What is the MTHFR Mutation?
The MTHFR (Methylenetetrahydrofolate Reductase) mutation refers to common genetic variants in the enzyme that converts folate to its active form (5-methyltetrahydrofolate) in homocysteine metabolism, with the most clinically significant being the C677T variant found in 30-40% of people as heterozygotes and 10-15% as homozygotes. 1, 2
Understanding the Genetic Variants
The MTHFR gene has two primary polymorphisms that affect enzyme function:
C677T mutation (most clinically significant): This variant causes an alanine-to-valine substitution at position 677, resulting in a thermolabile enzyme with reduced activity 1, 3. The homozygous form (677TT) reduces enzyme activity by approximately 50-70% and is present in 10-15% of the general population 1, 2.
A1298C mutation: This second common variant occurs in heterozygous form in 26.9% and homozygous form (1298CC) in 3.4% of populations 2, 4. Unlike C677T, the A1298C mutation alone does not significantly elevate homocysteine levels 4.
Compound heterozygosity (having both 677CT and 1298AC) occurs in approximately 5% of individuals and can increase homocysteine levels 2.
Clinical Significance and Health Implications
The key clinical concern is not the mutation itself, but whether it causes hyperhomocysteinemia (elevated homocysteine levels above 10 μmol/L). 1, 5
Cardiovascular and Thrombotic Risk
Homozygosity for the 677TT variant increases risk for hyperhomocysteinemia, which is associated with a 2-3 fold increased risk for atherosclerotic vascular disease and stroke 1, 5.
For every 5 μmol/L increase in homocysteine, stroke risk increases by 59% (95% CI: 29-96%) 1, 5.
The MTHFR C677T mutation shows a modest association with ischemic stroke (OR 1.24; 95% CI 1.08-1.42), particularly in younger patients under 55 years 1.
Critically, the mutation itself does not cause thrombosis—only elevated homocysteine does. 5 The American College of Medical Genetics explicitly states that plasma homocysteine measurement is more informative than molecular testing, as homozygosity for C677T accounts for only about one-third of hyperhomocysteinemia cases 1, 5.
Synergistic Effects with Other Risk Factors
Hyperhomocysteinemia interacts synergistically with Factor V Leiden to increase venous thrombosis risk 20-fold compared to individuals without either risk factor 1, 5.
The mutation's effects are strongly influenced by folate nutritional status—individuals with lower plasma folate (<15.4 nmol/L) and the 677TT genotype have homocysteine levels 24% higher than those with normal genotype 6.
When Testing is Appropriate
MTHFR genetic testing should NOT be used as routine screening for cardiovascular risk, thrombophilia evaluation, or pregnancy complications. 2, 5
Testing may be considered in specific circumstances:
- When elevated homocysteine levels are already documented (>10 μmol/L) to identify the underlying cause 2, 5.
- In young patients (<50 years) with unexplained arterial or venous thrombosis 1.
- When evaluating recurrent pregnancy loss in conjunction with other thrombophilia testing 7.
The preferred approach is to measure fasting plasma homocysteine levels (after at least 8 hours fasting) rather than genetic testing. 1, 2, 5
Management and Treatment
For Individuals with MTHFR Mutations and Elevated Homocysteine
The European Society of Cardiology recommends 5-methyltetrahydrofolate (5-MTHF) rather than regular folic acid for individuals with MTHFR mutations, as it bypasses the deficient enzyme and reduces homocysteine by 25-30%. 2, 5
The comprehensive treatment approach includes:
- 5-MTHF (not folic acid): 0.4-5 mg daily, depending on homocysteine severity 2, 5.
- Vitamin B12 (as methylcobalamin or hydroxycobalamin): 0.02-1 mg daily provides an additional 7% homocysteine reduction 2, 5.
- Vitamin B6: 10-50 mg daily to support the transsulfuration pathway 2, 5.
- Riboflavin: Particularly effective for TT homozygotes 2.
Critical Pre-Treatment Requirements
Never start folate supplementation without first ruling out vitamin B12 deficiency. 2, 5 Folate alone can mask the hematologic manifestations of B12 deficiency while allowing irreversible neurological damage to progress 2, 5.
Required baseline testing:
- Fasting plasma homocysteine (≥8 hours fasting) 2, 5
- Serum and erythrocyte folate 2, 5
- Serum cobalamin (vitamin B12) 2, 5
- Serum or urine methylmalonic acid to confirm true B12 deficiency 2, 5
For Individuals Without Elevated Homocysteine
If homocysteine levels are normal, no specific treatment is required based on MTHFR genotype alone. 2, 5 The mutation without hyperhomocysteinemia does not independently increase cardiovascular or thrombotic risk 1.
Common Pitfalls to Avoid
Do not order MTHFR genetic testing as routine screening—it has insufficient evidence to improve cardiovascular outcomes in the general population 2, 5.
Do not use regular folic acid in individuals with 677TT genotype—5-MTHF is superior as it doesn't require conversion by the deficient enzyme 2, 5.
Do not prescribe anticoagulation based solely on MTHFR mutation status—anticoagulation is only indicated if there is documented venous thrombosis, not for the mutation alone 1, 2.
Do not assume the mutation causes all cases of elevated homocysteine—other causes include B12 deficiency, folate deficiency, renal disease, and certain medications 1, 5.
Do not overlook dietary factors—individuals with MTHFR mutations have higher folate requirements, and folate supplementation (even population-wide fortification) can normalize homocysteine levels in many cases 1, 6.