ABSTRACT
The most common form of genetic hyperhomocysteinemia results from the production of a thermolabile variant of methylenetetrahydrofolate reductase (MTHFR) with reduced enzymatic activity (T mutation) (29). The gene encoding for this variant contains an alanine-to-valine substitution at amino acid 677 (C677T) (30). The responsible gene is common, with a population frequency estimated between 5% and 14% (31,32). A MTHFR polymorphism at A1298C is less common. Homozygosity for the thermolabile variant of MTHFR (TT genotype) is a relatively common cause of mildly elevated plasma homocysteine levels in the general population, often occurring in association with low serum folate levels (33,34). Increased blood levels of homocysteine may reflect deficiency of folate, vitamin B6, and/or vitamin B12 (35-38). Plasma folate and B12 levels, in particular, are strong determinants of the homocysteine concentration. Homocysteine levels are inversely related to folate consumption, reaching a stable baseline level when folate intake exceeds 400mg/day (39,40). Vitamin B6 is a weaker determinant (40). Isolated MTHFR mutations are not associated with increased risk of VTE, and therefore, should not be categorized as thrombophilias (11,41).
