What are the treatment options for individuals with Mthfr (methylenetetrahydrofolate reductase) gene variants?

Treatment Options for MTHFR Gene Variants

First-line treatment for individuals with MTHFR gene variants is folic acid supplementation at 400 μg (0.4 mg) daily, with consideration of 5-methyltetrahydrofolate (5-MTHF) instead of folic acid specifically for those with the MTHFR 677TT genotype. 1

Diagnosis and Evaluation

• Measure plasma homocysteine levels to determine if MTHFR mutation is causing hyperhomocysteinemia
• Confirm with repeat testing after an 8-hour fast
• Initial evaluation should include:
  • Plasma homocysteine levels
  • Serum and erythrocyte folate
  • Serum cobalamin (B12)
  • Serum/urine methylmalonic acid 1

Treatment Algorithm

First-line Treatment

• For most individuals with MTHFR variants:

  • Folic acid 400 μg (0.4 mg) daily - reduces homocysteine levels by 25-30% 1
  • Add vitamin B12 (0.02-1 mg daily) for an additional 7% reduction in homocysteine 1

• For individuals with MTHFR 677TT genotype:

  • Consider 5-methyltetrahydrofolate (5-MTHF) instead of folic acid 1
  • This bypasses the metabolic defect caused by the MTHFR polymorphism 2

Additional Supplements

• Vitamin B6 (50 mg/day) to support the transsulfuration pathway 1
• Riboflavin (Vitamin B2) at 1.6-10 mg daily, with higher doses (10 mg/day) potentially more effective for individuals with MTHFR mutations 1

Special Populations

• Women with recurrent pregnancy loss and MTHFR mutations:
  • Higher doses of methylfolate (5 mg/day)
  • Vitamin B6 (50 mg/day)
  • Vitamin B12 (1 mg/week) 1

Monitoring and Adjustment

• Target reduction of homocysteine to <15 μmol/L 1
• Monitor methylmalonic acid levels to detect functional B12 deficiency despite normal serum B12 1
• Regular follow-up of homocysteine levels to assess treatment efficacy 1

Important Considerations and Precautions

Potential Drug Interactions

• Antiepileptic drugs (AEDs): May impair folate absorption and increase metabolism of circulating folate 3
• Metformin: Can decrease serum folate in patients with type 2 diabetes 3
• Oral contraceptives: May depress serum folate levels 3
• NSAIDs: Can inhibit some folate-dependent enzymes 3

Important Cautions

• Folic acid in doses above 0.1 mg may mask vitamin B12 deficiency (specifically pernicious anemia) 3
• 5-MTHF may be less likely than folic acid to mask vitamin B12 deficiency 3
• Folate therapy alone is inadequate for treating B12 deficiency 3

Anesthetic Considerations

• For patients requiring surgery:
  • Avoid nitrous oxide as it inhibits methionine synthase, resulting in homocysteine elevation 4
  • Propofol and sevoflurane do not increase homocysteine levels and are considered safe 4
  • Use thrombosis prevention measures (compression stockings, intermittent pneumatic compression sleeves, subcutaneous heparin) 4

Efficacy of Different Folate Forms

Research shows that individuals with low MTHFR activity require 5-Me-THF to overcome metabolic defects caused by polymorphisms in their MTHFR genes 2. While folic acid supplementation results in a 2.5-fold increase in 5-Me-THF in cells with normal MTHFR activity, there is no increase after folic acid supplementation in low MTHFR activity cells 2.

For vascular health, 5-MTHF has been shown to improve endothelial NO bioavailability and lower vascular superoxide production 5. This effect is attributed to 5-MTHF's capacity to scavenge peroxynitrite radicals, leading to improvement of vascular BH4 bioavailability 5.

Lifestyle Modifications

• Maintain optimal blood pressure and normal weight (BMI 20-25 kg/m²)
• Maintain an active lifestyle
• Avoid excessive alcohol consumption
• Consume folate-rich foods (green leafy vegetables, citrus fruits, nuts, legumes) 1