What is the MTHFR (Methylenetetrahydrofolate Reductase) gene?

Understanding the MTHFR Gene

The MTHFR (Methylenetetrahydrofolate Reductase) gene encodes an enzyme that catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is essential for homocysteine metabolism and plays a central role in the folate cycle.

Function and Biochemistry

The MTHFR enzyme plays a critical role in several metabolic pathways:

• Catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate 1
• Generates the active form of folate required for remethylation of homocysteine to methionine 1
• Contributes to DNA and RNA synthesis through one-carbon metabolism 2
• Involved in amino acid metabolism 1

Common Polymorphisms

Two major polymorphisms have been identified in the MTHFR gene:

1. C677T (rs1801133):

   • Results in an alanine-to-valine substitution at codon 222 3
   • Creates a thermolabile enzyme with reduced activity 4
   • Homozygous mutation (TT genotype) reduces enzyme activity by approximately 70% 5
   • Heterozygous mutation (CT genotype) reduces enzyme activity by approximately 35% 5

2. A1298C (rs1801131):

   • Less studied but also affects enzyme function 6
   • Often occurs in combination with C677T polymorphism 4

Clinical Implications

MTHFR polymorphisms have been associated with various clinical conditions:

Cardiovascular Disease

• Reduced MTHFR activity can lead to elevated homocysteine levels, an independent risk factor for cardiovascular disease 2
• Individuals with the TT genotype and lower folate levels have approximately 24% higher homocysteine levels than those with the normal genotype 5

Pregnancy and Birth Defects

• Women with recurrent pregnancy loss and MTHFR mutations may benefit from supplementation with methylfolate, vitamin B6, and vitamin B12 2
• Associated with increased risk of neural tube defects 6

Neurological and Psychiatric Disorders

• Potential associations with autism spectrum disorder, Alzheimer's disease, schizophrenia, and major depressive disorder 6

Metabolic and Oncological Conditions

• Possible links to diabetes mellitus, inflammatory bowel disease, and various cancers 6

Interaction with Folate Status

The relationship between MTHFR polymorphisms and disease risk is often modulated by folate status:

• Individuals with the TT genotype and low folate levels (<15.4 nmol/L) show significantly higher homocysteine levels 5
• Adequate folate intake can compensate for reduced enzyme activity in individuals with MTHFR polymorphisms 5
• Different MTHFR genotypes may require different supplementation approaches 2

Management Considerations

For individuals with MTHFR polymorphisms and elevated homocysteine levels:

• 5-methyltetrahydrofolate is preferred over folic acid, especially in those with MTHFR mutations 2
• Vitamin B6 (50mg daily) acts as a cofactor for homocysteine metabolism 2
• Methylcobalamin (vitamin B12) at 0.5-1 mg daily is recommended over cyanocobalamin 2
• Homocysteine levels should be rechecked after 2-3 months of supplementation 2

Geographic and Ethnic Variations

The prevalence of MTHFR polymorphisms varies significantly:

• Distribution of the C677T polymorphism varies by geography and ethnicity 3
• Environmental factors, including dietary folate intake, influence the clinical expression of these polymorphisms 6

The clinical significance of MTHFR polymorphisms continues to be an active area of research, with emerging evidence suggesting their role in a wide range of medical conditions beyond cardiovascular disease.