MTHFR

The methylenetetrahydrofolate reductase (MTHFR) mutation test is used to detect two relatively common mutations in the MTHFR gene that are associated with elevated levels of homocysteine in the blood. It is not routinely ordered.

This test is sometimes ordered as a followup to an elevated homocysteine test and may be occasionally ordered along with other cardiac risk tests if a person has a personal or family history of premature cardiovascular disease (CVD) or thrombosis. It may be ordered if a person has a close relative with known MTHFR genetic mutations. MTHFR C677T and A1298C gene mutations are the most common and the ones that are typically tested. If someone has a different mutation in their family, then that specific mutation should be tested.

An MTHFR test may sometimes be ordered along with other inherited clotting risk tests, such as Factor V Leiden or Prothrombin 20210 mutation tests to help evaluate a person's overall risk of developing inappropriate blood clots.

Though the MTHFR test may be used to help determine the cause of elevated homocysteine, the value of measuring homocysteine levels is not clear. While evidence from some studies suggests that elevated homocysteine levels contribute to the risk of CVD and/or thrombosis, a direct link has not been established. Routine testing for homocysteine levels as a cardiac risk marker is not yet recommended. Furthermore, use of homocysteine levels for the purpose of determining risk of CVD, peripheral vascular disease, and stroke is in doubt at this time given that several studies showed no benefit or lowering of risk in people who were treated with folic acid and vitamin B supplements that lowered their homocysteine level.

The MTHFR test may sometimes be ordered when a person has elevated homocysteine levels, especially when they have a personal or family history of premature CVD or thrombosis. It may sometimes be ordered when a close relative has MTHFR gene mutations.

Only a small percentage of cases of elevated homocysteine are due to an inherited cause. Of these, MTHFR C677T and A1298C mutations are among the most common.

If a person has two copies (homozygous) of MTHFR C677T, or has one copy of C677T and one of A1298C, then it is likely that elevated homocysteine levels are due to these inherited mutations, or that the mutations are contributing to them.

Two copies of A1298C are not typically associated with increased homocysteine levels.

If the MTHFR test is negative, then the C677T and A1298C mutations were not detected and the tested person's elevated homocysteine level is likely due to another cause. Other, more rare MTHFR genetic mutations will not be detected with typical testing.

Those with MTHFR mutations and other clotting risk factors, such as Factor V Leiden or PT 20210 mutations, may be at an increased risk of thrombosis.

People who have elevated homocysteine levels may be at an increased risk of developing premature CVD and/or thrombosis, but many, including those with MTHFR mutations, will never develop CVD or thrombosis. The role of homocysteine in cardiac risk assessment is still in the process of being determined.

Besides MTHFR mutations, there are other causes of elevated homocysteine levels, including deficiency of vitamins B6, B12, and/or folate; these vitamins are required for homocysteine metabolism.

For MTHFR mutations, the C677T variant results in substitution of the amino acid alanine for valine. The A1298C variant results in an alanine substitution (versus a gultamine). The C677T valine substitution results in a less active form of the MTHFR enzyme.

Some studies have shown links between MTHFR genetic mutations and an increased risk of neural tube defects, pre-eclampsia, and certain cancers, but the test is not used clinically with these conditions.

The MTHFR enzyme is involved in folate metabolism. Because of this, those who have MTHFR mutations and take drugs that affect folate metabolism, such as methotrexate, may be more likely to experience toxicity. An MTHFR test may be performed on a person who is prescribed methotrexate in order to adjust dosages and reduce risk of toxicity.

MTHFR mutations are a rare cause of homocystinuria, a condition caused by a defective enzyme that disrupts methionine metabolism, leads to greatly increased amounts of homocysteine in the blood and urine, and causes a variety of complications. The most common cause of this condition is a deficiency in the cystathionine B-synthase (CBS) enzyme. The MTHFR mutations that cause homocystinuria are typically not detected by this test.