What is MTHFR (Methylenetetrahydrofolate Reductase)?
MTHFR is a critical enzyme that converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the active form of folate required for homocysteine remethylation to methionine—a process essential for DNA synthesis, protein production, and cardiovascular health. 1, 2
Biochemical Function and Metabolic Role
MTHFR catalyzes an irreversible reduction reaction using FAD (flavin adenine dinucleotide) as a cofactor, accepting reducing equivalents from NADPH to convert folate into its methylated form 2, 3
This enzyme provides the sole source of 5-methyltetrahydrofolate (5-MTHF), which serves as the methyl donor for methionine synthase in converting homocysteine back to methionine 1, 2
MTHFR plays a central role in one-carbon metabolism, affecting folate homeostasis, homocysteine levels, and methylation reactions throughout the body 1, 3
Common Genetic Variants
The C677T polymorphism (rs1801133) is the most clinically significant variant, where cytosine is replaced by thymine at position 677, resulting in an alanine-to-valine substitution at codon 222 1, 4, 5
This thermolabile variant occurs in 30-40% of the general population as heterozygotes (677CT) and 10-15% as homozygotes (677TT), with higher prevalence in certain ethnic groups (23.6% TT genotype in Chinese populations) 1, 6
The A1298C polymorphism (rs1801131) is another common variant that can compound the effects when present with C677T 6, 5
Homozygosity for C677T (677TT genotype) reduces MTHFR enzyme activity by 50-70% and increases thermolability, making the enzyme more susceptible to heat inactivation 4, 3
Clinical Significance and Disease Associations
Reduced MTHFR activity leads to hyperhomocysteinemia, which is associated with a 2-3 fold increased risk for atherosclerotic vascular disease and stroke 1, 7
For every 5 μmol/L increase in homocysteine, stroke risk increases by 59% (95% CI: 29-96%), while each 3 μmol/L decrease reduces stroke risk by 24% (95% CI: 15-33%) 1, 7
The 677TT genotype itself increases stroke risk (OR 1.26; 95% CI: 1.11-1.43) through a "mendelian randomization" mechanism independent of other cardiovascular risk factors 1
MTHFR polymorphisms have been associated with cardiovascular disease, neural tube defects, Alzheimer's disease, depression, autism spectrum disorder, pregnancy complications, and various metabolic disorders 2, 5
Causes of Impaired MTHFR Function
Genetic defects: Severe MTHFR deficiency from rare mutations causes hyperhomocysteinemia, hypomethioninemia, and neurological/vascular complications with variable age of onset 4, 8
Nutritional deficiencies: Folate, vitamin B12 (cobalamin), vitamin B6 (pyridoxine), and riboflavin deficiencies impair MTHFR function as these vitamins serve as essential cofactors 1, 7
Renal dysfunction: Decreased homocysteine clearance in chronic kidney disease contributes to hyperhomocysteinemia, with 85-100% prevalence in hemodialysis patients 1, 7
Medication effects: Drugs like methotrexate interfere with folate metabolism and can exacerbate MTHFR-related issues 1, 7
Management Implications
Plasma homocysteine measurement is more clinically informative than MTHFR genotyping alone, as the C677T mutation accounts for only one-third of hyperhomocysteinemia cases 6, 7
For individuals with the 677TT genotype, 5-methyltetrahydrofolate (5-MTHF) is preferred over folic acid because it bypasses the deficient enzyme and doesn't require conversion 1, 6
Supplementation with 5-MTHF (0.4-5 mg daily) reduces homocysteine by 25-30%, with additional vitamin B12 (0.02-1 mg daily) providing an extra 7% reduction 1, 6, 7
The combination of methylcobalamin (or hydroxycobalamin), vitamin B6 (50 mg daily), and riboflavin is recommended alongside 5-MTHF for optimal homocysteine management in MTHFR mutation carriers 1, 6
Key Clinical Pitfalls to Avoid
Never start folate supplementation without first ruling out vitamin B12 deficiency, as folate alone can mask hematologic manifestations of B12 deficiency while allowing irreversible neurological damage to progress 6, 7
Avoid using standard folic acid in patients with 677TT genotype when 5-MTHF is available, as the deficient enzyme cannot efficiently convert folic acid to its active form 1, 6
Do not use cyanocobalamin when methylcobalamin or hydroxycobalamin are available, as the latter forms are more effective for homocysteine reduction 1, 6
Recognize that MTHFR mutations create vulnerability to relative vitamin deficiencies that wouldn't affect individuals with normal enzyme function, requiring higher or more bioavailable forms of supplementation 6