What is a Methylenetetrahydrofolate Reductase (MTHFR) mutation and how is it treated, particularly in relation to Leucovorin (Folinic Acid)?

MTHFR Mutation: Understanding and Treatment Approaches

For individuals with MTHFR mutations, treatment with 5-methyltetrahydrofolate (5-MTHF) is recommended over standard folic acid supplementation, as it bypasses the enzymatic defect and more effectively reduces homocysteine levels, particularly in those with the 677TT genotype. 1, 2

What is MTHFR Mutation?

• MTHFR (Methylenetetrahydrofolate Reductase) is an enzyme that converts folate to its active form (5-methyltetrahydrofolate) in the homocysteine metabolism pathway 1
• The most common mutation is C677T, found in heterozygous form (677CT) in 30-40% of the general population and homozygous form (677TT) in 10-15% 1
• Another significant mutation is A1298C, with homozygosity observed in approximately 10% of individuals 3
• These mutations reduce enzyme activity, potentially leading to elevated homocysteine levels (hyperhomocysteinemia) 1, 3

Clinical Significance of MTHFR Mutations

• Homozygosity for the 677C→T variant (677TT) increases risk for hyperhomocysteinemia 1
• Elevated homocysteine is associated with:
  • 2-3 fold increased risk for atherosclerotic vascular disease and stroke 1
  • Increased risk of arterial thrombosis (but only when hyperhomocysteinemia is present) 1
  • Synergistic interaction with other risk factors (e.g., Factor V Leiden can increase thrombosis risk 20-fold) 1
• The A1298C mutation reduces enzyme activity to approximately 60% of normal in homozygotes 3
• Compound heterozygotes (individuals with both C677T and A1298C mutations) have 50-60% of normal enzyme activity 3

Treatment Approaches

General Recommendations

• Plasma homocysteine measurement is more informative than molecular testing alone, as homozygosity for MTHFR mutations accounts for only about one-third of hyperhomocysteinemia cases 1
• Treatment should be based on homocysteine levels and MTHFR genotype 1

Treatment Based on Homocysteine Levels

• Normal homocysteine levels: No specific treatment required 1
• Moderate homocysteinemia (15-30 μmol/L):
  • Identify and address underlying causes (poor diet, vitamin deficiencies, medication effects) 1
  • For those with MTHFR 677TT genotype, 5-methyltetrahydrofolate (5-MTHF) supplementation is recommended 1
• Intermediate homocysteinemia (30-100 μmol/L):
  • Treat underlying causes (moderate/severe cobalamin or folate deficiency, renal failure) 1
  • Folate treatment alone or in combination with vitamins B12 and B6 1
• Severe homocysteinemia (>100 μmol/L):
  • Requires immediate treatment due to increased prothrombotic state 1
  • Cobalamin supplementation (0.02-1 mg/day) for cobalamin deficiency 1

Specific Treatment for MTHFR Mutations

• For MTHFR 677TT genotype: 5-methyltetrahydrofolate (5-MTHF) is preferred over folic acid as it doesn't require conversion by the deficient MTHFR enzyme 1, 2
• For moderate enzyme deficiency: Folic acid (400 μg/day) can reduce homocysteine levels by 25-30% 1
• Additional benefit: Adding vitamin B12 (0.02-1 mg/day) can provide an additional 7% reduction in homocysteine levels 1

Relationship to Leucovorin (Folinic Acid)

• Leucovorin is N5-formyltetrahydrofolic acid, a derivative of tetrahydrofolic acid 4
• Folinic acid can be beneficial for individuals with MTHFR mutations because:
  • It's a reduced form of folate that bypasses the MTHFR enzyme defect 5
  • Recent research shows folinic acid supplementation significantly reduces homocysteine levels in individuals with MTHFR mutations 5
  • In individuals with the MTHFR 677CT genotype, folinic acid appears to be more effective than l-methylfolate in reducing homocysteine levels 5

Special Clinical Considerations

• Methotrexate treatment: Patients on methotrexate (especially those with MTHFR mutations) should receive folate supplementation to:

  • Reduce gastrointestinal side effects 1, 6
  • Protect against elevated liver function tests 1, 6
  • Reduce likelihood of drug discontinuation 1
  • Counteract methotrexate-induced hyperhomocysteinemia 6
  • For patients with MTHFR mutations receiving high-dose methotrexate, leucovorin rescue is particularly important 1

• Cardiovascular risk: While elevated homocysteine is associated with increased cardiovascular risk, the benefit of homocysteine-lowering treatment for primary prevention in the general population remains unclear 1

Important Caveats

• MTHFR genotyping should be considered when elevated homocysteine levels are present, not as a routine screening test 1
• Homocysteine-lowering strategies targeting specific causes are generally considered safe, even if their impact on cardiovascular outcomes is still being studied 1
• Patients with MTHFR mutations may have an endogenous upregulation of folic acid absorption to compensate for the enzyme deficiency 7
• The optimal form of folate supplementation should be based on MTHFR genotype, with 5-MTHF or folinic acid preferred for those with significant mutations 5, 2