What is a Methylenetetrahydrofolate Reductase (MTHFR) mutation?

What is an MTHFR Mutation?

An MTHFR mutation is a genetic variant in the methylenetetrahydrofolate reductase gene that reduces the enzyme's ability to convert folate into its active form (5-methyltetrahydrofolate), potentially leading to elevated homocysteine levels and associated health risks. 1

The Two Main MTHFR Variants

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

• C677T mutation: The most clinically significant variant where cytosine is replaced by thymine at position 677, present in 30-40% of the general population as heterozygotes (CT) and 10-15% as homozygotes (TT) 1, 2
• A1298C mutation: A second variant where adenine is replaced by cytosine at position 1298, also found in approximately 10% of individuals as homozygotes 3, 4

The C677T homozygous (TT) genotype significantly reduces MTHFR enzyme activity and is the variant most strongly associated with elevated homocysteine levels 1, 5.

How MTHFR Affects Homocysteine Metabolism

MTHFR catalyzes a critical step in folate metabolism—converting 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which serves as the methyl donor for remethylating homocysteine back to methionine 6, 7. When MTHFR activity is reduced:

• Homocysteine accumulates in the blood (hyperhomocysteinemia) 1
• This effect is most pronounced when folate levels are low—individuals with the TT genotype and low folate can have homocysteine levels of 16.0 nmol/mL compared to 12.3 nmol/mL in those without the mutation 7
• The A1298C mutation alone does not typically cause elevated homocysteine 4

Clinical Significance and Associated Risks

The MTHFR mutation itself is NOT directly pathogenic—the risk comes from the resulting hyperhomocysteinemia. 1 This is a critical distinction:

• Hyperhomocysteinemia is associated with a 2-3 fold increased risk of atherosclerotic vascular disease and stroke 1, 2
• For every 5 μmol/L increase in homocysteine, stroke risk increases by 59% 1
• The American Heart Association/American Stroke Association notes that inherited thrombophilias including MTHFR mutations rarely contribute to adult stroke but may play a larger role in pediatric stroke 8

Important Caveats About MTHFR and Disease Risk

The relationship between MTHFR mutations and cardiovascular disease is complex and often overstated:

• Meta-analyses show only weak associations between MTHFR C677T and ischemic stroke (OR 1.24-1.26), particularly in younger patients 8
• The mutation accounts for only about one-third of hyperhomocysteinemia cases—many other factors contribute 1, 2
• Plasma homocysteine measurement is more informative than MTHFR genotyping alone 1, 2

When MTHFR Testing Matters

MTHFR genotyping should be considered when:

• Elevated homocysteine levels are already documented 2
• Evaluating neurocognitive outcomes in childhood cancer survivors treated with methotrexate (which interferes with folate metabolism) 8
• Assessing thrombophilia in young patients with cryptogenic stroke 8

MTHFR testing should NOT be used as routine screening in the general population. 2

The Gene-Environment Interaction

The clinical impact of MTHFR mutations depends heavily on nutritional status:

• Individuals with the TT genotype who have adequate folate and B12 levels (above median values) show no difference in homocysteine compared to those without the mutation 5, 7
• The mutation only becomes problematic when folate status is low 1, 7
• This gene-nutrient interaction explains why supplementation can effectively mitigate the effects of MTHFR mutations 1, 2

Management Approach

For individuals with MTHFR mutations and elevated homocysteine:

• 5-methyltetrahydrofolate (5-MTHF) is preferred over folic acid because it bypasses the deficient enzyme and doesn't require conversion 1, 2
• Adding vitamin B12 (0.02-1 mg/day) provides an additional 7% reduction in homocysteine 1, 2
• Vitamin B6 and riboflavin supplementation support alternative homocysteine metabolism pathways 2
• Dietary modifications focusing on naturally folate-rich foods (leafy greens, legumes) rather than fortified foods 2

The American Heart Association suggests B-complex vitamins might be considered for stroke prevention in patients with hyperhomocysteinemia (Class IIb, Level of Evidence B), though the cardiovascular benefit of homocysteine-lowering treatment remains incompletely established 1, 2.