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.

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. This variant may also be referred to as MTHFR 677 C>T orMTHFR 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.

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 amount of folate in their blood that is only slightly lower (about 16% lower) than people with the MTHFR 677 CC genotype.

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, “A” is the expected DNA base and “C” is the gene variant. There is not enough evidence 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.

Normal Function

The MTHFR gene provides instructions for making an enzyme called methylenetetrahydrofolate reductase. This enzyme plays a role in processing amino acids, the building blocks of proteins. Methylenetetrahydrofolate reductase is important for a chemical reaction involving the vitamin folate (also called vitamin B9). Specifically, this enzyme converts a form of folate called 5,10-methylenetetrahydrofolate to a different form of folate called 5-methyltetrahydrofolate. This is the primary form of folate found in blood, and is necessary for the multistep process that converts the amino acid homocysteine to another amino acid, methionine. The body uses methionine to make proteins and other important compounds.

Health Conditions Related to Genetic Changes

Homocystinuria

At least 40 mutations in the MTHFR gene have been identified in people with homocystinuria, a disorder in which the body is unable to process homocysteine and methionine properly. People with this condition often develop eye problems, abnormal blood clotting, skeletal abnormalities, and learning problems. Most of the mutations that cause homocystinuria change single amino acids in methylenetetrahydrofolate reductase. These changes impair the function of the enzyme, and some cause the enzyme to be turned off (inactivated). Other mutations lead to the production of an abnormally small, nonfunctional version of the enzyme. Without functional methylenetetrahydrofolate reductase, homocysteine cannot be converted to methionine. As a result, homocysteine builds up in the bloodstream, and the amount of methionine is reduced. Some of the excess homocysteine is excreted in urine (homocystinuria). Researchers have not determined how altered levels of homocysteine and methionine lead to the various health problems affecting multiple parts of the body in people with homocystinuria.

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Anencephaly

Some studies have found that variations (polymorphisms) in the MTHFR gene have been associated with a small increased risk of neural tube defects, a group of birth defects that occur during the development of the brain and spinal cord. Anencephaly is one of the most common types of neural tube defect. Affected individuals are missing large parts of the brain and have missing or incompletely formed skull bones.

The most well-studied MTHFR polymorphism changes a single DNA building block (nucleotide) in the MTHFR gene. Specifically, it replaces the nucleotide cytosine with the nucleotide thymine at position 677 (written as 677C>T). This common variant results in a form of methylenetetrahydrofolate reductase that has reduced activity at higher temperatures (the enzyme is thermolabile). People with the 677C>T polymorphism, particularly those with the genetic change in both copies of the gene, have elevated levels of homocysteine in their blood (hyperhomocysteinemia) resulting from the reduced activity of methylenetetrahydrofolate reductase.

Researchers have studied MTHFR gene polymorphisms and hyperhomocysteinemia in individuals with neural tube defects and in their mothers, but it remains unclear how these variations affect the developing brain and spinal cord. The association with neural tube defects may be related to differences in the ability of methylenetetrahydrofolate reductase to process folate. While a shortage (deficiency) of this vitamin is an established risk factor for neural tube defects, there are many factors that can contribute to folate deficiency.

MTHFR gene polymorphisms are common worldwide, with an estimated 25 percent of Hispanics and 10 to 15 percent of North American whites having the 677C>T polymorphism in both copies of the gene. Most people with MTHFR gene polymorphisms do not have neural tube defects, and their children are also typically unaffected.

Spina bifida

Some studies have found that polymorphisms in the MTHFR gene are also associated with a small increased risk of spina bifida, another common type of neural tube defect. When the spine forms in people with this condition, the bones of the spinal column do not close completely around the developing nerves of the spinal cord. As a result, part of the spinal cord may stick out through an opening in the spine, leading to permanent nerve damage.

As described above, variations in the MTHFR gene generally result in hyperhomocysteinemia due to reduce activity of methylenetetrahydrofolate reductase and its ability to process folate. It is unclear how MTHFR gene changes might influence the development of neural tube defects. However, these variations are common in many populations worldwide. Most people with MTHFR gene polymorphisms do not have neural tube defects, nor do their children.

