What is MTHFR (Methylenetetrahydrofolate Reductase)?

What is MTHFR (Methylenetetrahydrofolate Reductase)?

MTHFR (Methylenetetrahydrofolate Reductase) is a key enzyme in folate metabolism that catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which serves as the primary methyl donor for homocysteine remethylation to methionine, playing a critical role in cardiovascular health and stroke prevention. 1

Biochemical Function and Role

MTHFR functions as a central enzyme in the folate cycle with two primary metabolic pathways:

1. Remethylation pathway:

   • MTHFR converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (active folate)
   • This active folate serves as a methyl donor for homocysteine conversion to methionine
   • Important cofactors include methylcobalamin (active B12), riboflavin, and betaine 1

2. Trans-sulfuration pathway:

   • Involves conversion of homocysteine through other pathways
   • Requires pyridoxal phosphate (active vitamin B6) and riboflavin as cofactors 1

Genetic Variants

The MTHFR gene has several common polymorphisms that affect enzyme function:

1. C677T variant (most common):

   • Results in an alanine-to-valine substitution at codon 222
   • Creates a thermolabile enzyme with reduced activity
   • Frequency varies by population:
     • Canada: 40.4% CC (wild type), 46.6% CT, 13.0% TT
     • France: 37.6% CC, 47.4% CT, 15.0% TT
     • China: 27.3% CC, 49.1% CT, 23.6% TT 1, 2

2. A1298C variant:

   • Results in glutamate-to-alanine substitution
   • Frequency in Canada: 69.7% AA, 26.9% AC, 3.4% CC
   • Frequency in China: 48.7% AA, 43.8% AC, 7.5% CC 1

3. Compound heterozygosity (having both variants) increases total homocysteine levels 1

Clinical Significance

Homocysteine Metabolism

• MTHFR deficiency can lead to hyperhomocysteinemia, an independent risk factor for cardiovascular disease 1, 3
• Homocysteine severity levels:
  • Moderate: 15-30 μmol/L
  • Intermediate: 30-100 μmol/L
  • Severe: >100 μmol/L 4

Stroke Risk and Prevention

• Elevated homocysteine is associated with 2-3 fold increased risk for atherosclerotic vascular disease, including stroke 1
• B-vitamin supplementation may reduce stroke risk by 18-25% in patients with elevated homocysteine 4
• In patients with the C677T variant and low folate status (<15.4 nmol/L), homocysteine levels are 24% higher than in those with normal genotype 5

Medication Interactions

• Methotrexate (MTX), an antirheumatic drug, inhibits folate-dependent pathways
• MTHFR polymorphisms may modify MTX-related toxicity
• Folic acid supplementation (≤7 mg/week) with MTX significantly reduces adverse effects without reducing drug efficacy 1

Management Implications

For individuals with MTHFR variants and elevated homocysteine:

• B-vitamin supplementation:

  • Methylcobalamin or hydroxycobalamin (not cyanocobalamin): 0.5-1 mg daily
  • Folic acid: 0.5-5 mg daily
  • Combined therapy can reduce homocysteine by 25-33% 4

• Target homocysteine level: <10 μmol/L 4

• Monitoring: Recheck homocysteine levels after 2-3 months of supplementation 4

Pitfalls and Caveats

1. Folate status interaction: Individuals with thermolabile MTHFR may have higher folate requirements to regulate homocysteine levels 5

2. Medication considerations:

   • Certain medications (antiepileptics, metformin, oral contraceptives, NSAIDs) can affect folate metabolism 4
   • Avoid nitrous oxide in anesthesia as it inhibits methionine synthase 4

3. Form of supplementation matters:

   • 5-methyltetrahydrofolate may be more effective than folic acid, particularly in those with MTHFR variants 1
   • Methylcobalamin or hydroxycobalamin is preferred over cyanocobalamin 1, 4

4. Pregnancy considerations:

   • Hyperhomocysteinemia is a risk factor for pregnancy complications
   • Higher supplementation doses may benefit women with recurrent pregnancy loss and MTHFR mutations 4