A blood sample drawn from a vein
When there are mutations or variations in the MTHFR gene, it can lead to serious genetic disorders such as homocystinuria, anencephaly, spina bifida, and others. The MTHFR enzyme is critical for metabolizing one form of B vitamin, folate, into another. It is also part of the process that converts homocysteine into methionine, an important building block for many proteins.
If someone has increased levels of homocysteine, that means the body is not processing it properly. One cause of that could be a mutation in the MTHFR gene, causing homocystinuria. While at least seven unique MTHFR mutations have been found in people with homocystnuria, there are two relatively common DNA sequence variants, known as single nucleotide polymorphisms (SNPs), that are tested. The two MTHFR variants are called C677T and A1298C, and individuals can inherit one or both variants. These SNPs result in changes in the DNA (or mutations) that are associated with decreased MTHFR activity and increased homocysteine levels in the blood, which may increase the risk of premature cardiovascular disease (CVD), formation of inappropriate blood clots (thrombosis), and stroke.
Approximately 5-14% of the U.S. population is homozygous for C677T, meaning that they have two copies of it. There is some ethnic variability in the frequency, with the highest being in those of Mediterranean ancestry and the lowest in those of African ancestry.
The C677T variant results in a less active form of the MTHFR enzyme and reduced ability to process folate and homocysteine. When a person has two copies of the MTHFR C677T gene mutation (homozygous) or one copy of MTHFR C677T and one copy of A1298C (compound heterozygous), decreased MTHFR enzyme activity slows down the homocysteine-to-methionine conversion process and can lead to a buildup of homocysteine in the blood.
The increase in homocysteine is often mild to moderate but will vary from person to person depending upon the amount of MTHFR enzyme activity. Even if a person has two copies of the MTHFR mutation, that person may not develop high homocysteine levels since adequate folate intake can "cancel out" the effect of the MTHFR mutation.
Results of some studies suggest that high levels of homocysteine in the blood may contribute to risk of CVD by damaging blood vessel walls and promoting formation of plaque (atherosclerosis) and inappropriate blood clots. However, a direct link between homocysteine levels and cardiovascular disease or thrombotic risk has not been found. For more on this, see the article on Homocysteine.
How is it used?
The methylenetetrahydrofolate reductase (MTHFR) mutation test may be 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 follow-up 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 inappropriate blood clots (thrombosis). However, its utility for assessing risk of CVD has not been established and some expert guidelines do not recommend it for thrombosis screening.
It may be ordered if a person has a close relative with known MTHFR genetic mutations, particularly if that person also has elevated homocysteine levels. 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.
Although the MTHFR mutation 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 recommended by the American Heart Association. The College of American Pathologists and the American College of Medical Genetics recommend against testing for the C677T variant, citing limited utility for patients with blood clots. 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 show no benefit or risk reduction in people who were treated with folic acid and vitamin B supplements that lowered their homocysteine level.
When is it ordered?
The MTHFR mutation test may sometimes be ordered when a person has elevated homocysteine levels, especially when the person has a personal or family history of premature cardiovascular disease or thrombosis. It may sometimes be ordered when a close relative has MTHFR gene mutations, although it may not be useful if that relative has normal homocysteine levels, and some laboratories and organizations recommend against using it for thrombophilia screening.
If a person is suspected to have high homocysteine levels, it is recommended to test for homocysteine level rather than MTHFR mutation. In a significant number of cases of homocysteinemia (increase in blood homocysteine level), the MTHFR mutation test is unnecessary.
What does the test result mean?
Results typically are reported as negative or positive and, if positive, the report will name the mutation(s) present. Often, an interpretation of the results is also provided.
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 mutation 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. Research suggests that women with two C677T variants have double the risk of having a child with a neural tube defect, but the risk is far below 1%.
Is there anything else I should know?
People who have elevated homocysteine levels may be at an increased risk of developing premature cardiovascular disease (CVD) and/or thrombosis, but many, including those with MTHFR mutations, will never develop CVD or thrombosis. A review of data published in 2012 determined that lifelong moderately elevated homocysteine levels had little to no effect on coronary heart disease.
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. The MTHFR mutation may not be present with these acquired, as opposed to inherited, causes of elevated homcysteine. Additionally, if a more rare mutation of MTHFR is causing elevated homocysteine levels, the C677T and A1298C tests will not detect those other mutations.
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 glutamine). The C677T valine substitution results in a less active form of the MTHFR enzyme.
A review of studies published in 2014 supported an association between the MTHFR C677T allele and congenital heart disease in Asian populations and the A1298C allele and CHD in the pediatric Caucasian population.
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 mutation test may be performed for a person who is prescribed methotrexate in order to adjust dosages and reduce risk of toxicity.
Who performs MTHFR testing?
Can my MTHFR genes change?
If I have the same MTHFR gene mutations as a relative, why is my homocysteine level significantly different?