Your patient received a direct-to-consumer genetic testing kit during the holidays. She took the test and learned that she has the methylenetetrahydrofolate reductase (MTHFR) 677 TT genotype (two copies of the MTHFR C677T variant). She is trying to become pregnant, so she looked online to learn more about what this means. The online search left her feeling anxious from the conflicting information about taking forms of folate other than folic acid to help prevent neural tube defects. She comes to your office for answers and guidance. What do you tell her?
Below, genetics experts from the Centers for Disease Control and Prevention (CDC) answer commonly asked questions about the MTHFR C677T variant and the use of folic acid to help prevent neural tube defects.
|Bottom line: Daily consumption of 400 μg of folic acid increases a woman's blood folate concentration to an adequate amount to help prevent a neural tube defect regardless of her MTHFR genotype (CC, CT, or TT). Folic acid is the only form of folate shown to help prevent neural tube defects. When taking supplements containing folic acid, more than 400 μg of folic acid each day is not necessarily better for preventing a neural tube defect. There are no clinical recommendations at this time to test for MTHFR status or for consuming a different amount of folate or folic acid on the basis of the MTHFR genotype.|
What is the MTHFR C677T variant?
The MTHFR gene provides instructions for the body to make the MTHFR enzyme, which helps the body process folate.
The most common variant in the MTHFR gene is MTHFR C677T. This variant may also be referred to as MTHFR 677 C>T or MTHFR 677 C→T. This means that at the 677 position in the MTHFR gene, "C" is the expected DNA base and "T" is the gene variant. The possible genotypes at the 677 position of the MTHFR gene are
MTHFR 677 CC (two copies of C, one copy from each parent);
MTHFR 677 CT (one copy of C from one parent, one copy of T from the other parent); or
MTHFR 677 TT (two copies of T, one copy from each parent).
The number of people who have each of these genotypes will vary by population. When consuming the same amount of folic acid, people with the MTHFR 677 TT genotype have an average amount of folate in their blood that is only slightly lower (about 16% lower) than in people with the MTHFR CC genotype. The MTHFR C677T variant is more common in some races and ethnicities than in others. For instance, Hispanic individuals are more likely than non-Hispanic whites and non-Hispanic blacks to have the variant.
No matter which genotype your patient has, you can assure her that folic acid is safe and essential for all women of reproductive age who could become pregnant.
Are there clinical recommendations to screen for the MTHFR C677T variant?
Routine screening for the MTHFR C677T variant is not recommended by The American College of Obstetricians and Gynecologists (ACOG) as a risk determinant of a neural tube defect.
Research has shown that neural tube defects are more common among people with the MTHFR 677 CT and TT genotypes, but these studies are generally conducted in countries without folic acid fortification. This means that women in these studies are not getting folic acid in their diets from fortified foods. The clinical recommendation of 400 μg of folic acid each day is sufficient to reduce the risk for neural tube defects for women who have any of the MTHFR genotypes.
If my patient has the MTHFR C677T variant, does she need to take a different form of folate?
Folate is a general term for many different forms of vitamin B9. Folate includes naturally occurring folates found in foods, such as leafy green vegetables, citrus fruits, and beans, and several types of folate in dietary supplements, such as folic acid and 5-methyltetrahydrofolate (5-MTHF).
Although it is important to eat a balanced diet rich in natural folate from food, it is very difficult to get the recommended amount of folate from food alone. This is because natural food folate is not stable to heat and light, in contrast with folic acid, which is stable. To get the recommended daily intake of folate equal to 400 μg of folic acid, your patients would have to eat 459 peanuts, 12.5 cups of raw green beans, or 14 small oranges, to name a few examples. Check out more examples in Table 2: Selected Food Sources of Folate and Folic Acid from the National Institutes of Health.
The types of folate other than folic acid found in vitamins or supplements (such as 5-MTHF) are different from the folate found in fruits and vegetables, even if the dietary supplement label claims it is "natural food folate." These forms of folate are manufactured and processed. Therefore, it is not the same as eating folate found naturally in food.
Studies to determine whether supplements containing other forms of folate (such as 5-MTHF) can prevent neural tube defects have yet to be done.