Other disorders

Polymorphisms in the MTHFR gene can alter or decrease the activity of methylenetetrahydrofolate reductase, leading to a mild increase of homocysteine in the blood (hyperhomocysteinemia). The two MTHFR gene polymorphisms that are the most common and the most frequently studied are 677C>T and a change that replaces the nucleotide adenosine with the nucleotide cytosine at position 1298 (written as 1298A>C).

An increase in homocysteine levels caused by MTHFR gene polymorphisms have been studied as possible risk factors for a variety of common conditions. These include high blood pressure (hypertension), blood clots, pregnancy loss, psychiatric disorders, and certain types of cancer. Research indicates that individuals who have the 677C>T polymorphism on both copies of the MTHFR gene have an increased risk of developing vascular disease, including heart disease and stroke. The 677C>T polymorphism has also been suggested as a risk factor for cleft lip and palate, a birth defect in which there is a split in the upper lip and an opening in the roof of the mouth.

Studies of MTHFR gene variations in people with these disorders have had mixed results, with associations found in some studies but not in others. Therefore, the role that changes in the MTHFR gene play in these disorders remains unclear. It is likely that additional factors influence the processing of homocysteine and that variations in homocysteine levels play a role in whether a person develops any of these conditions. A large number of genetic and environmental factors, most of which remain unknown, likely determine the risk of developing most common complex conditions.

Other Names for This Gene

• 5,10-methylenetetrahydrofolate reductase
• 5,10-methylenetetrahydrofolate reductase (NADPH)
• methylenetetrahydrofolate reductase (NAD(P)H)
• MTHR_HUMAN

Genomic Location

People with common MTHFR variants can have normal or elevated levels of homocysteine in their blood or urine. MTHFR variants and elevated homocysteine levels have been studied as risk factors for a number of health conditions.

When thinking about risk factors it is important to not only think about if the variants put you at risk for a condition, but if so, how much risk. You will find many studies on MTHFR and health risks. For most of these, evidence is lacking regarding an association.

One condition that is widely recognized to be associated with the common MTHFR variants is neural tube defects. Studies suggest that women with two C677T gene variants are twice as likely to have a child with a neural tube defect. However, because neural tube defects are rare, their actual risk is still far less than 1% (0.14%).

Risks associated with having one C677T and one A1298C is the same, or possibly slightly lower than, that of having two C677T gene changes.

For the vast majority of people the overall risk associated with the common MTHFR variants is small. So small, that having them does not change treatment. This is why testing for the variants is not recommended, unless a person has very high homocysteine levels. It is important to keep in mind that neural tube defects have many other risk factors.

Very high homocysteine levels rarely result from having the common variants alone. People with very high homocysteine levels should be carefully evaluated for other factors known to affect homocysteine, such as:

• Low thyroid hormones (hypothyroidism)
• Chronic conditions (obesity, diabetes, high cholesterol, physical inactivity, high blood pressure)
• Medications (atorvastatin, fenofibrate, methotrexate, andnicotinic acid)
• Smoking
• Advanced age

High homocysteine levels can also result from dietary deficiencies of folate, vitamin B6, and vitamin B12. It is very important to diagnose vitamin B12 deficiencies, as high dose folic acid supplements can mask B12 deficiencies, and put people at risk for serious and irreversible symptoms. Learn more about B12 deficiency.

If high levels of homocysteine can not be explained by factors such as those listed above, a consultation with a genetics professional may be helpful in identifying rare genetic causes of the high homocysteine.

Because each person has two copies of the MTHFR gene, people can inherit one copy of a MTHFR gene variant or two copies of it (one from each parent). People who inherit two copies of C677T have a higher riskfor having a child with a neural tube defect.

Risks associated with having one C677T and one A1298C is the same, or possibly slightly lower than, that of having two C677T gene changes.

Rare MTHFR gene variants can lead to homocystinuria, which is inherited in an autosomal recessive manner.

