MTHFR

Methylenetetrahydrofolate reductase (MTHFR) is a cytosolic enzyme that participates in folate metabolism. It catalyzes the conversion of 5,10-methylene-THF to 5-methyl-THF, the latter serving as the principal methyl donor for remethylation of homocysteine to methionine. This reaction links folate status to the methionine cycle and cellular methylation reactions.

The MTHFR gene encodes this enzyme and is widely expressed in human tissues. The most studied genetic variants are C677T (rs1801133) and A1298C (rs1801131). The C677T variant reduces enzyme activity, particularly in homozygotes (TT), and is sensitive to folate status; A1298C lowers activity by a different mechanism.

People may carry one or two copies of these variants, and some individuals harbor both variants on different alleles (compound heterozygosity). The effects on homocysteine levels are greatest with low folate intake and may vary by ethnicity and nutritional status.

Clinical relevance is debated. Elevated homocysteine has been associated with cardiovascular disease and adverse pregnancy outcomes in some studies, but MTHFR variants are not consistently proven to be independent risk factors. Genetic testing for MTHFR is not routinely recommended for risk assessment.

In rare cases, MTHFR deficiency due to severe variants causes homocystinuria in infancy, with developmental delay and vascular problems. Management includes high-dose B vitamins, folate, and sometimes betaine to lower homocysteine levels.

Overall, MTHFR is a key enzyme in folate and homocysteine metabolism. Common variants can influence enzyme activity but are not definitive determinants of disease; folate and B vitamin status largely modulate any associated risk.