Treatment with Mefolinate (5-Methyltetrahydrofolate), but Not Folic Acid or Folinic Acid, Leads to Measurable 5-Methyltetrahydrofolate in Cerebrospinal Fluid in Methylenetetrahydrofolate Reductase Deficiency

Abstract

S-adenosyl methionine, which is formed from methionine, is an essential methyl donor within the central nervous system. Methionine is formed by the enzyme methionine synthase for which 5-methyltetrahydrofolate (5-MTHF) and homocysteine are substrates. Patients with severe methylenetetrahydrofolate reductase (MTHFR) deficiency cannot make 5-MTHF and have extremely low levels in the CSF. As a consequence, methylation reactions in the CNS are compromised, and this is likely to play an important role in the neurological abnormalities that occur in MTHFR deficiency. Although treatment with oral betaine can remethylate homocysteine to methionine in the liver, betaine crosses the blood-brain barrier poorly, and CSF levels of methionine remain low. We report three patients with severe MTHFR deficiency (enzyme activity 1% of controls) who had undetectable levels of CSF 5-MTHF at diagnosis and while on treatment with either folic acid or calcium folinate. Only treatment with oral 5-MTHF given as calcium mefolinate at doses of 15-60 mg/kg/day resulted in an increase in CSF 5-MTHF.

Methionine increases yolk production to offset the negative effect of caloric restriction on reproduction without affecting longevity in C. elegans

“…through DNA methylation, resulting in permanent structural and physiological alternations in the offspring [1,2,53]. DNA methylation requires S-adenosylmethionine (SAM) as the major methyl group donor in the cell, which is derived largely from Met, in addition to betaine, choline, and 5-methyltetrahydrofolate (5-MTHF) [54,55]. Since methionine is an essential methyl group donor for DNA methylation, the rescuing effect of methionine could be due to epigenetic changes favoring gene expression for embryonic maintenance.…”

Astronaut ophthalmic syndrome

“…Riboflavin supplementation has been shown to reduce blood pressure in hypertensive patients with the minor form of the MTHFR 677 polymorphism (TT), and may play a role in preventing endothelial dysfunction (97, 98). Attention to details, including the dose and form of vitamins, would need to be considered because folic acid can inhibit 5‐MTHF transport across the BBB and potentially exacerbate a cerebral folate deficiency (22, 99, 100); therefore, use of reduced folate (5‐MTHF or THF) should be considered. Although the temptation to provide antioxidants is often an immediate reaction, providing the precursors to mitigate these effects in the first place seems a more likely solution than trying to provide the downstream intermediates.…”

Cerebral folate deficiency: Analytical tests and differential diagnosis

“…5‐MTHF, which represents >90% of total plasma folate has important advantages over other folate forms, since it is well absorbed in the intestine and its bioavailability is not affected by DHFR and MTFHR deficiencies. The use of 5‐MTHF could also prevent the potential negative effects of unconverted folic acid in the brain, and it is thought to be the most efficient way to restore CSF 5‐MTHF concentrations …”

“…The use of 5-MTHF could also prevent the potential negative effects of unconverted folic acid in the brain, and it is thought to be the most efficient way to restore CSF 5-MTHF concentrations. 111…”