Having MTHFR gene variants alone does not impact treatment. If a person has high homocysteine levels they should be carefully evaluated to identify all causes. Very high homocysteine levels rarely result from having the common variants alone. People with very high homocysteine levels should be carefully evaluated for other factors known to affect homocysteine, such as:

• Low thyroid hormones (hypothyroidism)
• Chronic conditions (obesity, diabetes, high cholesterol, physical inactivity, high blood pressure)
• Medications (atorvastatin, fenofibrate, methotrexate, andnicotinic acid)
• Dietary deficiencies (folate, vitamin B6, vitamin B12)
• Smoking
• Advanced age

Treatments and life-style changes are given based upon the patient's circumstances. As mentioned above, homocysteine levels can rise in people with and without MTHFR gene variants if they lack folate, choline, or B vitamins (B12, B6, and riboflavin). It is very important to diagnose vitamin B12 deficiencies, as high dose folic acid supplements can mask B12 deficiencies, and put people at risk for serious and irreversible symptoms. People with concerns about their nutrition should speak with a healthcare professional. Supplements may be recommended if the person is found to have a nutritional deficiency.

Current clinical guidelines do not recommend changes in prenatal care or prenatal vitamins based upon MTHFR gene variant status alone. Women of childbearing age should take the standard dose of folate supplementation to reduce the risk of neural tube defects. Women with a previous child with a neural tube defect or a family history of neural tube defect should talk to their doctors about requirements for extra folate supplementation.

We recommend you speak with a trusted healthcare professional before taking any supplement.

If you are pregnant or could become pregnant, the amount of folate in your blood is important to help prevent a neural tube defect (a serious birth defect of the brain or spine) in a developing baby. You can increase the amount of folate in your blood to help prevent a neural tube defect by consuming folic acid in addition to food with folate from a varied diet. Folic acid can be found in some vitamins and in fortified foods labeled as “enriched.”

The amount of folate in your blood depends on how much folic acid you consume each day and the number of days that you consume folic acid. To make sure you have enough folate in your blood to help prevent a neural tube defect

• Get the recommended 400 micrograms (mcg) of folic acid each day.
  • It can take several months to reach an amount of folate in your blood to help prevent neural tube defects.
  • You can get folic acid by taking a vitamin with folic acid in it, eating fortified foods, or a combination of the two.
  • You don’t need to consume more than 400 mcg of folic acid each day unless you have already had a baby or pregnancy affected by a neural tube defect.

How the MTHFR gene variant affects the amount of folate in your blood

In addition to the amount of folic acid consumed and the length of time it is consumed, your MTHFR genotype affects the amount of folate in your blood. The MTHFR protein affects how your body processes folate, which, in turn, affects the amount of folate in your blood.

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 people with the MTHFR 677 CC genotype. However, reseachers have shown that people with any of the MTHFR genotypes who consume 400 mcg of folic acid each day will increase (almost double) the amount of folate in their blood to an amount that is high enough to help prevent a neural tube defect in a developing baby. This means that your folic acid intake is more important than your MTHFR genotype for determining the amount of folate in your blood.

Research shows that the MTHFR C677T variant is related to a small increased chance of poor health outcomes and birth defects. This shows the importance of consuming enough folate for optimal health and the possible role of folic acid in preventing other health disorders. Research has also 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. If you have the MTHFR 677 CT or TT genotype, consuming 400 mcg of folic acid each day almost doubles the amount of folate in your blood. This amount of folate in your blood is enough to help lower the chance of having a baby with a neural tube defect, no matter which MTHFR C677T genotype (CC, CT, or TT) you have.

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 the different types of folate, including folic acid.

Folic acid is the only type of folate shown to help prevent neural tube defects.

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).

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 “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.

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. 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.

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 foods fortified with folic acid, and vitamins or supplements containing folic acid and
2. The length of time folic acid is consumed before becoming pregnant.

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.

Sometimes a woman may still have a baby with a neural tube defect even though she consumed the recommended 400 micrograms (mcg) of folic acid.

Studies have shown that a woman who consumes 400 mcg of folic acid each day generally has enough folate in her blood to help prevent neural tube defects, regardless of her 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. Although consuming 400 mcg of folic acid each day can prevent the majority of neural tube defects, some neural tube defects have other causes that are not related 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.