Several variations (polymorphisms) in the MTHFR gene have been associated with an 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 polymorphism related to neural tube defects 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 (thermolabile). People with the 677C>T polymorphism, particularly those with two copies of the genetic change, have elevated levels of homocysteine in their blood resulting from the reduced activity of methylenetetrahydrofolate reductase.

Researchers have studied MTHFR gene polymorphisms in individuals with neural tube defects and in their mothers, but it remains unclear how these variations could affect the developing brain and spinal cord. The increased risk of neural tube defects may be related to differences in the ability of methylenetetrahydrofolate reductase to process folate; a shortage of this vitamin is an established risk factor for neural tube defects.

Although MTHFR gene polymorphisms are associated with an increased risk of neural tube defects, these variations are common in many populations worldwide. Most people with MTHFR gene polymorphisms do not have neural tube defects, and their children are also typically unaffected. Changes in the MTHFR gene are only one of many genetic and environmental factors that are thought to contribute to these complex conditions.

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 cognitive 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.

Polymorphisms in the MTHFR gene are also associated with an increased risk of spina bifida, another common type of neural tube defect. In people with this condition, when the spine forms, 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 protrude through an opening in the spine, leading to permanent nerve damage.

As described above, variations in the MTHFR gene may increase the risk of neural tube defects by changing the ability of methylenetetrahydrofolate reductase to process folate. 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.

Polymorphisms in the MTHFR gene have also been studied as possible risk factors for a variety of common conditions. These include heart disease, stroke, high blood pressure (hypertension), high blood pressure during pregnancy (preeclampsia), an eye disorder called glaucoma, 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. Many of the MTHFR gene polymorphisms alter or decrease the activity of methylenetetrahydrofolate reductase, leading to an increase of homocysteine in the blood. This increase in homocysteine levels may contribute to the development of many of these conditions.

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, it remains unclear what role changes in the MTHFR gene play in these disorders. 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.