What is the recommended treatment for MTHFR (Methylenetetrahydrofolate Reductase) deficiency?

Treatment of MTHFR Deficiency

For patients with MTHFR deficiency, oral 5-methyltetrahydrofolate (5-MTHF) supplementation is the recommended first-line treatment, particularly for those with the 677TT genotype, as this agent bypasses the enzymatic block and directly provides the active form of folate. 1

Understanding MTHFR Deficiency

MTHFR (Methylenetetrahydrofolate Reductase) deficiency is a genetic condition that affects the body's ability to process folate properly. This enzyme is critical for converting 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is necessary for remethylation of homocysteine to methionine.

The severity of hyperhomocysteinemia can be classified as:

• Moderate: 15-30 μmol/L
• Intermediate: 30-100 μmol/L
• Severe: >100 μmol/L 1

Treatment Protocol

First-Line Treatment

1. 5-Methyltetrahydrofolate (5-MTHF): 400 μg/day

   • Particularly important for patients with the MTHFR 677TT genotype 2
   • Bypasses the MTHFR enzymatic block 1
   • More effective than standard folic acid for these patients 3

2. Vitamin B12 (Cobalamin): 0.02-1 mg/day

   • Provides an additional 7% reduction in homocysteine levels 2
   • Essential co-factor in homocysteine metabolism 1

3. Riboflavin (Vitamin B2): 1.6-10 mg/day

   • Particularly important for patients with MTHFR mutations 2
   • Higher doses (10 mg/day) may be more effective in lowering homocysteine 2

For Severe Cases

For patients with severe hyperhomocysteinemia (>100 μmol/L) or homocystinuria:

• Betaine (Trimethylglycine): Acts as a methyl donor in the remethylation of homocysteine to methionine 4
  • Dosage: 6 g/day (typically 3 g twice daily) 4
  • FDA-approved for homocystinuria including MTHFR deficiency 4

Monitoring and Adjustment

• Measure plasma homocysteine levels before treatment and periodically during treatment
• Target reduction of homocysteine to <15 μmol/L if possible 1
• Adjust supplementation based on homocysteine levels and clinical response

Special Considerations

MTHFR Genotype

• Patients with the 677TT genotype show the most marked reductions in homocysteine with proper supplementation 5
• Individuals with MTHFR 677CT genotype may benefit more from folinic acid than l-methylfolate supplementation 5

Renal Disease

• Patients with chronic kidney disease have a high prevalence (85-100%) of hyperhomocysteinemia 1
• These patients may require higher doses but are unlikely to achieve complete normalization of homocysteine levels 6

Clinical Benefits

Treatment of MTHFR deficiency and resulting hyperhomocysteinemia is important due to:

1. Reduced risk of thromboembolic events 2
2. Potential reduction in cardiovascular disease risk 1
3. Improved pregnancy outcomes in couples with fertility issues 3

Pitfalls to Avoid

• Do not use high-dose folic acid (5 mg/day) in patients with MTHFR mutations as this can lead to unmetabolized folic acid syndrome 3
• Do not rely solely on standard folic acid for patients with the 677TT genotype; use 5-MTHF instead 2, 3
• Do not overlook vitamin B12 status when treating hyperhomocysteinemia, as B12 deficiency can limit the effectiveness of folate supplementation 6

By following this treatment approach, patients with MTHFR deficiency can effectively manage their condition and potentially reduce associated health risks.