults

BackgroundPlasma folate levels are closely related to antioxidant capacity and are regulated by folate pathway gene polymorphism. However, few studies have explored the gender-specific association of folate pathway gene polymorphism with oxidative stress biomarkers. The present study was designed to explore the gender-specific independent and combined impacts of solute carrier family 19 member 1 (SLC19A1) and methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms on oxidative stress biomarkers in older adults. MethodsA total of 401 subjects were recruited, including 145 males and 256 females. Demographic characteristics of the participants were collected by using a self-administered questionnaire. Fasting venous blood samples were taken for folate pathway gene genotyping, circulating lipids parameters and erythrocyte oxidative stress biomarkers measurement. The difference of genotype distribution and the Hardy-Weinberg equilibrium was calculated by the Chi-square test. The general linear model was applied to compare the plasma folate levels and erythrocyte oxidative stress biomarkers. Multiple linear regression was used to explore the correlation between genetic risk scores and oxidative stress biomarkers. Logistic regression was used to explore the association of genetic risk scores of folate pathway gene with folate deficiency. ResultsThe male subjects have lower plasma folate and HDL-C levels than the female ones, and the male carrying MTHFR rs1801133 (CC) or MTHFR rs2274976 (GA) genotypes have higher erythrocyte SOD activity. The plasma folate levels, erythrocyte SOD and GSH-PX activities were negatively correlated with genetic risk scores in the male subjects. A positive correlation between the genetic risk scores and folate deficiency was observed in the male subjects. ConclusionsThere was association between folate pathway gene polymorphism of Solute Carrier Family 19 Member 1 (SLC19A1) and Methylenetetrahydrofolate Reductase (MTHFR) with erythrocyte SOD and GSH-PX activities, and folate levels in male but not in female aging subjects. Genetic variant of genes involved in folate metabolism has strong impact on plasma folate levels in the male aging subjects. Our data demonstrated that there was a potential interaction of gender and its genetic background in affecting the body's antioxidant capacity and the risk of folate deficiency in aging subjects.

Biochemical and structural characterization of meningococcal methylenetetrahydrofolate reductase.

Methylenetetrahydrofolate reductase (MTHFR) is a key metabolic enzyme in colonization and virulence of Neisseria meningitidis, a causative agent of meningococcal diseases. Here, the biochemical and structural properties of MTHFR from a virulent strain of N. meningitidis serogroup B (NmMTHFR) were characterized. Unlike other orthologs, NmMTHFR functions as a unique homohexamer, composed of three homo-dimerization partners, as shown in our 2.7 Å resolution crystal structure. Six active sites were formed solely within monomers and located away from the oligomerization interfaces. Flavin adenine dinucleotide cofactor formed hydrogen bonds with conserved sidechains, positioning its isoalloxazine ring adjacent to the overlapping binding sites of nicotinamide adenine dinucleotide (NADH) coenzyme and CH2 -H4 folate substrate. NmMTHFR utilized NADH (Km = 44 μM) as an electron donor in the NAD(P)H-CH2 -H4 folate oxidoreductase assay, but not nicotinamide adenine dinucleotide phosphate (NADPH) which is the donor required in human MTHFR. In silico analysis and mutagenesis studies highlighted the significant difference in orientation of helix α7A (Phe215-Thr225) with that in the human enzyme. The extended sidechain of Met221 on helix α7A plays a role in stabilizing the folded structure of NADH in the hydrophobic box. This supports the NADH specificity by restricting the phosphate group of NADPH that causes steric clashes with Glu26. The movement of Met221 sidechain allows the CH2 -H4 folate substrate to bind. The unique topology of its NADH and CH2 -H4 folate binding pockets makes NmMTHFR a promising drug target for the development of new antimicrobial agents that may possess reduced off-target side effects.

