In order to enter the folate cycle, FA must first be converted to tetrahydrofolate (THF) via two reducing biochemical steps catalyzed by DHFR—dihydrofolate reductase, (co-factor NADP(H)). This is a rate-limiting step, and DHFR has very weak activity in humans even in the absence of SNP mutations, with considerable inter-individual variation. Therefore, experiments carried out in animal systems (especially rats, where activity can be estimated as 25× higher than in humans), should take this specificity into account. High doses of FA leads to a rapid saturation/inhibition of the DHFR enzyme, leading to an accumulation of un-metabolized folic acid (UMFA) and the UMFA syndrome ^[1]. These authors confirm that the capacity to metabolize folic acid in humans is low, especially at high FA doses (5 mG or more); the efficacy of prescribing such high doses is questionable, as this may be associated with several pathological issues. Levels of circulating UMFA (unmetabolized folic acid) in the population is persistent in countries where the FA fortification of grains and cereals is implemented ^[3]. In the BBC (Boston Birth Control) cohort, UMFA was always detected at birth ^[4]. UMFA may compete with natural folate (5-MTHF) for the folate transporter (SLC19A1) and the folate receptor (FolR1), thus depleting active folate for participation in the two metabolic cycles. The PCFT-SLC46A1, proton-coupled folate transporter, responsible for transport of folates in the intestine, at low pH; is not detected/active in the early embryos, where all the fluids are at an alkaline bicarbonate-mediated pH. However, this transporter is expressed in fetal tissues as early as ten weeks gestation, at high levels in the intestine of a 20-week old fetus, and in the placenta, and this could be a factor in the appearance of UMFA in cord blood at birth. Tetrahydrofolate (THF) produced by DHFR is converted to 5–10 methylene THF by methylene tetrahydrofolate dehydrogenase (MTHFD1), without specific problems. However, five rare but significant SNPs that affect this step have been described in association with cancers, migraines, congenital anomalies such as neural tube defects, and congenital heart disease ^[5]. The most hazardous mutation appears to be G1958A. THF/5–10 methylene THF accumulates at the level of MTHFR, and the accumulation of unmetabolized folates upstream from the enzyme may lead to competitive inhibition, leading to Hcy accumulation ^[6][7]. MTHFR is allosterically inhibited by SAM, and this also means that an excess of 5-MTHF may be deleterious and that circulating Met level is controlled. This level of fine-tuned regulation must be respected: a high consumption of FA may lead to a pseudo- MTHFR deficiency in healthy patients.

4. Folinic Acid (5 Formyl THF, FLA)

Folinic acid binds the classical receptor FolR1 and is transported into cells by the solute carrier SLC19A1. Its metabolism leads to the formation of THF and 5, 10 Methylene THF; an important part of these metabolic steps allows the formation of thymidylate, and the failure of this pathway in folate deficiency leads to DNA damage that has been associated with carcinogenesis ^[8]. Purine nucleotide biosynthesis de novo (PNB) requires two folate-dependent transformylases utilizing formylTHF. FLA is sometimes prescribed as a treatment for problems associated with MTHFR SNPs, but its metabolites do not succeed in compensating for low MTHFR activity. FLA prevents UMFA accumulation by bypassing weak DHFR activity.

5. Methyl THF

5 methyl THF is the natural folate which does not induce UMFA; It is present in "green" vegetable. It The efficiency and safety of 5-MTHF has been established, including in children , and has been demonstrated to be at least as efficient as FA in reducing homocysteine levels in healthy women . It is effective in reducing Hcy in men and women of reproductive age who are of carriers of the MTHFR T677T variant (31-38). 5-methylTHF can/could effectively prevent NTDs by improving folate biomarkers in young women during early pregnancy . No large-scale clinical studies have been performed yet.  250+ pregnancies have started, followed by deliveries, with MTHF treatment at a daily dose of 600-800 µG per day . This includes women having previously suffered NTDs or miscarriages with FA at 5 mG/Day.  5MTHF supply could be a better alternative to FA in reducing the incidence of NTD, especially in countries that do not implement a program of FA fortification. It is at least as effective before and during pregnancy. Sperm of men carrying MTHFR SNPs have a significant impact on the cytogenetic quality of early embryos, (with a subsequent increased risk of miscarriage (48,49). A similar feature can be seen for women. 5-MTHF can provide a solution for problems related to folate cycle metabolism : 5-MTHF supplementation can overcome MTHFR SNPs in patients who have failed to conceive even after treatment with high doses of FA, 5 to 15 mg per day.

In conlusion 5 MTHF seems to be a better option for the support of "folate. " in population needing it.  This is especially true in MTHFR SNP carrriers aither men and women. UMFA is a source of concern