Pilot Study on Neonatal Screening for Methylmalonic Acidemia Caused by Defects in the Adenosylcobalamin Synthesis Pathway and Homocystinuria Caused by Defects in Homocysteine Remethylation

Neonatal screening (NS) for methylmalonic acidemia uses propionylcarnitine (C3) as a primary index, which is insufficiently sensitive at detecting methylmalonic acidemia caused by defects in the adenosylcobalamin synthesis pathway. Moreover, homocystinuria from cystathionine β-synthase deficiency is screened by detecting hypermethioninemia, but methionine levels decrease in homocystinuria caused by defects in homocysteine remethylation. To establish NS detection of methylmalonic acidemia and homocystinuria of these subtypes, we evaluated the utility of indices (1) C3 ≥ 3.6 μmol/L and C3/acetylcarnitine (C2) ≥ 0.23, (2) C3/methionine ≥ 0.25, and (3) methionine < 10 μmol/L, by retrospectively applying them to NS data of 59,207 newborns. We found positive results in 116 subjects for index (1), 37 for (2), and 15 for (3). Second-tier tests revealed that for index 1, methylmalonate (MMA) was elevated in two cases, and MMA and total homocysteine (tHcy) were elevated in two cases; for index 2 that MMA was elevated in one case; and for index 3 that tHcy was elevated in one case. Though data were anonymized, two cases identified by index 1 had been diagnosed with maternal vitamin B12 deficiency during NS. Methylene tetrahydrofolate reductase deficiency was confirmed for the case identified by index 3, which was examined because an elder sibling was affected by the same disease. Based on these data, a prospective NS study is underway.

Methylene tetrahydrofolate reductase A1298C polymorphisms influence the adult sequelae of chemotherapy in childhood-leukemia survivors

This retrospective correlation study investigated the putative link between methylene tetrahydrofolate reductase (MTHFR) A1298C mutations and chemotherapy-related brain function changes in adult childhood-leukemia survivors. To this end, we determined the relationship between the particular MTHFR1298 genotype (AA, AC or CC) of 31 adult childhood-leukemia survivors, and (1) their CSF Tau and phosphorylated Tau (pTau) levels at the time of treatment, (2) their adult performance intelligence quotient (PIQ), and (3) their regional brain connectivity using diffusion magnetic resonance imaging (dMRI) and resting-state functional MRI (rsfMRI). We confirmed that neuropathology markers Tau and pTau significantly increased in CSF of children after intrathecal methotrexate administration. Highest concentrations of these toxicity markers were found during the induction phase of the therapy. Moreover, CSF concentrations of Tau and pTau during treatment were influenced by the children’s particular MTHFR1298 genotype. CSF Tau (but not pTau) levels significantly dropped after folinic acid supplementation. At adult age (on average 13.1 years since the end of their treatment), their particular MTHFR1298 genotype (AA, AC or CC) influenced the changes in PIQ and cortical connectivity that we found to be related to their childhood exposure to chemotherapeutics. In summary, we suggest that homozygous MTHFR1298CC individuals are more vulnerable to the adult sequelae of antifolate chemotherapy.

Polymorphisms of Methylene Tetrahydrofolate Reductase (MTHFRC677T and A1298C) and Probable Depression in Postpartum Period in South Indian Women

Background: Two common variants of Methylene tetrahydrofolate reductase (MTHFR) are C677T and A1298C, which have been associated with general depression. Main objective of the study was to explore how these functional polymorphisms of MTHFR gene associate with the risk to develop postpartum depression. Method: 434 women were recruited in a study period of 3 years (January 2014 to December 2017) in a tertiary care centre. EPDS was administered at 6 weeks postpartum, with a cut-off score of ≥10 to define probable postpartum depression. Plasma was used for the estimation of circulating vitamin B12 metabolites and whole blood for extraction of DNA. Real time PCR using Taqman probes was used for genotyping the proposed SNP’s. Results: T allele of MTHFR C677T was associated with the risk of probable PPD (p = 0.024, OR = 1.67; 95% CI: 1.06-2.62) and presence of suicidal ideations in these women (p<0.001, OR = 2.90; 95% CI: 1.61-5.24). Haplotype 677T-1298A was associated with both the risk of probable PPD (p = 0.029, OR = 1.66; 95% CI: 1.05-2.64) and suicidal ideations (p <0.001, OR = 2.933; 95% CI: 1.60-5.35), whereas 677C-1298A was protective against suicidal ideations (p = 0.011; OR = 0.558; 95% CI: 0.35-0.88). Women with risk allele T were also associated with higher levels of circulating holotranscobalamin levels, and lower levels of vitamin B12, whereas risk allele C of A1298C had lower levels of holotranscobalamin. Limitations: Cross-sectional studyConclusion: Polymorphic variants of MTHFR gene might indicate susceptibility to develop probable depression in postpartum period. SignificanceMTHFR C677T has been widely reported in the literature to be associated with general depression. The association of this variant in susceptibility to develop postpartum depression is not widely studied. We observed T allele of MTHFR C677T to be associated with the risk of to develop depression and suicidal ideation in postpartum period. Higher levels of MMA and holotranscobalamin, and lower levels of vitamin B12 were associated with T allele of MTHFR C677T. Polymorphic variants of MTHFR gene might indicate susceptibility to develop depression in postpartum period.

