What happens if someone with an MTHFR (methylenetetrahydrofolate reductase) gene mutation takes folic acid?

MTHFR Gene Mutation Prevalence and Folic Acid Supplementation

Prevalence of MTHFR Mutations

The MTHFR C677T mutation is extremely common, affecting 30-40% of the general population as heterozygotes (CT) and 10-15% as homozygotes (TT), with significant ethnic variation—Chinese populations show 23.6% TT homozygosity. 1, 2

• The A1298C variant shows different distribution patterns: 69.7% CC (wild-type), 26.9% CT, and 3.4% TT in Canadian populations 1
• Compound heterozygosity (C677T/A1298C) occurs in approximately 5% of individuals and increases homocysteine levels 1

What Happens When Someone with MTHFR Mutation Takes Folic Acid

The critical issue is that individuals with MTHFR mutations, particularly TT homozygotes, cannot efficiently convert folic acid to its active form (5-methyltetrahydrofolate), making standard folic acid supplementation significantly less effective than 5-MTHF supplementation. 1, 2

The Biochemical Problem

• MTHFR enzyme converts folic acid through multiple steps to reach the active 5-methyltetrahydrofolate (5-MTHF) form 1
• The C677T mutation reduces MTHFR enzyme activity by approximately 50-70%, creating a metabolic bottleneck 2
• An additional 19-base pair deletion in dihydrofolate reductase (DHFR) occurs in 29.5% of people (del/del genotype), further impairing folic acid conversion—only 26.1% with the ins/ins genotype can efficiently process folic acid 1
• Folic acid supplementation increases plasma folate levels but has only modest effects on intracellular 5-MTHF concentrations in those with MTHFR mutations 3

Genotype-Specific Responses to Folic Acid

For TT homozygotes, folic acid supplementation (5 mg/day) reduces homocysteine by 40%, compared to only 10% reduction in CC wild-type individuals, but this response is still suboptimal compared to 5-MTHF. 4

• CT heterozygotes show intermediate response with 23% homocysteine reduction on folic acid 4
• Laboratory studies demonstrate that cells with low MTHFR activity show NO increase in intracellular 5-MTHF after folic acid supplementation, while normal MTHFR activity cells show a 2.5-fold increase 3
• When given 5-MTHF directly, even low MTHFR activity cells achieve a 10-fold increase in intracellular levels, bypassing the enzymatic defect entirely 3

Clinical Implications for Cardiovascular Risk

Despite the reduced efficiency, folic acid still provides cardiovascular benefit in MTHFR mutation carriers, but the American Heart Association now recommends using 5-MTHF with methylcobalamin instead of folic acid with cyanocobalamin for stroke prevention. 1

• In stroke prevention trials, individuals with MTHFR 677CC genotype (normal) showed greater benefit from folic acid supplementation (HR 0.49,95% CI 0.31-0.78) 1
• Paradoxically, TT homozygotes responded better when both folate AND B12 levels were above median (HR 0.28,95% CI 0.10-0.75), suggesting they need higher doses or active forms 1
• The DHFR deletion polymorphism showed cognitive benefits from folic acid in only 26% of participants (those with ins/ins genotype), while the remaining 74% showed no benefit 1

Recommended Supplementation Strategy

For individuals with confirmed MTHFR mutations, particularly TT homozygotes, use 5-methyltetrahydrofolate (5-MTHF) instead of folic acid, combined with methylcobalamin or hydroxycobalamin (NOT cyanocobalamin), vitamin B6, and riboflavin. 1, 2

Specific Dosing Recommendations

• 5-MTHF: 0.4-5 mg daily (reduces homocysteine by 25-30%) 1, 2
• Vitamin B12 (as methylcobalamin or hydroxycobalamin): 1 mg weekly provides an additional 7% homocysteine reduction 2, 5
• Vitamin B6 (pyridoxal phosphate): 50 mg daily to support the transsulfuration pathway 2, 5
• Riboflavin: Particularly important for TT homozygotes as a cofactor 1, 2

Evidence Supporting 5-MTHF Over Folic Acid

• A study of women with MTHFR mutations and recurrent pregnancy loss showed methylfolate (5 mg/day) plus B6 and B12 reduced homocysteine from 19.4 to 6.9 μmol/L, with 7 of 16 women achieving successful pregnancies 5
• Folinic acid and 5-MTHF both effectively reduce homocysteine, but CT heterozygotes showed statistically greater reduction with folinic acid 6
• The 677TT genotype showed significantly higher homocysteine reduction regardless of which active folate form was used 6

Critical Pitfalls to Avoid

Never start folate supplementation without first checking vitamin B12 status—folate alone can mask the hematologic signs of B12 deficiency while allowing irreversible neurological damage to progress. 2, 7

• Measure serum and erythrocyte folate, serum cobalamin, and methylmalonic acid before starting supplementation 2
• Using cyanocobalamin instead of methylcobalamin/hydroxycobalamin is less effective for homocysteine reduction 1
• Relying on MTHFR genotype testing alone without measuring homocysteine levels—homozygosity accounts for only one-third of hyperhomocysteinemia cases 2, 7
• Assuming all individuals with MTHFR mutations need treatment—only those with elevated homocysteine (>10-15 μmol/L) require intervention 1, 7

When Folic Acid May Still Be Acceptable

In populations living in folate-fortified areas (North America), additional high-dose folic acid provides no vascular benefit beyond what fortification already provides, as intracellular 5-MTHF reaches maximum levels at doses equivalent to 400 μg/day. 1

• Standard folic acid at 400 μg/day (the RDA) achieves maximum vascular benefit even in those with normal MTHFR function 1
• Higher doses increase plasma but not intracellular 5-MTHF levels in fortified populations 1
• For pregnancy prevention of neural tube defects in areas without fortification, standard folic acid remains effective across all genotypes 8