What is the MTHFR gene mutation?

What is the MTHFR Gene Mutation?

The MTHFR (methylenetetrahydrofolate reductase) gene mutation is a common genetic variant that reduces the enzyme's ability to convert folate into its active form (5-methyltetrahydrofolate), which can lead to elevated homocysteine levels and is associated with a 2-3 fold increased risk of atherosclerotic vascular disease and stroke, particularly in individuals with the homozygous C677T (TT) genotype. 1, 2

Understanding the Genetic Variants

The MTHFR enzyme catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the predominant circulatory form of folate and the methyl donor for remethylation of homocysteine to methionine. 3 Two main polymorphic variants exist:

C677T Mutation (Most Common)

• The C677T mutation involves a point mutation where cytosine is replaced by thymidine at position 677, creating a thermolabile (heat-sensitive) variant of the enzyme. 1
• Heterozygous form (677CT) occurs in 30-40% of the general population. 2
• Homozygous form (677TT) occurs in 10-15% of the general population and causes the most significant enzyme dysfunction. 1, 2
• The TT genotype results in approximately 70% reduced enzyme activity compared to normal. 3

A1298C Mutation (Less Common)

• The A1298C variant shows different distribution patterns: 69.7% CC (normal), 26.9% CT (heterozygous), and 3.4% TT (homozygous) in Canadian populations. 2
• This variant in heterozygous form does not significantly elevate homocysteine levels or increase cardiovascular risk independently. 4
• Compound heterozygosity (having both C677T and A1298C mutations) occurs in approximately 5% of individuals and increases homocysteine levels. 2

Clinical Significance and Health Implications

Cardiovascular and Stroke Risk

• Homozygosity for the 677TT variant increases risk for hyperhomocysteinemia, which is associated with a 2-3 fold increased risk for atherosclerotic vascular disease and stroke. 1, 2, 4
• For each 5 μmol/L increase in homocysteine, stroke risk increases by 59% (95% CI, 29-96%). 1
• For each 3 μmol/L decrease in homocysteine, stroke risk decreases by 24% (95% CI, 15-33%). 1
• A meta-analysis found increased stroke risk in those with the TT genotype (OR 1.26; 95% CI, 1.11-1.43). 1

Thrombosis Risk

• The MTHFR mutation itself is not an independent risk factor for deep vein thrombosis (DVT); however, it increases DVT risk indirectly by causing hyperhomocysteinemia, which is the actual thrombotic risk factor. 4
• Hyperhomocysteinemia combined with Factor V Leiden creates a 20-fold increased risk of venous thrombosis compared to individuals without either risk factor. 1, 4
• The link between MTHFR mutations and arterial stroke is tenuous in adults but may play a larger role in pediatric stroke. 1

Gene-Environment Interaction

• The phenotypic expression of MTHFR polymorphism depends critically on folate and vitamin B12 status: individuals with low levels of these vitamins and the TT genotype have disproportionately high homocysteine levels. 4, 5
• Nutritional deficiencies of pyridoxine (vitamin B6), folic acid, and cobalamin (vitamin B12) can exacerbate the effects of MTHFR mutations. 1

Diagnostic Approach

When to Test

• Plasma homocysteine measurement is more informative than molecular MTHFR testing alone, as homozygosity for MTHFR mutations accounts for only about one-third of hyperhomocysteinemia cases. 2, 4
• MTHFR genotyping should be considered when elevated homocysteine levels are present, not as routine screening. 2
• The American College of Medical Genetics recommends that MTHFR gene screening is not used as a routine test for general cardiovascular risk assessment, thrombophilia evaluation, or pregnancy complications. 4

Testing Protocol

• Obtain fasting plasma homocysteine level after at least 8 hours of fasting; a single elevated value should be retested for confirmation. 4
• Measure serum and erythrocyte folate levels to assess folate status. 4
• Check serum cobalamin (vitamin B12) to identify B12 deficiency. 4
• Measure serum or urine methylmalonic acid to confirm B12 deficiency, as this helps differentiate true B12 deficiency from folate deficiency. 4

Treatment and Management

Supplementation Strategy for MTHFR Mutations

For individuals with MTHFR 677TT genotype and elevated homocysteine, 5-methyltetrahydrofolate (5-MTHF) is preferred over folic acid as it bypasses the enzymatic defect and more effectively reduces homocysteine levels by 25-30%. 2, 4

Specific Dosing Recommendations

• 5-MTHF: 0.4-5 mg daily (preferred over folic acid for TT genotype). 2, 4
• Vitamin B12 (as methylcobalamin or hydroxycobalamin): 0.02-1 mg daily or 1 mg weekly provides an additional 7% reduction in homocysteine levels. 2, 4
• Vitamin B6: 50 mg daily supports the transsulfuration pathway of homocysteine metabolism. 2
• Riboflavin: Supplementation appears particularly effective for individuals with the TT genotype. 2

Why 5-MTHF Over Folic Acid?

• 5-MTHF is immediately bioavailable as it is already in the active form, while folic acid requires hepatic conversion through multiple enzymatic steps involving the deficient MTHFR enzyme. 2
• 5-MTHF provides direct vascular benefits independent of homocysteine lowering, including scavenging peroxynitrite radicals, protecting tetrahydrobiopterin from oxidation, and improving endothelial nitric oxide synthase coupling. 2
• The European Society of Cardiology specifically recommends 5-MTHF for individuals with MTHFR mutations, particularly the 677TT genotype. 2

Dietary Recommendations

• Focus on foods naturally rich in folate, such as leafy greens, legumes, fruits, and vegetables, rather than those fortified with folic acid. 2

Critical Pitfalls to Avoid

Pre-Treatment Requirements

• Never start folate supplementation without first ruling out B12 deficiency, as folate alone can mask the hematologic manifestations of B12 deficiency while allowing irreversible neurological damage to progress. 2, 4
• Measure serum or urine methylmalonic acid to confirm true B12 deficiency, as normal B12 serum levels can mask functional deficiency. 4

Common Supplementation Errors

• Using standard folic acid instead of 5-MTHF in individuals with TT genotype, as it requires conversion by the deficient MTHFR enzyme, making it less effective. 2
• Using cyanocobalamin instead of methylcobalamin or hydroxycobalamin, as it is less effective in reducing homocysteine levels. 2
• Failing to include riboflavin, which is particularly important for TT homozygotes. 2
• Overlooking the need for comprehensive B vitamin supplementation rather than focusing solely on folate. 2

Anticoagulation Misconceptions

• Patients with MTHFR mutations and no history of blood clots should not undergo routine anticoagulation; instead, focus on measuring homocysteine levels and treating elevated homocysteine with appropriate supplementation. 2
• MTHFR mutation status alone does not warrant anticoagulation without a history of thrombosis. 2

Severe MTHFR Deficiency (Rare)

While the common polymorphisms (C677T and A1298C) cause mild enzyme dysfunction, rare mutations can cause severe MTHFR deficiency leading to homocystinuria, an autosomal recessive disorder with hyperhomocysteinemia, hypomethioninemia, and neurological and vascular findings with variable age at onset. 6, 7, 8 This severe form is distinct from the common polymorphisms and requires specialized management.