Mudd et al 1st identified a patient with homocystinuria due to a severe deficiency of the MTHFR enzyme. This type of deficiency is relatively rare. In 1988, a thermolabile variant of MTHFR enzyme was identified in patients with cardiovascular disease. With the identification of a MTHFR polymorphism (i.e., a common mutation) that results in mild hyperhomocysteinemia, it became clear that some diseases of adulthood, such as CVD, reflect milder versions of the fulminant biochemical defect present in the newborn or child with severe MTHFR deficiency. This milder deficiency, which appeared to be more common, resulted in a mild to moderate elevation of plasma total homocysteine, an emerging risk factor for cardiovascular disease.
The 2 most common polymorphic variants that affect enzyme activity are the C677T & the A1298C variants. Because there are 2 copies of each gene, an individual can be homozygous for the C677T variant. This can cause hyperhomocysteinemia if the individual also has a low plasma folate. Individuals who are heterozygous for C677T have one copy of the C677T variant and one "wild type" or normal copy. These C677T heterozygous individuals do not demonstrate elevated homocysteine. C677T homozygous variant enzyme is thermolabile and demonstrates 70% reduced enzyme activity in vitro. The heterozygous C677T MTHFR enzyme has 35% reduced activity in vitro. It is estimated that 32% of Mexicans, 10-15% of North American Caucasians, and 6% of people of African descent are C677T homozygous.
An Italian study investigating forms of folate (dietary, 5-MTHF, and folic acid) & effect on total plasma homocysteine levels found that all 3 experimental groups had lowered plasma homocysteine levels compared to the controls. The study showed that a folic acid-enriched food diet (400 µg/day), supplemental folate in the form of 5-MTHF (200 µg/day), and folic acid (200 µg/day) are comparable in reducing total homocysteine levels irrespective of MTHFR genotype status.
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