Folic acid inhibits 5‐methyltetrahydrofolate transport across the blood–cerebrospinal fluid barrier: Clinical biochemical data from two cases

Abstract

Objective The use of folic acid (FA) has been discouraged in cerebral folate deficiency (CFD) because, theoretically, it could inhibit the transport of 5‐methyltetrahydrofolic acid (5MTHF) across the blood–cerebrospinal fluid (CSF) barrier. We present the clinical biochemical data of two cases with CFD to support this hypothesis. Methods We measured CSF and serum 5MTHF concentrations in a patient with Kearns‐Sayre syndrome (KSS) and a patient homozygous for MTHFR C677T polymorphism before and during folate supplementation therapy. To evaluate these 5MTHF concentrations, we also analyzed CSF and serum samples in pediatric patients without folate supplementation. Results Both patients had low CSF 5MTHF before treatment and high‐dose FA therapy did not normalize CSF 5MTHF. There was a dissociation between serum total folate and 5MTHF concentrations during FA therapy, which was considered to be due to the appearance of unmetabolized FA. The addition of folinic acid did not improve low CSF 5MTHF in the KSS patient and the cessation of FA resulted in the normalization of CSF 5MTHF. In the patient homozygous for MTHFR C677T, minimization of the FA dosage resulted in the normalization of CSF 5MTHF and an increased CSF‐to‐serum 5MTHF ratio. Conclusions Our data suggest that excess supplementation of FA impaired 5MTHF transport across the blood–CSF barrier. In the treatment of CFD, supplementation of folinic acid or 5MTHF (in cases of impaired 5MTHF synthesis) is preferred over the use of FA. The reference values of CSF 5MTHF concentration based on 600 pediatric cases were also provided.

Diverse avenues of research support the transmethylation theory of psychosis: implications for neuroprotection

“…Even in cases of low folate and high homocysteine, supplementation with folic acid, folinic acid, or 5-methyl-THF (a tertiary amine with a low Estate value for its N) should be done with care in an individual with psychosis or at ultra-high risk of psychosis when trying to mitigate positive symptoms. High doses of folic acid supplementation come with the mental health risks covered in previous sections, and as reviewed decades ago by Young and Ghadirian [288]. In a small clinical study, there is also new evidence to suggest that folic acid and folinic acid can either inhibit transport of 5-methyl-THF across the BBB [289], or diminish its synthesis.…”

Excess folic acid exposure increases uracil misincorporation into DNA in a tissue-specific manner in a mouse model of reduced methionine synthase expression

“…Interestingly, brain total folate concentrations decreased by 10% with exposure to the HFA diet (Fig 3E). The modest reduction in brain folate may not be surprising since both experimental and case studies suggest UMFA in plasma impairs transport of 5-methyl-THF across the blood brain barrier (BBB) (25,26). DHFR is the enzyme responsible for converting DHF to THF, though it also converts folic acid to DHF, necessary for it to enter the folate cofactor pool.…”

“…Interestingly, brain total folate concentrations decreased by 10% with exposure to the HFA diet (Fig 3E). The modest reduction in brain folate may not be surprising since both experimental and case studies suggest UMFA in plasma impairs transport of 5-methyl-THF across the blood brain barrier (BBB) (25,26).…”