Folate & MTHFR

Folate is an essential micronutrient and a critical cofactor in one-carbon metabolism, which mammals cannot synthesize and must obtain from diet or supplementation. ^[1] Folic acid is a synthetic form of the vitamin found only in fortified foods, supplements and pharmaceuticals, whereas L-5-methyltetrahydrofolate is the predominant form of dietary folate and the only species normally found in the circulation. ^[2] The MTHFR (5,10-methylenetetrahydrofolate reductase) gene is mapped on chromosome 1 at the end of the short arm (1p36.6), and the enzyme is important for folate metabolism and thus for DNA, RNA and protein methylation. ^[3] The C677T polymorphism (rs1801133) is the most established genetic factor that increases plasma total Homocysteine, and it is a common variant whose frequency varies with geography and ethnicity. ^{[4] [3]} Common MTHFR polymorphisms are distinct from severe MTHFR deficiency, a rare inherited remethylation disorder in which impaired remethylation of homocysteine to methionine leads to homocysteine accumulation and perturbation of numerous methylation reactions. ^[5]

Folic acid is inactive in the body and must be converted by the liver into 5-methyltetrahydrofolate (5-MTHF), which acts as a methyl donor for the conversion of homocysteine into methionine, the synthesis of glycine from serine and the synthesis of DNA precursors. ^[6] Through the one-carbon cycle, the MTHFR enzyme maintains the balance between methionine and Homocysteine and supports protein, DNA and RNA synthesis. ^[7] The C677T variant, located in exon 4 and altering codon 222, is a common polymorphism that reduces the activity of the enzyme. ^[3] The amino acid change produced by C677T prevents optimal functioning of the enzyme at temperatures above 37 °C, which is why the TT genotype is described as thermolabile. ^{[7] [8]} Homozygous carriers of the variant have higher homocysteine levels, while heterozygous carriers have mildly raised levels compared with non-carriers. ^[3]

Folate status is assessed by blood folate concentrations and by functional indicators such as plasma Homocysteine. ^[2] A 2017 GRADE-based guideline strongly recommends measuring plasma total homocysteine in any patient presenting with neurological, visual or haematological symptoms, subacute spinal cord degeneration, atypical haemolytic uraemic syndrome or unexplained vascular thrombosis, to detect remethylation disorders including MTHFR deficiency. ^[5] A meta-analysis of 256 studies and 114,799 participants found that the effect of rs1801133 on homocysteine varies significantly with sex, age, race, folic acid intake, smoking and alcohol consumption, reflecting the limited penetrance of the variant. ^[4] Because of this covariate dependence, a carrier's risk of hyperhomocysteinemia has to be predicted individually, and the authors note that the public increasingly receives MTHFR results from commercial genetic services without interpretation of their clinical relevance. ^[4] In a meta-analysis of retinal vascular occlusion, elevated plasma homocysteine and low serum folate were associated with the disease while the TT genotype was not, and the authors advised determining plasma homocysteine and serum folate levels in affected patients.