What is the MTHFR (Methylenetetrahydrofolate Reductase) gene mutation and what are the associated diseases?

MTHFR Gene Mutation and Associated Diseases

The MTHFR (Methylenetetrahydrofolate Reductase) gene mutation is a common genetic variant that affects folate metabolism and can lead to elevated homocysteine levels, which is associated with increased risk of cardiovascular disease, stroke, thrombotic events, and neural tube defects. 1

What is the MTHFR Gene?

MTHFR is an enzyme that plays a crucial role in folate metabolism by catalyzing the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is essential for:

• Converting homocysteine to methionine
• DNA methylation processes
• Protein synthesis
• Gene regulation

Common MTHFR Mutations

The most common MTHFR gene mutation is the C677T variant:

• Found in heterozygous form in 30-40% of the general population
• Found in homozygous form in 10-15% of the general population 2
• Results in an alanine-to-valine substitution at codon 222 3
• Creates a thermolabile enzyme with reduced activity
• Homozygous individuals (677TT) have approximately 30% of normal enzyme activity
• Heterozygous individuals (677CT) have approximately 65% of normal enzyme activity

Another common variant is A1298C, which has also been studied in relation to MTHFR function 4.

How MTHFR Mutations Affect Health

Homocysteine Levels

The primary effect of MTHFR mutations is on homocysteine metabolism:

• Homozygosity for the C677T variant increases risk for hyperhomocysteinemia 1
• Elevated homocysteine levels begin to increase cardiovascular risk when fasting plasma concentrations exceed 10 μmol/L 2
• The effect is more pronounced in individuals with lower folate status 5
• Homozygous individuals with folate levels below 15.4 nmol/L have homocysteine levels 24% higher than those with normal genotype 5

Disease Associations

MTHFR mutations have been associated with increased risk for:

1. Cardiovascular Disease

   • Increased risk of arterial thrombosis when hyperhomocysteinemia is present 2
   • The mutation by itself is not associated with arterial thrombosis in the absence of hyperhomocysteinemia 2

2. Venous Thromboembolism

   • Hyperhomocysteinemia interacts synergistically with other thrombophilias like Factor V Leiden, increasing thrombosis risk 20-fold 2
   • The C677T variant alone is not associated with venous thrombosis 2

3. Neural Tube Defects

   • Folate deficiency is associated with neural tube defects
   • MTHFR mutations may increase this risk, especially with inadequate folate intake 1, 4

4. Pregnancy Complications

   • Recurrent pregnancy loss has been studied in relation to MTHFR variants 4
   • Preeclampsia risk may be increased 2

5. Other Conditions Under Investigation

   • Cancer susceptibility
   • Neurodevelopmental disorders
   • Psychiatric conditions 4

Important Clinical Considerations

Diagnosis

• Plasma homocysteine measurement is generally more informative than MTHFR genetic testing 2
• Homozygosity for the C677T mutation accounts for only about one-third of cases of hyperhomocysteinemia 2
• Levels >15 μmol/L are considered diagnostic for hyperhomocysteinemia 2
• Patients with elevated homocysteine should be retested after fasting for confirmation 2

Management

For individuals with hyperhomocysteinemia:

• B vitamin supplementation can lower homocysteine levels:

  • Folate (0.4-5.0 mg daily) can reduce homocysteine by approximately 25%
  • Vitamin B12 (0.5 mg daily) provides an additional 7% reduction 1
  • Higher doses may be needed in patients with renal dysfunction

• Folate supplementation is particularly important for those with the C677T mutation and low folate status 5

• Other important cofactors include:

  • Vitamin B6
  • Vitamin B12
  • Riboflavin (B2) 1

Key Pitfalls to Avoid

1. Don't overinterpret MTHFR genetic testing

   • The presence of mutations alone does not necessarily indicate disease risk
   • Clinical significance depends on homocysteine levels and other risk factors

2. Don't treat with folate alone

   • Supplementation with folate alone can mask vitamin B12 deficiency
   • This could allow neurological damage to progress while masking hematologic findings 2

3. Don't ignore other causes of hyperhomocysteinemia

   • Kidney disease
   • Vitamin deficiencies
   • Other genetic factors
   • Medications
   • Lifestyle factors (smoking)

4. Remember that lowering homocysteine may not reduce all risks

   • Despite the effectiveness of B-vitamin supplementation in reducing homocysteine levels, multiple trials have failed to demonstrate that this intervention reduces cardiovascular events or mortality 1

The clinical approach to MTHFR mutations should focus on measuring homocysteine levels rather than genetic testing alone, with appropriate nutritional supplementation when hyperhomocysteinemia is present.