MTHFR Gene, Folic Acid, and Preventing Neural Tube Defects

What is the MTHFR gene?

The MTHFR gene provides instructions for your body to make the MTHFR protein, which helps your body process folate. Your body needs folate to make DNA and modify proteins.¹

A gene variant is a change in a DNA sequence that is different from the expected DNA sequence. The most common variant in the MTHFR gene is MTHFR C677T.² This variant may also be referred to as MTHFR 677 C>T or MTHFR 677 C→T. This means at the 677 position in the MTHFR gene, “C” is the expected DNA base and “T” is the gene variant.³

Each person has two copies of the MTHFR gene: one from his or her mother and one from his or her father. These are the possible genotypes* of the MTHFR gene (see illustration):

• 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).

*A genotype is the combination of the set of genes responsible for a particular trait.

The number of people who have each of these genotypes will vary from population to population. When consuming the same amount of folic acid, people with the MTHFR 677 TT genotype have an average blood folate concentration (amount of folate in their blood) that is only slightly lower (about 16% lower) than people with the MTHFR 677 CC genotype.⁴

Another common gene variant is the MTHFR A1298C variant. This gene variant occurs at the 1298 position in the MTHFR gene. This means at the 1298 position in the MTHFR gene, the expected DNA base “A”, is replaced by “C”, the gene variant.⁵ There is 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. These gene variants may have significant effects on your health. Talk to your doctor or a genetic counselor if you have concerns about what having one of these extremely rare MTHFR gene variants means for your health care.

5 things to know about the MTHFR C677T variant and folic acid

1. People with MTHFR C677T variants can process all types of folate, including folic acid.

Folate is a general term for many different types of vitamin B9. Folate includes naturally occurring folates 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). The MTHFR C677T variant affects how your body processes folate. You might have read or heard that folic acid is not safe if you have one or two copies of the MTHFR C677T variant. This is not true. Even if you have one or two copies of the MTHFR C677T variant, your body can safely and effectively process all different types of folate, including folic acid.

Read more about folate vs folic acid>>

General Information About NTDs, Folic Acid, and Folate>>

2. Folic acid is the only type of folate shown to help prevent neural tube defects.^{1, 3, 4, 6, 10}

Learn More about Folic Acid

Folic acid helps prevent some birth defects.

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You may have heard or read that if you have an MTHFR C677T variant, you should take other types of folate (such as 5-MTHF), but this is not true. Folic acid is the only type of folate shown to help prevent neural tube defects (severe birth defects of the brain or spine).^1-4,6

No scientific studies exist that show that supplements containing other types of folate (such as 5-MTHF) can help prevent neural tube defects.

Folic acid is the common type of folate found in many vitamins and supplements. The other types of folate found in some vitamins or supplements (such as 5-MTHF) are different from the folate found in fruits and vegetables, even if the nutrition label claims it is “natural food folate.” These types of folate, just like folic acid, are not made from food but are man-made. You can find natural food folates in vegetables (especially dark green leafy vegetables), fruits and fruit juices, nuts, beans, peas, seafood, eggs, dairy products, meat, poultry, and grains. Spinach, liver, asparagus, and brussels sprouts are among the foods with the highest amounts of folate per serving.

You should eat a balanced diet rich in natural folate from food, but it is very difficult to get the recommended amount of folate from food alone.

• See the National Institute of Health’s Table 2: Selected Food Sources of Folate and Folic Acid for the amount of micrograms of folate and folic acid available per serving in specific foods.

3. MTHFR gene variants are common.

Gene variants are common and normal. In fact, there are more people in the United States who have one or two copies of the MTHFR C677T variant than people who do not have it.⁷ Variants in genes are what make us unique. They cause differences, such as eye color, hair color, and blood type.

You may have seen the MTHFR C677T variant referred to as a “gene mutation;” however, the word, “mutation,” usually refers to a change in the gene that is much less common. It is more accurate to refer to MTHFR C677T as a “gene variant.”

The MTHFR C677T variant is more common in some races and ethnicities than in others. Hispanic individuals are more likely than non-Hispanic whites and non-Hispanic blacks to have the MTHFR C677T variant.⁷

Learn more about genetics>>

4. CDC urges all women of reproductive age who could become pregnant to consume 400 micrograms (mcg) of folic acid each day, including those with an MTHFR C677T variant.

