What are the health implications for a patient with Methylenetetrahydrofolate Reductase (MTHFR) mutations or deficiencies?

What MTHFR Means for a Patient

MTHFR (methylenetetrahydrofolate reductase) is a common genetic variant that typically has minimal clinical significance unless it causes elevated homocysteine levels, which is the actual risk factor that matters—not the gene mutation itself. 1

The Key Distinction: Gene vs. Homocysteine Level

The critical point is that plasma homocysteine measurement is more informative than molecular MTHFR testing, as homozygosity for the C677T mutation accounts for only about one-third of hyperhomocysteinemia cases. 1, 2 The MTHFR C677T variant by itself is not associated with arterial thrombosis in the absence of hyperhomocysteinemia, and is not associated with venous thrombosis in any case. 1

Prevalence and Enzyme Function

• The thermolabile MTHFR C677T variant is present in 30-40% of the general population as heterozygotes and 10-15% as homozygotes. 1, 2
• This variant reduces enzyme efficiency in converting folate to its active form (5-methyltetrahydrofolate), which is needed to remethylate homocysteine to methionine. 1, 3
• The variant significantly increases risk of hyperhomocysteinemia, particularly when folate nutritional status is marginal. 2, 4

Clinical Implications Based on Homocysteine Levels

When Homocysteine is Normal

If homocysteine levels are normal (<10-15 μmol/L), the MTHFR variant has no established clinical significance and requires no specific treatment. 1 The American Heart Association/American Stroke Association guidelines note that MTHFR mutations rarely contribute to adult stroke but may play a larger role in pediatric stroke. 1

When Homocysteine is Elevated

Elevated homocysteine is the actual risk factor that requires intervention, with risk beginning to increase when fasting plasma homocysteine exceeds 10 μmol/L. 1, 2 The cardiovascular implications include:

• For every 5 μmol/L increase in homocysteine, stroke risk increases by 59%. 2
• Hyperhomocysteinemia is associated with a 2-3 fold increased risk of atherosclerotic vascular disease. 2
• Meta-analyses show modest associations between MTHFR C677T and stroke (OR 1.24-1.26), particularly in younger patients (<55 years). 1

Diagnostic Approach

Measure fasting plasma homocysteine after at least 8 hours of fasting, not MTHFR genotype, as the initial test. 2, 4 If elevated:

1. Confirm with repeat testing. 4
2. Measure serum and erythrocyte folate (not just serum folate for long-term status). 2, 4
3. Check serum cobalamin (vitamin B12). 2, 4
4. Measure serum or urine methylmalonic acid to confirm true B12 deficiency, as normal B12 serum levels can mask functional deficiency. 2, 4

Critical caveat: Never start folate supplementation without first ruling out B12 deficiency, as folate alone can mask hematologic manifestations of B12 deficiency while allowing irreversible neurological damage to progress. 2, 4

Treatment Strategy Based on Homocysteine Level

Moderate Hyperhomocysteinemia (15-30 μmol/L)

• Folic acid 0.4-1 mg daily reduces homocysteine by approximately 25-30%. 2, 4
• Add vitamin B12 (0.02-1 mg daily) for an additional 7% reduction. 2, 4
• For patients with MTHFR 677TT genotype, 5-methyltetrahydrofolate (5-MTHF) is preferred over folic acid as it doesn't require conversion by the deficient enzyme. 2, 4

Intermediate Hyperhomocysteinemia (30-100 μmol/L)

Combination therapy with folic acid (0.4-5 mg/day), vitamin B12 (0.02-1 mg/day), and vitamin B6 (10-50 mg/day) is recommended. 2, 4 This level typically results from moderate/severe folate or B12 deficiency or renal failure. 2

Severe Hyperhomocysteinemia (>100 μmol/L)

High-dose pyridoxine (50-250 mg/day) combined with folic acid (0.4-5 mg/day) and vitamin B12 (0.02-1 mg/day) is required. 2 This level usually indicates severe cobalamin deficiency or rare homocystinuria from severe MTHFR deficiency. 2, 5, 6

Special Consideration: Riboflavin

Riboflavin (vitamin B2) supplementation at 1.6 mg/day is specifically recommended for individuals with MTHFR mutations to normalize homocysteine levels, particularly in those with hypertension and the 677 TT genotype. 4

Cardiovascular Risk Reduction Evidence

The evidence for cardiovascular benefit from treating elevated homocysteine is mixed but shows some benefit for stroke prevention:

• The HOPE 2 study showed combination therapy with vitamins B6, B12, and folic acid reduced stroke risk by 25% (RR 0.75,95% CI 0.59-0.97) in patients with established vascular disease or diabetes. 2
• Meta-analysis found folic acid supplementation reduced stroke risk by 18%. 2
• The American Heart Association/American Stroke Association provides a Class IIb recommendation that B complex vitamins might be considered for stroke prevention in patients with hyperhomocysteinemia, though effectiveness is not well established. 1, 2

The strongest evidence for stroke reduction comes from trials where treatment duration exceeded 3 years and homocysteine decrease was >20%. 2

Thrombosis Considerations

The MTHFR C677T mutation itself is not an independent risk factor for deep vein thrombosis; it increases DVT risk indirectly only by causing hyperhomocysteinemia. 2 However:

• Hyperhomocysteinemia interacts synergistically with Factor V Leiden to increase relative risk of venous thrombosis to 20-fold. 1, 2
• Patients with arterial ischemic stroke or TIA with established inherited thrombophilia should be evaluated for DVT, which is an indication for anticoagulation (Class I recommendation). 1

When MTHFR Testing is NOT Recommended

MTHFR gene screening should not be used as a routine test for:

• General cardiovascular risk assessment 2
• Thrombophilia evaluation 2
• Pregnancy complications 2

The American College of Medical Genetics explicitly recommends against routine MTHFR testing because genomic profiling including MTHFR has insufficient evidence to improve cardiovascular health outcomes in the general population. 2

Rare Severe MTHFR Deficiency

Severe MTHFR deficiency from rare homozygous or compound heterozygous mutations (not the common C677T variant) presents with dramatic hyperhomocysteinemia (>100 μmol/L), homocystinuria, and progressive neurological distress, typically in childhood but occasionally in adulthood. 5, 6, 7 These patients require aggressive treatment with betaine, high-dose B vitamins, and methionine supplementation. 5, 6

Practical Bottom Line

For the vast majority of patients with common MTHFR variants, the gene result itself means nothing—measure homocysteine instead. If homocysteine is elevated, treat with appropriate B vitamin supplementation based on the level, always excluding B12 deficiency first. If homocysteine is normal, no intervention is needed regardless of MTHFR genotype.