What diseases are connected to the MTHFR (methylenetetrahydrofolate reductase) gene?

MTHFR Gene Mutations and Associated Diseases

MTHFR gene mutations are associated with multiple diseases including cardiovascular disease, stroke, thrombotic events, neural tube defects, pregnancy complications, psychiatric disorders, and certain cancers due to their role in homocysteine metabolism and methylation pathways. 1

MTHFR Gene Function and Common Mutations

The methylenetetrahydrofolate reductase (MTHFR) gene encodes an enzyme that catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is essential for:

• Remethylation of homocysteine to methionine
• DNA methylation and gene regulation
• Folate metabolism

Two primary polymorphisms affect enzyme function:

• C677T (rs1801133) - most common, affects 10-15% of the general population 1
• A1298C (rs1801131) - second most common polymorphism 2

Disease Associations

Cardiovascular and Thrombotic Disorders

• Hyperhomocysteinemia: MTHFR mutations, particularly C677T homozygosity, reduce enzyme activity leading to elevated homocysteine levels 1
• Cardiovascular disease: Associated with increased risk, especially when homocysteine levels exceed 10 μmol/L 1
• Venous thromboembolism: Increased risk, particularly when combined with other thrombophilias like Factor V Leiden 3
• Stroke: The American Heart Association/American Stroke Association suggests B-complex vitamins might be considered for prevention of ischemic stroke in patients with hyperhomocysteinemia 1
• Myocardial infarction: Associated with increased risk, especially in young women 3

Pregnancy and Fetal Development Complications

• Neural tube defects: Increased risk due to impaired folate metabolism 2, 4
• Recurrent pregnancy loss: Associated with MTHFR polymorphisms 2, 4
• Pre-eclampsia and pregnancy complications: Higher risk in women with certain MTHFR variants 3, 2
• Preterm birth and low birth weight: Potential associations reported 2

Neurological and Psychiatric Disorders

• Autism Spectrum Disorder: Possible association with MTHFR variants 2
• Alzheimer's disease: Some evidence suggests a link 2
• Schizophrenia and Major Depressive Disorder: Associations reported in some studies 2

Metabolic and Other Disorders

• Chronic Kidney Disease: Elevated homocysteine levels are common in CKD patients, with 85-100% of hemodialysis patients affected 1
• Metabolic disorders: Including diabetes mellitus and non-alcoholic fatty liver disease 2
• Cancer: Associations with breast, prostate, ovarian cancers, and leukemia 2
• Autoimmune diseases: Particularly rheumatoid arthritis 2

Severity of Homocysteinemia and Clinical Implications

Homocysteine levels correlate with disease risk:

• Moderate hyperhomocysteinemia: 15-30 μmol/L
• Intermediate hyperhomocysteinemia: 30-100 μmol/L
• Severe hyperhomocysteinemia: >100 μmol/L 1

Genetic and Environmental Interactions

The clinical impact of MTHFR mutations depends on:

1. Genotype: Homozygosity for C677T (TT) has greater impact than heterozygosity (CT) 1
2. Compound heterozygosity: Having multiple MTHFR variants increases risk 3
3. Folate status: Adequate folate intake can compensate for reduced MTHFR activity 1
4. B vitamin levels: B12, B6, and riboflavin status affect homocysteine metabolism 1
5. Other genetic factors: Interactions with other genes in the folate/homocysteine pathway 3

Clinical Considerations

• MTHFR testing alone has limited clinical utility; measuring homocysteine levels provides more direct assessment of metabolic impact 3
• B vitamin supplementation (folate, B6, B12) can effectively lower homocysteine levels 1
• Despite lowering homocysteine levels, B vitamin supplementation has shown inconsistent results in reducing cardiovascular events in clinical trials 1

Important Caveats

1. The presence of MTHFR polymorphisms does not guarantee disease development
2. Environmental factors, especially folate intake, can significantly modify disease risk
3. MTHFR variants are extremely common in the general population (30-40% heterozygous, 10-15% homozygous for C677T) 3
4. Testing should be interpreted in the context of clinical presentation and family history

Understanding the complex relationship between MTHFR mutations and disease risk requires consideration of both genetic and environmental factors, with homocysteine levels serving as an important biomarker of metabolic impact.