What are the indications and recommendations for an MTHFR (methylenetetrahydrofolate reductase) gene screen?

MTHFR Gene Screening: Clinical Indications and Recommendations

MTHFR gene screening is not recommended as a routine test and should not be ordered for general cardiovascular risk assessment, thrombophilia evaluation, or pregnancy complications. 1, 2

When MTHFR Testing Should NOT Be Ordered

The most important clinical guidance is understanding when NOT to test:

• Do not order MTHFR testing for cardiovascular disease risk assessment - genomic profiling including MTHFR has insufficient evidence to improve cardiovascular health outcomes in the general population 1

• Do not order MTHFR testing as part of thrombophilia workup - the MTHFR C677T mutation itself is not an independent risk factor for venous thromboembolism; hyperhomocysteinemia is the actual risk factor 3

• Do not order MTHFR testing for recurrent pregnancy loss, neural tube defect risk, or other pregnancy complications - the evidence linking MTHFR polymorphisms to these outcomes is insufficient 4

• Do not order MTHFR testing for stroke evaluation - while the mutation was studied in stroke patients, plasma homocysteine measurement is more clinically informative than genotyping 1, 2

The Critical Distinction: Test Homocysteine, Not MTHFR

Plasma homocysteine measurement is more informative than molecular MTHFR testing because homozygosity for MTHFR mutations accounts for only about one-third of hyperhomocysteinemia cases 2, 3, 5

When to Measure Homocysteine Instead:

• Patients with unexplained arterial or venous thrombosis - measure fasting plasma homocysteine (≥8 hours fasting) to identify hyperhomocysteinemia as a treatable risk factor 3, 5

• Patients with premature cardiovascular disease - elevated homocysteine confers 2-3 fold increased risk for atherosclerotic vascular disease 2, 3, 5

• Women with cerebral venous thrombosis on oral contraceptives - the combination of MTHFR 677TT genotype and oral contraceptive use increases stroke risk (OR 5.4), but this is mediated through hyperhomocysteinemia 1

The Only Legitimate Indication for MTHFR Testing

MTHFR genotyping may be considered when elevated homocysteine levels are already documented and you need to guide supplementation strategy:

• If homocysteine is elevated (>15 μmol/L) and you've confirmed the patient has adequate B12 and folate status, MTHFR genotyping can help determine whether to use 5-methyltetrahydrofolate (5-MTHF) instead of folic acid 2, 3

• For patients with MTHFR 677TT genotype, 5-MTHF is preferred over folic acid because it bypasses the deficient enzyme and reduces homocysteine by 25-30% 2, 3, 5

Treatment Algorithm When Hyperhomocysteinemia is Found

The treatment is based on homocysteine level, not MTHFR genotype:

Moderate Hyperhomocysteinemia (15-30 μmol/L):

• First-line: 5-MTHF 0.4-1 mg daily (reduces homocysteine by 25-30%) 2, 3, 5
• Add vitamin B12 (methylcobalamin) 0.02-1 mg daily (provides additional 7% reduction) 2, 3, 5
• Add vitamin B6 50 mg daily to support transsulfuration pathway 2
• Add riboflavin (particularly effective for TT genotype) 2

Intermediate Hyperhomocysteinemia (30-100 μmol/L):

• Combination therapy: Folic acid 0.4-5 mg/day + vitamin B12 0.02-1 mg/day + vitamin B6 10-50 mg/day 3, 5
• Identify underlying cause (moderate/severe B12 or folate deficiency, renal failure) 3, 5

Severe Hyperhomocysteinemia (>100 μmol/L):

• High-dose pyridoxine 50-250 mg/day + folic acid 0.4-5 mg/day + vitamin B12 0.02-1 mg/day 3, 5
• Consider betaine (trimethylglycine) as adjunct 3

Critical Pre-Treatment Evaluation

Before starting any folate supplementation, you must:

1. Measure serum and erythrocyte folate to assess true folate status 2, 3

2. Check serum cobalamin (B12) - never start folate without ruling out B12 deficiency 2, 3

3. Measure serum or urine methylmalonic acid to confirm true B12 deficiency, as normal B12 levels can mask functional deficiency 3

4. Never initiate folate supplementation without excluding B12 deficiency first - folate alone can mask hematologic manifestations of B12 deficiency while allowing irreversible neurological damage to progress 2, 3

Common Clinical Pitfalls to Avoid

• Ordering MTHFR testing reflexively for any thrombosis or pregnancy complication - this is the most common misuse of the test 1, 3

• Using standard folic acid instead of 5-MTHF in patients with documented 677TT genotype - 5-MTHF doesn't require conversion by the deficient enzyme 2, 3

• Using cyanocobalamin instead of methylcobalamin or hydroxycobalamin - the methylated forms are more effective for homocysteine reduction 2, 3

• Failing to check B12 status before starting folate - this can cause irreversible neurological damage 2, 3

• Treating MTHFR genotype instead of treating elevated homocysteine - the genotype alone without hyperhomocysteinemia does not require treatment 2, 3, 5

Special Population Considerations

Patients on methotrexate with MTHFR mutations should receive folate supplementation (≥5 mg/week) to reduce gastrointestinal side effects and protect against elevated liver function tests 2, 3

Patients with chronic kidney disease may require higher doses of folic acid (1-5 mg daily) though homocysteine may not normalize completely 3, 5

The Bottom Line on Cardiovascular Outcomes

While B-vitamin supplementation reduces homocysteine levels effectively, the cardiovascular benefit remains uncertain - the American Heart Association gives only a Class IIb recommendation (usefulness not well established) for B-complex vitamins in stroke prevention with hyperhomocysteinemia 3, 5

However, combination therapy with vitamins B6, B12, and folic acid reduced stroke risk by 25% in the HOPE-2 trial in patients with established vascular disease, particularly when treatment exceeded 3 years and homocysteine reduction was >20% 3, 5