High doses of folic acid induce a pseudo-methylenetetrahydrofolate syndrome

Abstract

A 41-year-old Caucasian woman with a history of infertility dating from 2011 was identified as wild-type (no mutations) for methylenetetrahydrofolate reductase single nucleotide polymorphisms (MTHFR-SNPs). Previous treatment included three failed in vitro fertilization/intracytoplasmic sperm injection cycles as well as one failed cycle of in vitro fertilization/ intracytoplasmic sperm injection with donated oocytes. Counseling for a further oocyte donation cycle included advice to take high doses of folic acid (5 mG per day). Prior to initiation of this cycle, in October 2017 she attended our unit for general gynecological assessment and was found to have a slightly increased level of homocysteine, 12.2 µmol/L. A further test in February 2018 showed an increase to 17.2 µmol/L. Folic acid was stopped, and she was treated with 5-MTHF (500 µG daily), which supports the one-carbon cycle. After 5 days of treatment, her homocysteine level dropped to a baseline level of 8.2 µmol/L. As previously described in mice, high doses of folic acid can induce a "pseudo MTHFR" syndrome in wild-type patients, leading to an elevated unmetabolized folic acid syndrome which results in increased serum levels of homocysteine.

Micronutrients in support to the one carbon cycle for the modulation of blood fasting homocysteine in PCOS women

“…A total of 33 PCOS ladies (mean age 26.8, range [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] were enrolled between June 2017 and October 2018, and one patient withdrew her participation for personal reasons after the basal visit. Out of 32 patients randomized, 22 entered the active treatment group, and 10 the no treatment group.…”

“…It must be activated with a double reductive passage by the enzyme DiHydroFolate Reductase (DHFR) to which it has a very low affinity, so that at concentrations above 2 μMol, it behaves as a competitive inhibitor [20]. This may lead to the "pseudo MTHFR syndrome", where patients treated with high doses of folic acid experience a paradox blockade of the pathway [21]. Any folic acid not activated by DHFR may enter circulation as UnModified Folic Acid (UMFA), which has been linked to a variety of possible negative outcomes including derangement of immunity, neurodegeneration, and cancer, although a direct causal link cannot be stated [22].…”

MTHFR (methylenetetrahydrofolate reductase: EC 1.5.1.20) SNPs (single-nucleotide polymorphisms) and homocysteine in patients referred for investigation of fertility

“…This strategy has yielded good results in patients with a lengthy duration of infertility [17]: it decreases serum homocysteine [24,37], and its safety and efficacy are proven [37][38][39]. Synthetic folic acid has a low capacity for entering the folate cycle [40,41] and is very poorly effective and transformed into 5-MTHF in carriers of MTHFR SNPs [28,29]; Moreover, treatment with folic acid at high doses (5 to 15 mG/day) is known to cause an unmetabolized folic acid (UMFA) accumulation, a source of health questioning [42][43][44][45][46][47].…”

5-methyltetrahydrofolate: A mandatory support for T677T MTHFR SNP women suffering from premature ovarian insufficiency, endometriosis and/or multiple ART failures

“…It avoids uncertainties due to treatments with high doses of synthetic folic acid, such as Unmetabolized Folic Acid (UMFA) and pseudo-MTHFR syndrome, while possibly improving ovarian quality, and pregnancy outcome [3]. High doses of folic acid can also increase homocysteine via a pseudo MTHFR effect [13] and lead to an adverse competition between natural folate (5-MTHF) and unmetabolized folic acid, for cellular transport and metabolism. Testing patients for an MTHFR mutation prior to IUIs, expensive ART procedure, or pre-implantation genetic screening could possibly help avoid unexplained lack of implantation or recurrent pregnancy losses.…”