What is MTHFR mutation?

By Carolyn Ledowsky, Founder of MTHFR Support Australia

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With every passing year MTHFR (an enzyme critical for folate metabolism) seems to be becoming more important for anyone looking to educate themselves on how they can improve their fertility, and have fantastic pregnancy outcomes. To understand fertility, pregnancy, and what specifically makes your body and mind healthy – you need to have a basic understanding of what MTHFR is, what role MTHFR plays in the grand scheme of your health, and if you have an MTHFR mutation that is affecting you, what to do about it. We will try our best to get you up to speed on MTHFR, and outline why MTHFR is crucial for your general and reproductive health.

WHAT IS MTHFR?

As mentioned earlier, the MTHFR gene encodes for an MTHFR enzyme which is important for metabolizing folate into its active form called active folate, or 5-methyltetrahydrofolate (5-MTHF). It is called “active folate” because this is the form of folate your body uses to do work.

ACTIVE FOLATE, VITAMIN B12 AND HOMOCYSTEINE

The primary function of active folate is to convert homocysteine into methionine. Converting homocysteine to methionine requires the use of vitamin B12 as an enzymatic cofactor (a molecule that is needed for an enzyme to perform its correct function). If the body does not have enough vitamin B12 available for the enzyme converting homocysteine to methionine to work, or if there is not enough active folate, the reaction cannot continue and homocysteine levels within the body begin to rise – causing an increased risk of several health and pregnancy complications we will cover later in this article.

WHY IS KNOWING YOU HAVE AN MTHFR MUTATION IMPORTANT?

You may be thinking “If it’s only B12 and folate I need to worry about, what’s all this talk about MTHFR?” Since the MTHFR enzyme is the final step in the folate cycle, without it, your body could not create active folate on it’s own. If you have an MTHFR mutation that reduces your ability to create the active form of folate, it’s easy for your body to create biochemical imbalances such as elevated homocysteine or low folate levels that lead to health and fertility problems.

ELEVATED HOMOCYSTEINE

Disturbances in homocysteine levels during pregnancy, can be caused by lack of folate and/or MTHFR mutations, and can lead to placental abruptions, pre-eclampsia, recurrent pregnancy loss, and neural tube defects.[1] The pregnancy complications driven by high homocysteine levels, or hyperhomocysteinemia, are because high homocysteine levels increase the likelihood of cardiovascular problems and cardiovascular events. The placenta can develop vascular deficiencies during pregnancy if homocysteine levels are too high; increasing the risk of one of the previously mentioned pregnancy complications occurring.

High homocysteine levels also reduces myelin production (a fatty tissue encasing neurons that promote efficient signalling throughout the nervous system). Less myelination of a child’s neurons during pregnancy can lead to insufficient growth of the nervous system, and can produce birth defects such as neural tube defects.[2]

LOW FOLATE

Folate plays many critical roles within the human body. Folate is important for:[3]

  • The synthesis of DNA and RNA

  • Methylation and the transfer of methyl groups via S-adenosyl methionine (SAM)

  • Production and recycling of neurotransmitters

  • Creation of red blood cells, white blood cells, and blood platelets

A lack of folate can lead to the following pregnancy complications:[4]

  • Neural tube defects (anencephaly, encephalocele, and spina bifida)

  • Poor sperm quality

  • Premature birth

  • Slow prenatal growth rate

  • Miscarriage

  • Increased risk of thrombosis (formation of blood clot inside of a blood vessel)

Low folate is primarily caused by MTHFR mutations, and lack of dietary folate consumption. If you have an MTHFR mutation, you will need to consume more folate than someone who does not have an MTHFR mutation. For example, the Mayo Clinic recommends adults get 400 mcg of folate per day, and women looking to get pregnant get between 400-800 mcg of folate per day.[5] If you have an MTHFR mutation, your ability to complete the folate cycle is diminished and you need to consume more than the recommended amount of folate per day in order for your body to have access to sufficient levels of active folate.

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This is a detailed diagram of the folate and methionine- homocysteine cycles. Remember that active folate can also be referred to as 5-MTHF, and you can see that it is the final product of the folate cycle (left), and is required for the methionine-homocysteine cycle (right). If you look at the top of the folate cycle diagram, you see two green bubbles, one for dietary folate and one for folic acid. You will notice that dietary folates enter directly into the folate cycle, while folic acid needs to go through an extra step of being converted to dihydrofolate (DHF) by an enzyme called dihydrofolate reductase (DHFR).

