Methylenetetrahydrofolate Reductase (MTHFR) Thermolabile Variant, DNA Analysis

Follow-up evaluation in individuals with hyperhomocysteinemia; evaluation of patients with venous thrombosis.

This assay detects only the C677T and A1298C mutations in the MTHFR gene. The diagnosis of hyperhomocysteinemia cannot rely on DNA testing alone but should take into consideration clinical findings and other studies, such as serum homocysteine levels. Prenatal testing is not available.

This test was developed, and its performance characteristics determined, by LabCorp. It has not been cleared or approved by the US Food and Drug Administration (FDA).

Hyperhomocysteinemia (high blood levels of homocysteine) is a risk factor for cerebrovascular disease, cerebral vein thrombosis, coronary artery disease, myocardial infarction, and venous thrombosis. The levels of homocysteine in the serum are influenced by both genetic and environmental factors. One of the genetic factors involves point mutations in the methylenetetrahydrofolate reductase (MTHFR) gene (OMIM 607093). Thermolabile variants of the MTHFR enzyme are mildly deficient at reducing 5,10-methylenetetrahydrofolate to 5-methylenetetrahydrofolate, a cofactor in the remethylation of homocysteine to methionine. The result is an elevation of serum homocysteine levels, especially in individuals with insufficient folate. One mutation, C677T, results in the MTHFR enzyme being 20% less efficient in metabolizing homocysteine, thus increasing serum levels, especially when plasma folate levels are at the lower end of normal. Five percent of Caucasians and 1.4% of African-Americans are C677T homozygotes, and are likely to have elevated serum homocysteine levels. A second mutation, A1298C, is also relatively common. Data suggests that combined heterozygosity for the two mutations may result in features similar to those of C677T homozygotes. Neither heterozygosity nor homozygosity for A1298C has been shown to be a risk factor for hyperhomocysteinemia. In patients with hyperhomocysteinemia, follow-up testing for the MTHFR mutation might be warranted to rule it out as a causative.

Hyperhomocysteinemia has been found in women who have experienced two or more early pregnancy losses, placental infarction, and fetal growth retardation, but MTHFR mutation as a cause for early pregnancy loss is still controversial. Homozygosity for C677T has been shown to have a two- to threefold increased risk for neural tube defects (NTDs), such as anencephaly and spina bifida, and compound heterozygosity for C677T and A1298C may also be a risk factor for NTDs. Dietary folic acid supplementation before the fourth week of gestation is well documented in reducing the recurrence risk for open neural tube defects by approximately 75%. It may act by normalizing homocysteine levels.

Thrombophilia investigations should include the most common genetic causes of thrombosis, the factor VLeiden mutation (R506Q), as well as the factor II/prothrombin mutation, G20210A. Beyond these, evaluation of plasma homocysteine levels, as well as testing for deficiencies of antithrombin III, protein C, and protein S may be indicated. Genetic counselors are available for health care providers to discuss results and for information on how to order additional testing, if desired, at 1-800-345-GENE.

Adams M, Smith PD, Martin D, Thompson JR, Lodwick D, Samani NJ. Genetic analysis of thermolabile methylenetetrahydrofolate reductase as a risk factor for myocardial infarction. QJ Med. 1996 Jun; 89(6):437-444. PubMed 8758047

Cattaneo M, Tsai MY, Bucciarelli P, et al. A common mutation in the methylenetetrahydrofolate reductase gene (C677T) increases the risk for deep-vein thrombosis in patients with mutant factor V (factor V:Q506).Arterioscler Thromb Vasc Biol. 1997 Sep; 17(9):1662-1666. PubMed 9327760

Eskes TK. Open or closed? A world of difference: a history of homocysteine research. Nutr Rev. 1998 Aug; 56(8):236-244. Erratum: 1998 Oct; 56(10):313. PubMed 9735677

Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995 May; 10(1):111-113. PubMed 7647779

Reich LM, Bower M, Key NS. Role of the geneticist in testing and counseling for inherited thrombophilia. Genet Med. 2003 May-Jun; 5(3):133-143. PubMed 12792420

Rozen R. Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase (MTHFR). Thromb Haemost. 1997 Jul; 78(1):523-526 (review). PubMed 9198208

Schneider JA, Rees DC, Liu YT, Clegg JB. Worldwide distribution of a common methylenetetrahydrofolate reductase mutation. Am J Hum Genet. 1998 May; 62(5):1258-1260. PubMed 9545406

van der Put NM, Gabreëls F, Stevens EM, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998 May; 62(5):1044-1051. PubMed 9545395