Hyperhomocysteinemia is an independent risk factor for coronary artery disease (CAD), acute myocardial infarction (MI), peripheral arterial disease, stroke, and venous thromboembolism.
Homocysteine is a sulfhydryl-containing amino acid formed as an intermediary during the conversion of methionine to cystathionine. Genetic or nutrition-related disturbances (eg, deficiency of vitamins B12, B6, or folic acid) may impair the transsulfuration or remethylation pathways of homocysteine metabolism and cause hyperhomocysteinemia.
The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyzes reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the major form of folate in plasma. 5-Methyltetrahydrofolate serves as a methyl donor for remethylation of homocysteine to methionine. Patients with severe MTHFR deficiency (enzymatic activity 0%-20% of normal) develop homocystinuria, a severe disorder with a wide range of associated clinical manifestations, including developmental delay, mental retardation, and premature vascular disease.
Several unique MTHFR gene mutations have been associated with homocystinuria, all among patients who were either homozygous or compound heterozygotes for 1 or more of these mutations.
MTHFR C677T, a milder deficiency of MTHFR, with approximately 50% residual enzyme activity and marked enzyme lability to heat inactivation, is associated with a cytosine to thymine mutation at nucleotide position C677->T, encoding for an alanine-223 to valine substitution. This mutation is quite common, with an allelic frequency of 31% to 39% (homozygote frequency =9%-17%) among the Caucasian North American population. Homozygosity for the mutant allele confers a markedly increased risk of hyperhomocysteinemia when vitamin deficiency is present, especially folic acid. Heterozygosity for the mutation appears to confer less risk for hyperhomocysteinemia and may not warrant intervention.
The weight of current evidence suggests that the MTHFR C677T mutation is not an independent risk factor for CAD in the absence of hyperhomocysteinemia; data is not available for the risk of venous thromboembolism conveyed by the MTHFR C677T mutation.
At this time, the utility of direct mutation analysis for the MTHFR C677T mutation in an asymptomatic family member with a normal basal homocysteine level is unknown.
Folic acid supplementation can reduce blood homocysteine levels to normal.
For patients with suspected hyperhomocysteinemia, we recommend measurement of basal plasma homocysteine levels (HCYSP/80379 Homocysteine, Total, Plasma). Vitamin B12, B6, and folic acid levels should be measured in patients with hyperhomocysteinemia.