The DHFR enzyme converts folic acid to DHF VERY SLOWLY. If you supplement with folic acid, the DHFR enzyme becomes the rate limiting step within the folate cycle, and can lead to elevated levels of unmetabolized folic acid (UMFA) within cells – and ultimately blood serum.[6] UMFA is a problem when it reaches the bloodstream in blood serum and is known to impair the immune system, promote cancer growth, lower iron levels, and impair memory and cognition.[7,8]

Watch my video explaining why avoiding folic acid is important.

HOW TO GET MORE OF THE RIGHT TYPE OF FOLATE INTO YOUR BODY

You can get more folate into your diet by consuming more leafy green vegetables and legumes. It is important to avoid foods fortified with folic acid to make sure UMFA does not begin to build up within the body. If you have chronic low folate levels and want to begin supplementing, we recommend that you supplement with folinic acid or 5-MTHF. Folinic acid enters the folate cycle at a later stage than folic acid and by-passes the slow DHFR enzyme. Folinic acid is directly involved in creating the building blocks of DNA.

5-MTHF is the final “active folate” product of the folate cycle and is the most common form of folate taken by people with MTHFR mutations.

For a more detailed list of foods to eat to get more folate into your diet you can read our blog ‘What To Eat If You Are Low In Folate’ and if you want a more detailed guide on folate supplementation check out our ‘Folate Supplementation Guide’.

WHAT ARE THE CONSEQUENCES OF HAVING AN MTHFR GENE MUTATION?

Before diving into the specifics of MTHFR mutations, it is important to have a basic understanding of what enzymes are, and why they are so important. Enzymes play important roles in the body by helping speed up biochemical processes. Examples of what enzymes do include: digesting food, making hormones, breaking down neurotransmitters, and making active folate. Without enzymes many of these biochemical processes would be too slow for our daily biochemical needs; taking days, weeks, or years to occur instead of milliseconds with the help of enzymes.

MTHFR mutations slow down the speed at which your body can make active folate. There are many MTHFR mutations, but the ones you need to be aware of, and the ones that will impact your health and fertility the most, are MTHFR C667T and MTHFR A1298C. Both of these mutations are the most researched MTHFR mutations and the data on them is solid.

If you inherit one of the mutations from one of you parents that means you are heterozygous. If both of your parents have the same MTHFR mutation and you inherit both from them, that means your are homozygous. Heterozygous (1 gene) and homozygous (2 genes) are terms used by geneticists to determine how many copies of each specific gene are present in your genetic code. Here is a quick summary of which combinations and mutations are going to reduce the function of the MTHFR enzyme.[9,10,11]

HETEROZYGOUS

  • C677T = ~40% reduction in function

  • A1298C = ~20% reduction in function

  • Combined heterozygous (one C667T and one A1298C) = ~50% reduction in function

HOMOZYGOUS

  • C667T = ~70% reduction in function

  • A1298C = ~40% reduction in function

WHAT’S THE CONNECTION BETWEEN FERTILITY, FOLATE, METHYLATION, & MTHFR?

The other key reason we need active folate for fertility is because it’s one of the body’s primary methyl donors and plays a key role in methylation. Methylation is a process that is responsible for turning certain functions on and off within the body at the right time and place. For example, adequate active folate and methylation levels allow us to create “good” DNA without any defects, and DNA that can be used by the body when and where it is needed. Without “good” DNA we cannot successfully conceive. Pregnancy requires A LOT of DNA production, and if “good” DNA production is disturbed by not having enough active folate – the likelihood of miscarriages and birth defects rises greatly.

If the body is having trouble methylating during pregnancy the body cannot use, or suppress, certain genes when they are needed or not needed. During the rapid growth of a baby during pregnancy, the baby needs to have full access to its own genetic code to successfully grow. It is the mother’s responsibility to ensure she is doing all she can to provide her growing baby with adequate active folate levels, and methylation ability, during pregnancy. One of the best ways a mother can accomplish this is by ensuring she is getting enough folate through diet and supplementation (if needed).

There is something you should be aware of – not all folate is created equal! Folic acid is not equivalent to naturally occuring folates, active folate, or folinic acid. I have done a webinar explaining the differences between folates, and why/how you can make sure you are getting enough of the right kinds of folate into your body for a successful pregnancy. Watch my webinar here on ‘How to pick your folate’.

