What is the MTHFR Gene?
The MTHFR (Methylenetetrahydrofolate Reductase) gene encodes a critical enzyme that converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the active form of folate required for homocysteine remethylation to methionine. 1, 2
Gene Structure and Function
The MTHFR gene produces an enzyme with both catalytic and regulatory domains that serves as a key regulatory component in folate and homocysteine metabolism. 3, 4
The enzyme catalyzes the conversion of 5,10-methylenetetrahydrofolate (5,10-CH₂-THF) to 5-methyltetrahydrofolate (5-CH₃-THF), which acts as a methyl donor for converting homocysteine back to methionine. 1, 5
The human MTHFR gene has a complex structure with multiple transcript variants arising from alternative transcription initiation and alternative splicing, producing putative polypeptides of 657,698, and 680 amino acids. 4
Common Genetic Variants
The most clinically significant polymorphism is C677T (rs1801133), where cytosine is replaced by thymine at position 677, creating a thermolabile enzyme with reduced activity. 1, 2
The C677T variant occurs in heterozygous form (677CT) in 30-40% of the general population and in homozygous form (677TT) in 10-15% of individuals, making it the most common genetic cause of hyperhomocysteinemia. 2, 3
A second common polymorphism is A1298C (rs1801131), which also affects enzyme function but to a lesser degree than C677T. 1, 5
The 677TT homozygous genotype significantly reduces MTHFR enzyme activity and is associated with a 2-3 fold increased risk for atherosclerotic vascular disease and stroke when hyperhomocysteinemia is present. 1, 2
Rare Pathogenic Mutations
More than 50 rare but deleterious mutations in MTHFR have been identified that cause severe MTHFR deficiency, an autosomal recessive disorder resulting in homocystinuria, hypomethioninaemia, and progressive neurological symptoms. 3, 6
Severe MTHFR deficiency typically presents within the first two decades of life with multisystem involvement, predominantly affecting the central nervous system. 6, 7
Compound heterozygosity for the common C677T variant combined with a severe MTHFR mutation can lead to moderate hyperhomocysteinemia (72-186 μmol/L) with variable clinical presentations ranging from asymptomatic to neurological symptoms. 6
Clinical Significance in Disease
The MTHFR gene's role in folate metabolism means that polymorphisms disrupting enzyme activity lead to elevated homocysteine levels, which independently increase cardiovascular and thrombotic risk. 1, 8
Homozygosity for C677T increases risk for hyperhomocysteinemia, which is associated with increased carotid intima-media thickness, carotid artery stenosis, and a 59% increase in stroke risk for every 5 μmol/L increase in homocysteine. 1, 8
MTHFR variants have been implicated in neurocognitive outcomes, with ALL survivors carrying the A1298C variant showing a 7.4-fold increased risk of attention-deficit/hyperactivity disorder. 1
The gene's influence extends to multiple disease processes including cardiovascular disease, neural tube defects, pregnancy complications, metabolic disorders, and certain cancers, though the strength of association varies by condition and is influenced by environmental factors like dietary folate intake and ethnic background. 5
Interaction with Medications
Methotrexate inhibits dihydrofolate reductase and influences the MTHFR enzyme pathway, making individuals with MTHFR mutations potentially more susceptible to methotrexate-related side effects. 1
Patients on methotrexate, especially those with MTHFR mutations, should receive folate supplementation to reduce gastrointestinal side effects, protect against elevated liver function tests, and reduce likelihood of drug discontinuation. 2
Key Clinical Pitfall
Plasma homocysteine measurement is more informative than MTHFR genotyping alone, as homozygosity for MTHFR mutations accounts for only about one-third of hyperhomocysteinemia cases. 2, 8 Treatment decisions should be based on both homocysteine levels and MTHFR genotype rather than genetic testing in isolation, as multiple nutritional, renal, and lifestyle factors contribute to elevated homocysteine beyond genetic variants. 8