Associations Among Methylene Tetrahydrofolate Reductase rs1801133 C677T Gene Variant, Food Groups, and Non-alcoholic Fatty Liver Disease Risk in the Chinese Population

ObjectivesTo investigate the associations among the methylene tetrahydrofolate reductase rs1801133 C677T gene variant, food groups, and the risk of non-alcoholic fatty liver disease in the Chinese population.MethodsA study of gene polymorphism was conducted using the polymerase chain reaction method. A total of 4,049 adults participated in the study, and all underwent physical examination and genotyping. Participants filled out a dietary questionnaire to enable us to assess the frequency and quantity of food consumption.ResultsThe important variables identified as risk factors of non-alcoholic fatty liver disease were age, smoking, sex, body mass index, hyperlipidemia, diabetes, and methylene tetrahydrofolate reductase genotype (T – allele carriers). The homocysteine content was higher in the non-alcoholic fatty liver disease group than in the control group, and was higher in the T- allele than C- allele carriers. The homocysteine content was the highest in the T- allele carriers. Additionally, certain food groups such as milk and beans were associated with a lower risk of non-alcoholic fatty liver disease. Food groups such as meat, were associated with a higher risk of non-alcoholic fatty liver disease. Fresh fruit and vegetables, salted and smoked foods, desserts, cereals, fish, and eggs were not associated with the risk of non-alcoholic fatty liver disease. However, the influence of salted and smoked foods on non-alcoholic fatty liver disease was different in the C-allele and T-allele carriers of methylene tetrahydrofolate reductase (CT + TT vs. CC, OR = 1.196, P = 0.041 for 1–4 times food per week, OR = 1.580, P = 0.004 for 5–7 times per week). Similarly, salted and smoked foods were also a risk factor for the development of non-alcoholic steatohepatitis in patients with non-alcoholic fatty liver disease.ConclusionThis study found that the T-allele of the C677T variant of methylene tetrahydrofolate reductase was a risk factor for non-alcoholic fatty liver disease among Chinese people. These results can likely aid the development of novel approaches for managing non-alcoholic fatty liver disease risk.

Methylene Tetrahydrofolate Reductase (MTHFR) Mutation in a Young Patient with Stroke: A Case Report

The etiology of young stroke is mainly contributed by genetic mutations in coagulation and metabolic pathways. We present a 29-year-old male, who presented with headache and weakness and later diagnosed to have posterior cerebral artery territory infarct. We highlight MTHFR mutation as an etiology of young stroke and the importance of family screening in such patients.

Correlation between methylene tetrahydrofolate reductase (MTHFR) gene rs1801133 C>T polymorphisms and risk of osteoporosis

Objective To evaluate the correlation between methylene tetrahydrofolate reductase (MTHFR) gene rs1801133 C>T polymorphisms and risk of osteoporosis. Methods We searched the clinical studies related to MTHFR gene rs1801133 C>T polymorphisms and risk of osteoporosis in the electronic databases of PubMed, Web of Science, EMBASE, China National Knowledge Infrastructure (CNKI), Chinese BioMedical Literature Database (CBM) and included the suitable publications in the present meta-analysis according to the inclusion and exclusion criteria. The data of included studies were extracted and pooled by a random or fixed-effect model. The odds ratio (OR) and 95% confidence interval (95% CI) were applied to demonstrate the correlation between MTHFR gene rs1801133 C>T polymorphisms and the risk of osteoporosis. Publication bias was assessed by Begg’s funnel plot and Egger’s line regression test. Results Seven case–control clinical studies were included and a data combination was made. The data was pooled by the fixed effect model because of no obvious statistical heterogeneity. The pooled results indicated that people with the T allele had increased risk of developing osteoporosis under the homologous gene model (TT vs CC) (OR = 2.36, 95% CI: 1.81–3.08, p < 0.05), dominant gene model (TT + CT) vs CC (OR = 1.47, 95% CI: 1.21–1.77, p < 0.05) and recessive gene model TT vs (CC + CT) (OR = 2.16, 95% CI: 1.71–2.74, p < 0.05). Egger’s line regression test indicated no significant publication bias for the present meta-analysis in the above homologous, dominant, and recessive gene models. Conclusion The MTHFR gene rs1801133 C>T polymorphisms are associated with osteoporosis and subjects with the T allele have an increased risk of developing osteoporosis.