The two most important factors that determine whether you have enough folate in your blood to help prevent a neural tube defect are

1. The amount of folic acid you consume each day from fortified foods and vitamins/supplements containing folic acid.
2. The length of time folic acid is consumed before becoming pregnant.²

Consuming 400 mcg of folic acid each day helps prevent neural tube defects, even if you have an MTHFR C677T variant. Taking a supplement with more than 400 mcg of folic acid each day is not necessarily better for preventing a neural tube defect. However, a doctor might recommend taking more than 400 mcg if you have other health conditions, or you have already had a baby with a neural tube defect.

Learn more about how consuming enough folate helps prevent neural tube defects>>

5. Sometimes a woman may still have a baby with a neural tube defect despite having consumed the recommended 400 micrograms (mcg) of folic acid.

Studies have shown that women who consume 400 mcg of folic acid each day generally has enough folate in their blood to help prevent neural tube defects, regardless of their MTHFR C677T genotype (CC, CT, or TT). This means your folic acid intake is more important than your MTHFR genotype for determining the amount of folate in your blood.^{3, 4, 9 10} Although consuming 400 mcg of folic acid each day can prevent the majority of neural tube defects, some neural tube defects have other causes unrelated to folic acid intake (for example, chromosomal abnormalities or medical conditions, such as diabetes). Some causes of neural tube defects are not known. Therefore, CDC is dedicated to learning more about the causes of neural tube defects.

If you have had a pregnancy affected by a neural tube defect, CDC recommends that you consume 400 mcg of folic acid each day, even when not planning to become pregnant. If you are planning to become pregnant, CDC recommends consuming 4,000 mcg of folic acid each day, starting 1 month before becoming pregnant and continuing through the first 3 months of pregnancy.

If you have had a baby with a neural tube defect, talk with your doctor or a genetic counselor about the chance of having another pregnancy affected by a neural tube defect and the specific prevention steps that you can take.

Learn more about CDC’s folic acid recommendations>>

Learn more about preventing birth defects>>

Learn more about genetic testing and counseling>>

References

1. 1. Crider KS, Yang TP, Berry RJ, Bailey LB. Folate and DNA methylation: A review of molecular mechanisms and the evidence for folate’s role. Adv Nutr. 2012;3(1):21-38.
   2. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 236250: 12/11/2014: https://omim.org/entry/236250#genotypePhenotypeCorrelations
   3. Wilcken B, Bamforth F, Li Z, et al. Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): Findings from over 7000 newborns from 16 areas world wide. J Med Genet. 2003;40(8):619-625.
   4. Tsang BL, Devine OJ, Cordero AM, et al. Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies. Am J Clin Nutr. 2015;101(6):1286-1294.
   5. van der Put NMJ, Gabreëls F, Stevens EMB, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: An additional risk factor for neural tube defects? Am J Hum Genet. 1998;62(5):1044-1051.
   6. Seyoum E, Selhub J. Properties of food folates determined by stability and susceptibility to intestinal pteroylpolyglutamate hydrolase action. J Nutr. 1998;128(11):1956-1960.
   7. Yang Q, Bailey L, Clarke R, et al. Prospective study of methylenetetrahydrofolate reductase (MTHFR) variant C677T and risk of all-cause and cardiovascular disease mortality among 6000 US adults. Am J Clin Nutr. 2012;95(5):1245-1253.
   8. Williams J, Mai CT, Mulinare J, et al. Updated estimates of neural tube defects prevented by mandatory folic acid fortification – United States, 1995-2011. MMWR Morb Mortal Wkly Rep. 2015;64(1):1-5.
   9. Crider KS, Zhu JH, Hao L, et al. MTHFR 677C->T genotype is associated with folate and homocysteine concentrations in a large, population-based, double-blind trial of folic acid supplementation. Am J Clin Nutr. 2011;93(6):1365-1372.
   10. Crider KS, Devine O, Hao L, et al. Population red blood cell folate concentrations for prevention of neural tube defects: Bayesian model. BMJ. 2014;349:g4554.