If my patient has the MTHFR C677T variant, does she need an amount of folic acid greater than 400 μg each day to help prevent a neural tube defect?
No. Getting 400 μg of folic acid each day helps prevent neural tube defects, even for women with the MTHFR C677T variant.
Consuming more than 400 μg of folic acid each day is not necessarily better for helping to prevent a neural tube defect, unless your patient has already had a pregnancy or baby affected by a neural tube defect.
If your patient has had a pregnancy or baby affected by a neural tube defect, the CDC recommends she consume 400 μg of folic acid each day, even if she is not planning to become pregnant. If she is planning to become pregnant, the CDC recommends she consume 4000 μg of folic acid each day, starting 1 month before becoming pregnant and continuing through the first 3 months of pregnancy.
A person's blood folate concentration depends on the amount of folic acid consumed daily and the length of time it is consumed. It can take several months to reach a blood folate concentration high enough to help prevent a neural tube defect. To ensure your patients have blood folate concentrations high enough to help prevent neural tube defects, they should start taking 400 μg of folic acid daily before becoming pregnant. Neural tube defects, such as anencephaly and spina bifida, occur within the first 3-4 weeks of pregnancy, often before a woman knows she is pregnant.
How do the MTHFR 677 CC, CT, and TT genotypes affect blood folate concentration?
The World Health Organization recommends a red blood cell (RBC) folate concentration threshold of 906 nmol/L at the population level. However, this threshold is not intended to be used to predict individual risk of having a pregnancy affected by a neural tube defect. Read the ACOG recommendation.
Research has shown that neural tube defects are more common in populations with the MTHFR 677 CT and TT genotypes, but these studies have generally been conducted in countries without folic acid fortification. For women in the United States, folic acid is available in some supplements and in fortified foods such as breads, breakfast cereals, pasta, and corn masa and wheat flours labeled "enriched."
Consider the following example, which compares two women and shows how the MTHFR genotype affects the RBC folate concentration.
Lia's MTHFR genotype is CC.
Adela's MTHFR genotype is TT (MTHFR gene variant).
If both women have the same low intake of folate,
Lia's RBC folate concentration is 650 nmol/L.
Adela's RBC folate concentration is 546 nmol/L.
Adela's RBC folate concentration is 16% lower than Lia's RBC folate concentration due to the average effect of the TT genotype compared with the CC genotype. The T allele is associated with lower RBC folate concentrations because it produces an MTHFR enzyme with a reduced capacity to process folate.
If Lia and Adela start taking a daily supplement containing the recommended 400 μg of folic acid, both women will increase their RBC folate concentrations by approximately 178% after 9 months.
Lia's RBC folate concentration will increase to about 1160 nmol/L.
Adela's RBC folate concentration will increase to about 970 nmol/L.
After 9 months, on the basis of this calculation, both women (regardless of their MTHFR genotypes) have RBC folate concentrations that can help prevent a neural tube defect.
NOTE: This example does not support individual testing for RBC folate concentration. The purpose of this example is to demonstrate that by consuming the recommended 400 μg of folic acid each day, women can increase their RBC folate concentrations to a level that can help prevent neural tube defects, no matter which MTHFR genotype they have.
Are there other MTHFR gene variants I should know about?
Another common gene variant is the MTHFR A1298C variant. This gene variant occurs at the 1298 position in the MTHFR gene. This means that at the 1298 position in the MTHFR gene, "A" is the expected DNA base and "C" is the gene variant. There is currently not enough evidence to show that the MTHFR A1298C variant alone significantly affects how the body processes folate.
It is important to know that there are other extremely rare MTHFR gene variants not discussed here that may have a significant effect on your patients' health.
Where can I find more information for my patients about the MTHFR C677T variant and folic acid?
Check out the CDC's new resource, MTHFR Gene and Folic Acid, and print the page for your patients.
If you have additional questions about the MTHFR C677T variant, please contact the CDC:
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
Public Information from the CDC and Medscape
Cite this: MTHFR and Birth Defects: Does Type of Folate Matter? - Medscape - Feb 24, 2020.