What is MTHFR?
The methylenetetrahydrofolate reductase (MTHFR) enzyme converts synthetic folic acid and dietary folate into its active form, L-methylfolate, which plays a critical role in neurotransmitter synthesis.1 Some individuals carry a mutation at the C677T SNP of the MTHFR gene, which results in 45% reduction in activity for heterozygotes (C/T) and a 70% reduction in activity for homozygotes (T/T).2 Individuals who carry this mutation will have a reduced capacity to create L-methylfolate.
How can clinicians treat individuals with reduced MTHFR activity?
There are a variety of ways that clinicians use this information. One option for patients with reduced MTHFR activity is to directly supplement with oral L-methylfolate. By bypassing the conversion step mediated by MTHFR, supplementation with L-methylfolate should improve serum and CNS folate levels in individuals with reduced MTHFR activity. Another option is to increase folic acid supplementation, which compensates for the reduced MTHFR enzyme activity leading to normal levels of the active L-methylfolate. Multiple studies have demonstrated that, in patients with reduced MTHFR activity (particularly in C/T individuals), increasing the daily dose of folic acid from no supplementation to 0.4 mg (the standard dose in a multivitamin), or from 0.4 mg to 0.8 mg (the standard dose in a prenatal multivitamin) can increase serum folate levels.3-5
Does folic acid compete with L-methylfolate for entry into the CNS?
Concern has been raised about the correlation between serum and CNS folate levels for patients who are supplemented with additional folic acid.6 Some have theorized that folic acid may compete with L-methylfolate for entry through the blood brain barrier and, therefore, CNS folate levels may not correlate with the improved serum folate levels observed with increased dosing of folic acid.6-9 However, in vivo studies have demonstrated that CNS folate levels are correlated with serum levels, and that CNS folate levels improve when low folate patients are supplemented with folic acid.10,11
What are the risks of folic acid supplementation?
Some caution is warranted in the administration of high doses of folic acid and L-methylfolate. High dose (i.e., > 0.8 mg) folic acid administration can mask vitamin B12 deficiency, and some data indicates that chronic exposure may exacerbate neurologic and neuropsychiatric effects of vitamin B12 deficiency, although this remains controversial.6,12,13 Clinicians should weigh the benefits of folic acid or L-methylfolate supplementation with possible risks associated with these treatment strategies.
Both l-methylfolate and folic acid are plausible treatment options for patients with the MTHFR C677T mutation.
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