Nutritional deficiency and MTHFR gene polymorphism in obstetrics

: This study was carried out to determine the association of folic acid deficiency, vitamin B12 deficiency, hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) gene polymorphism with obstetrical events linked to folic acid deficiency like neural tube defects (NTD); unexplained abruption placentae (AP), recurrent pregnancy loss (RPL) and preterm labour(PTL).: In the present study 87 pregnant females with past or present history of either neural tube defect (NTD), abruptio placentae, recurrent pregnancy loss (RPL) or preterm labour and 100 pregnant females without any such history were enrolled. Serum levels of folic acid, vitamin B12 and homocysteine in these females were estimated using chemiluminescence and Polyacrylamide gel electrophoresis (PAGE) was used to detect MTHFR gene polymorphism.: No significant association was observed between serum folic acid levels and NTD (p = 0.495), RPL (p = 0.832) or preterm labour (p = 0.724). However, folic acid deficiency had significant association with the occurrence of abruptio placenta (p = 0.001). Serum vit B12 deficiency was found to be a significant risk factor only in patients with RPL. Increased homocysteine revealed significant association with RPL (p= 0.024), abruption placentae (p=0.002) and preterm labour (0.015). No polymorphism in MTHFR gene could be revealed in the above pregnancy complications.: In the present study, deficiency of folic acid was uncommon probably due to its routine supplementation throughout the first trimester. However, preconceptional folic acid supplementation still needs to be emphasized to build up adequate folic acid levels required during embryogenesis. The relationship between vit B12 and RPL needs studies on larger number to establish the association before supplementation is suggested. MTHFR677 gene polymorphism may have remained undetected due to small sample size.

A RARE TREATABLE CAUSE OF ADULT ONSET SPASTIC PARAPARESIS

pastic paraparesis refers to weakness and stiffness of both lower limbs caused by lesions affecting the Pyramidal tract. It could be due to genetic or acquired etiology. Genetic causes include leukodystophies, Heriditary Spastic Paraplegia (HSP), metabolic disorders etc,. Acquired causes include B12 and folate deficiency , infections like HTLV-1 virus, HIV, neurosyphilis , vascular malformations and so on. Here we encounter a rare treatable cause of spastic paraparesis. A 28 year old male born out of 3o Consanguinous parents with normal developmental history came with insidious onset slowly progressive spastic paraparesis for the past 4 years. Initially at onset he noticed difficulty in getting up from squatting position, which was associated with stiffness of lower limbs. Then he noticed there was slippage of slippers while walking and he was aware about it. Physical examination revealed marfanoid Habitus ,increased tone and exaggerated reflexes involving both lower limbs .Motor power was MRC Grade 4/5 in both lower limbs in both proximal and distal muscles. Ocular Examination revealed Ectopia Lentis. MRI Spine screening was normal. MRI Brain revealed symmetric T2/FLAIR hyperintensities involving periventricular and deep white matter of bilateral frontoparietal region. Possibilities of Primary demyelinating diseases and genetic/degenerative leukoencephalopathies were considered. CSF examination was normal and oligoclonal bands were absent. Clinical Exome sequence testing was done in suspicion of Adult onset leukodystrophy which showed Homozygous MTHFR gene mutation on exon4. Plasma Homocysteine levels were elevated ( 60 µmol/L).Patient was started on Oral Vitamin B12 1500mcg/day, Folic acid and pyridoxine supplementation. Patient showed symptomatic improvement and is under follow up. MTHFR deficiency in adults is a mimicker of leukodystrophies and other white matter disease. It is a potentially treatable disease. Before considering degenerative diseases like HSP, treatable diseases should be considered.

No association between MTHFR gene C677T/A1298C polymorphisms, serum folate, vitamin B12, homocysteine levels, and prostate cancer in an Algerian population.

Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate and homocysteine metabolism, which are necessary for DNA methylation and nucleotide synthesis. Genetic polymorphisms that reduce MTHFR activity have been linked to several diseases, including prostate cancer. In this study, we aimed to investigate whether MTHFR polymorphisms, along with serum levels of folate, vitamin B12, and homocysteine, are associated with prostate cancer risk in the Algerian population. A total of 106 Algerian men with newly diagnosed prostate cancer and 125 healthy controls were included in this case-control study. The MTHFR C677T and A1298C polymorphisms were analyzed using PCR/RFLP and Real-Time PCR TaqMan® assays, respectively. Serum levels of folate, total homocysteine, and vitamin B12 were measured using an automatic biochemistry analyzer. We found no significant differences in the genotype frequency of A1298C and C677T between prostate cancer patients and controls. Moreover, serum levels of folate, total homocysteine, and vitamin B12 were not significantly associated with prostate cancer risk (p > 0.05). However, age and family history were identified as significant risk factors (OR = 1.178, p = 0.00 and OR = 10.03, p = 0.007, respectively). Our study suggests that MTHFR C677T and A1298C, as well as serum levels of folate, total homocysteine, and vitamin B12, are not associated with prostate cancer risk in the Algerian population. However, age and family history are significant risk factors. Further studies with a larger sample size are required to confirm these findings.