How Are MTHFR Gene Mutations and Disease Risk Linked?

Their role in disease risk is debated

If you have a mutation in the gene MTHFR, your body may have difficulty breaking down an amino acid called homocysteine. More than 40 MTHFR genetic mutations are linked to homocystinuria, a condition where the amino acid builds up in the bloodstream.

Homocystinuria is associated with eye issues, thrombosis, bone fractures, and Alzheimer's disease. While having one or more MTHFR gene mutations doesn't necessarily mean you will have certain health problems, it's thought to increase your risk.

MTHFR gene mutations are also linked to other medical conditions, including birth defects, cardiovascular disease, hearing loss, autoimmune disorders, and thyroid disease.

Keep in mind that research is limited in terms of how much MTHFR genetic mutations contribute to the development or severity of certain conditions.

This article discusses MTHFR genetic mutations and the associated conditions. It also covers testing recommendations.

MTHFR genetic mutations are common and it's not unlikely for individuals to have one or two copies of certain MTHFR variants. Examples of common ones include the gene mutations MTHFR A1298C and MTHFR C677T. Only certain, more rare MTHFR variants tend to be associated with health conditions.

Illustration of a chromosome
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Understanding MTHFR Genetic Mutations

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme produced by the MTHFR gene. MTHFR interacts with folate (vitamin B9) to break down homocysteine so that it can be converted into another amino acid known as methionine. The body uses methionine to build protein and other important compounds.

An MTHFR mutation is an error in the MTHFR gene that causes it to malfunction. If this happens, the gene may be less able to break down homocysteine, causing an accumulation of the enzyme in the blood. Depending on the genetic variant, a person may either have normal or elevated levels of homocysteine in their blood or urine.

Hyperhomocysteinemia and Associated Conditions

An MTHFR genetic mutation can lead to abnormally high levels of homocysteine, or hyperhomocysteinemia. This is associated with an array of medical conditions, in part because it depletes the amount of folate that the body needs to function normally. This is especially true of heart, brain, and other bodily tissues that rely on folate to repair damaged DNA and ensure the healthy production of red blood cells.

Conditions associated with hyperhomocysteinemia include:

  • Thrombosis (blood clots)
  • Microalbuminuria (increased albumin in urine associated with kidney and heart disease)
  • Atherosclerosis (hardening of the arteries)
  • Alzheimer's disease
  • Ectopia lentis (the displacement of the lens of the eye)
  • Bone fractures in older people

Despite their association with certain diseases, the overall risk imposed by most MTHFR variants appear to be quite small. In most studies finding an association between MTHFR variants and diseases, there is no evidence of a cause and effect relationship.

Other Diseases Linked to MTHFR Genetic Mutations

The five conditions considered strongly linked to MTHFR genetic mutations, per findings published by the National Institutes of Health, are:

  • Alopecia areata, an autoimmune disorder in which the immune system attacks hair follicle roots, causing hair loss
  • Anencephaly, one of several neural tube defects associated with the MTHFR mutation, in which large parts of the brain are missing and/or a person is missing or has incomplete skull bones
  • Homocystinuria, the inability to process homocysteine and methionine normally, contributing to the onset of hyperhomocysteinemia and the risk of associated disorders
  • Presbycusis (aging-related hearing loss), in which certain MTHFR polymorphisms affect folate levels needed to maintain the cellular integrity of the organs of the ear
  • Spina bifida, a birth defect in which the bones of the spinal column do not close completely around the nerves of the spinal cord

Having an MTHFR genetic mutation doesn't mean that you will develop a disease or pass one on to your baby. Especially with regard to neural tube defects, MTHFR-associated diseases are passed in an autosomal pattern, meaning that both parents have to contribute a copy of the genetic mutation.

The risk that parents with known MTHFR mutations will have a baby with a neural tube defect is extremely low, roughly 0.14 percent.

Other conditions tangentially associated with MTHFR mutations include:

  • Heart disease
  • Stroke
  • Hypertension (high blood pressure)
  • Preeclampsia (high blood pressure during pregnancy)
  • Glaucoma
  • Cleft palate

MTHFR and Hypothyroidism

The association between the MTHFR genetic mutation and hypothyroidism has been discussed but remains largely speculative. There have been a number of smaller studies that suggest a link, including one from the University of Tbilisi in which certain MTHFR polymorphisms were found in people with hypothyroidism with no observable symptoms, but not in others.

While the presence of hyperhomocysteinemia in people with hypothyroidism may suggest an association with the MTHFR mutation, it is important to note that hypothyroidism can trigger high homocysteine levels irrespective of whether the MTHFR mutation is there or not.

So can:

  • Smoking
  • Older age
  • Medications like methotrexate, Lipitor (atorvastatin), Tricor (fenofibrate), and niacin (vitamin B3)

Testing Recommendations

A test, called the MTHFR genotype, may be ordered if:

  • You have excessively high levels of homocysteine with no known cause
  • You or a family member has a history of blood clots or heart disease at an early age
  • You are unable to control your homocysteine levels with levothyroxine or folic acid and you are at an increased risk of cardiovascular disease and no other causes for the homocysteine elevation can be found

The aim of the test is not to screen for diseases but rather to identify if an MTHFR genetic mutation affects how your body processes folate. Doing so can aid in the selection of the right medications and supplements to treat cardiovascular disorders and other conditions.

Neither the American Congress of Obstetricians and Gynecologists (ACOG), the American College of Medical Genetics, the American Heart Association, nor the College of American Pathologists recommends the test for the screening of disease or the identification of your carrier status.

6 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
  1. MedlinePlus. MTHFR gene.

  2. U.S. National Library of Science. MTHFR gene (methylenetetrahydrofolate reductase). Genetics Home Reference.

  3. Centers for Disease Control and Prevention. MTHFR gene, folic acid, and preventing neural tube defects.

  4. Ansari R, Mahta A, Mallack E, Luo JJ. Hyperhomocysteinemia and neurologic disorders: a review. J Clin Neurol. 2014;10(4):281-8. doi:10.3988/jcn.2014.10.4.281

  5. National Center for Advancing Translational Sciences. MTHFR gene variant. Bethesda, Maryland: National Institutes of Health.

  6. Kvaratskhelia T, Kvaratskhelia E, Kankava K, et al. MTHFR gene 677T polymorphism and levels of DNA methyltransferases in subclinical hypothyroidism. Georg Med News. 2017(265):19-24.

Additional Reading

By Mary Shomon
Mary Shomon is a writer and hormonal health and thyroid advocate. She is the author of "The Thyroid Diet Revolution."