Useful For

Methlyenetetrahydrofolate reductace (MTHFR) is a key enzyme in the metabolism of homocysteine. Mutations in the MTHFR gene have been reported as causes of hyperhomocysteinemia. The most common MTHFR mutation, C677T, is an autosomal recessive mutation that results in the production of thermolabile enzyme with decrease activity for methylating homocysteine. This mutation involves a single nucleotide substitution of thymidine for cytosine at nucleotide position 667 of the MTHFR gene. Carriers of this mutation are associated with elevated levels of homycyteine in plasma. The prevalence of the MTHFR C667T mutation in the general population is estimated to be 10-15%. Individuals homozygous (both alleles mutated) for the C677T mutation are predisposed to developing hyperhomocysteinemia, particularly when deficient in folate. The frequency of C667T homozygosity is increased in individuals with coronary artery disease (to 17%), arterial disease (to 19%), and venous thromboembolism (to 11%).

Another mutation in the MTHFR gene also associated with decreased MTHFR activity and hyperhomocysteinemia is A1298C. The frequency of the A1298C mutation is reported to be as high as 30% in the general Caucasian population. Heterozygosity or homozygosity for A1298C alone does not result in hyperhomocysteinemia. MTHFR mutations, when present with other genetic thrombophilic factors (e.g., factor V Leiden), dramatically increase risk for venous thrombosis.

Hyperhomocysteinemia is found in women who have experienced two or more early pregnancy losses, placental infarction and fetal growth retardation; however, MTHFR mutation as a cause of early pregnancy loss is still controversial. Homozygosity for C677T has been shown to have a 2-3 fold increased risk for neural tube defects (NTD) such as anencephaly and spina bifida, and compound heterzygosity for C677T and A1298C may also be a risk factor for NTDs.