5,10-Methylenetetrahydrofolate Reductase C677T and A1298C Mutations, Blood
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Hyperhomocysteinemia is an independent risk factor for coronary artery disease, acute myocardial infarction, 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, and folic acid) may impair the transsulfuration or remethylation pathways of homocysteine metabolism and cause hyperhomocysteinemia. The enzyme MTHFR catalyzes reduction of 5,10-methylene tetrahydrofolate to 5-methyl tetrahydrofolate, the major form of folate in plasma; 5-methyl tetrahydrofolate serves as a methyl donor for remethylation of homocysteine to methionine. Patients with severe MTHFR deficiency (enzymatic activity 0%-20% of normal) develop homocysteinuria, a severe disorder with a wide range of associated clinical manifestations, including developmental delay, mental retardation, and premature vascular disease. Seven unique MTHFR mutations have been associated with homocysteinuria, all among patients who were either homozygous or compound heterozygotes for 1 or more of these mutations.
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 677, encoding for an alanine-223 to valine substitution (MTHFR C677T). A second mutation in MTHFR exon 7, A1298C, results in a conversion of a glutamic acid codon to an alanine codon. The MTHFR A1298C mutation reduces MTHFR activity to a lesser extent than C677T, but compound heterozygous MTHFR A1298C/C677T may develop hyperhomocysteinemia.
For suspected hyperhomocysteinemia, we recommend that a basal plasma homocysteine level be measured. Vitamin B12, B6, and folic acid levels should be measured in patients with hyperhomocysteinemia.
Direct mutation analysis for the MTHFR C677T and/or A1298C mutations should be reserved for patients with coronary artery disease, acute myocardial infarction, peripheral vascular artery disease, stroke, or venous thromboembolism who have increased basal homocysteine levels or an abnormal methionine-load test.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
For Mayo Clinic patients, Cardiovascular, Vascular, Thrombophilia Center, Special Coagulation Clinic, and Medical Genetics consultations and counseling are available for questions regarding DNA diagnostic testing, test interpretation, and patient management, and may be especially helpful in complex cases.
Neither the MTHFR A1298C nor the C677T mutation test detects other causes of hyperhomocysteinemia, such as occur with other mutations within the MTHFR gene or the cystathionine beta-synthase gene. In addition, the MTHFR gene mutation may not be present when hyperhomocysteinemia is due to acquired disorders, such as deficiency of vitamins B12, B6, or folic acid; chronic renal failure; zinc deficiency; leukemia; psoriasis; or antifolate drug therapy.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Rees MM, Rodgers GM: Homocysteinemia: association of a metabolic disorder with vascular disease and thrombosis. Thromb Res 1993;71:337-359
2. Frosst P, Blom HF, Goyette P, et al: A candidate gene risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genet 1995;10:111-113
3. Ma J, Stampfer MJ, Hennekens CH, et al: Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infarction in US physician. Circulation 1996;94:2410-2416
4. Deloughery TG, Evans A, Sadeghi A, et al: Common mutation in methylenetetrahydrofolate reductase: correlation with homocysteine metabolism and late-onset vascular disease. Circulation 1996;94:3074-3078
5. Heit JA: Thrombophilia: clinical and laboratory assessment and management. In Consultative Hemostasis and Thrombosis. Fourth edition. Edited by CS Kitchens, BM Alving, CM Kessler. Saunders, 2012