What are the implications of the MTHFR (Methylenetetrahydrofolate Reductase) C677T mutation?

From the Guidelines

Individuals with the MTHFR C677T variant should consider taking methylfolate (L-methylfolate) supplements of 400-1000 mcg daily, along with adequate vitamins B6 (1.3-1.7 mg daily) and B12 (2.4 mcg daily), to support proper homocysteine metabolism and reduce the risk of stroke. The MTHFR C677T variant affects the body's ability to process folate and homocysteine, potentially leading to elevated homocysteine levels and increased risk of stroke 1. While routine testing or treatment is not recommended for asymptomatic individuals, those with specific symptoms or conditions like recurrent pregnancy loss or thrombosis may benefit from targeted interventions.

Key Considerations

• The MTHFR C677T variant reduces the efficiency of the MTHFR enzyme by approximately 30-40% in heterozygotes and up to 70% in homozygotes 1.
• Elevated homocysteine levels are associated with a 2- to 3-fold increased risk for atherosclerotic vascular disease, including stroke 1.
• Folic acid, vitamins B6 and B12, and methylfolate supplements can help lower homocysteine levels and support proper homocysteine metabolism 1.
• Recent studies suggest that using methylcobalamin and 5-methyltetrahydrofolate instead of cyanocobalamin and folic acid may be more efficacious in preventing stroke 1.

Recommendations

• Ensure adequate folate intake through diet or supplements (400-800 mcg daily) 1.
• Consider taking methylfolate (L-methylfolate) supplements (400-1000 mcg daily) instead of regular folic acid, especially for homozygous individuals 1.
• Maintain adequate levels of vitamins B6 (1.3-1.7 mg daily) and B12 (2.4 mcg daily) to support proper homocysteine metabolism 1.

From the FDA Drug Label

A significant proportion of the general population, however, has one or another polymorphisms in the methyltetrahydrofolate reductase (MTHFR) gene which catalyzes the rate limiting final conversion of 5,10-MTHF into the active 5-MTHF and, therefore, require 5-MTHF rather than folic acid. At least 90 polymorphisms have been found in the MTHFR gene locus. The most common and important of these, found in up to 20% of people in the U. S. and up to 50% of Europeans, is the C677T polymorphism which in its various forms greatly reduces enzyme activity or renders the enzyme inactive.

The MTHFR C677T polymorphism is a common genetic variation that affects the metabolism of folate. Individuals with this polymorphism have a reduced ability to convert folic acid into its active form, 5-MTHF. As a result, they may require supplementation with L-5-methyltetrahydrofolate instead of folic acid to meet their nutritional needs 2.

• The C677T polymorphism is found in up to 20% of people in the U.S. and up to 50% of Europeans.
• This polymorphism can reduce enzyme activity or render it inactive, leading to impaired folate metabolism.
• Supplementation with L-5-methyltetrahydrofolate may be necessary to overcome the effects of this polymorphism 2.

From the Research

MTHFR C677T Polymorphism

• The MTHFR C677T polymorphism is associated with various diseases, including vascular, cancers, neurology, diabetes, and psoriasis, with varying epidemiology depending on geography and ethnicity 3.
• The polymorphism results in a conversion of valine to alanine at codon 222, reducing the activity of the MTHFR enzyme, which is crucial for folate metabolism 3.
• Individuals with the TT genotype have higher homocysteine levels and lower serum folate levels compared to those with the CT or CC genotypes 4, 3.

Folate Status and Supplementation

• The MTHFR 677TT genotype is associated with higher plasma homocysteine and lower serum folate levels, which can be mitigated by adequate folate intake 4.
• Supplementation with folic acid can reduce plasma homocysteine levels, but individuals with the TT genotype may have a lower serum folate response to supplementation 4.
• Conversion of 5-formyltetrahydrofolic acid to 5-methyltetrahydrofolic acid is not impaired in individuals with the TT genotype, suggesting that folate metabolism is not entirely disrupted by the polymorphism 5.

Disease Associations and Risk Factors

• The MTHFR C677T polymorphism is associated with an increased risk of recurrent pregnancy losses, particularly in individuals with the TT genotype 6.
• Vitamin D insufficiency, hyperhomocysteinemia, and the MTHFR C677T polymorphism are risk factors for recurrent pregnancy losses, with a significant negative correlation between vitamin D and homocysteine levels in individuals with the TT genotype 6.
• The polymorphism is also associated with hyperhomocysteinemia in patients with Parkinson's disease, particularly those treated with levodopa, highlighting the importance of monitoring and supplementation with vitamins B6, B12, and folic acid 7.