WHAT SYMPTOMS MAY LEAD YOU TO SUSPECT YOU HAVE AN MTHFR MUTATION?

There are a few ways to get tested for MTHFR mutations. You can get your entire genome sequenced (most expensive option but you get a lot more information beyond MTHFR about your DNA) through companies such as Ancestry or 23andme – or you can take a less expensive blood spot or buccal swab test that will let you know your MTHFR mutation status. Regardless of what test you decide to take to find out if you have MTHFR mutations; you will find out if you have MTHFR mutations, which mutations, and if you are heterozygous or homozygous for those MTHFR mutations. If genetic testing is not something you are willing to do quite yet, then there are common symptoms and signs associated with MTHFR mutations.

SIGNS AND SYMPTOMS OF MTHFR MUTATIONS

  • Family or previous history of miscarriage

  • Family or previous history of cardiovascular disease – heart attack, stroke, high blood pressure

  • Family or previous history of mental illness such as ADD/ADHD, depression, anxiety, bipolar, schizophrenia

  • Neural tube defects

  • Infertility

  • In ammation issues - arthritis, slow healing, fatigue

  • Elevated homocysteine > 8 pmol/L

  • Allergies, asthma, hives, migraines

  • Troubling detoxing

  • Impaired immune system

LIFESTYLE CHANGES THAT WILL HELP YOU MAKE UP FOR MTHFR MUTATIONS

If you have never heard of MTHFR mutations before reading this article, and you suspect that you may have an MTHFR mutation, there are many changes you can implement into your lifestyle that will help mitigate negative health and fertility consequences associated with MTHFR mutations.

Below is a list of lifestyle changes you can make to improve your health and fertility if you have an MTHFR mutation.

  • Eat more folate rich foods

  • Supplement with methylfolate and/or folinic acid

  • Reduce consumption of processed foods

  • Reduce alcohol use

  • Quit smoking

  • Try your best to eliminate environmental and household toxin exposure

  • Make time for things that help you reduce stress

  • Get tested for MTHFR mutations to make a proper strategy on how to combat your specific genetics

FREE MTHFR PATIENT RESOURCE CENTER AND MTHFR FERTILITY RESOURCE CENTER

If you want to learn more about MTHFR after reading this, check out our free MTHFR Patient Resource Center.

FURTHER READING

‘B12 insufficiency and folate – a crucial factor in pregnancy’

‘Top five action steps for MTHFR in preconception’

‘Intraventricular haemorrhaging and MTHFR in newborns’

‘MTHFR and hormones’

REFERENCES

  • Hague, W. M. (2003). Homocysteine and pregnancy. Best practice & research Clinical obstetrics & gynaecology, 17(3), 459-469.

  • Mills, J. L., Lee, Y. J., Conley, M. R., Kirke, P. N., McPartlin, J. M., Weir, D. G., & Scott, J. M. (1995). Homocysteine metabolism in pregnancies complicated by neural-tube defects. The Lancet, 345(8943), 149-151.

  • Bailey, L. B., Stover, P. J., McNulty, H., Fenech, M. F., Gregory III, J. F., Mills, J. L., ... & Molloy, A. M. (2015). Biomarkers of Nutrition for Development—Folate Review–5. The Journal of nutrition, 145(7), 1636S-1680S.

  • Fekete, K., Berti, C., Trovato, M., Lohner, S., Dullemeijer, C., Souverein, O. W., ... & Decsi, T. (2012). E ect of folate intake on health outcomes in pregnancy: a systematic review and meta-analysis on birth weight, placental weight and length of gestation. Nutrition journal, 11(1), 75.

  • https://www.mayoclinic.org/drugs-supplements-folate/art-20364625

  • Mudryj, A. N., de Groh, M., Aukema, H. M., & Yu, N. (2016). Folate intakes from diet and supplements may place certain Canadians at risk for folic acid toxicity. British Journal of Nutrition, 116(7), 1236-1245.

  • Plumptre, L., Masih, S. P., Ly, A., Aufreiter, S., Sohn, K. J., Croxford, R., ... & Kim, Y. I. (2015). High concentrations of folate and unmetabolized folic acid in a cohort of pregnant Canadian women and umbilical cord blood. The American journal of clinical nutrition, 102(4), 848-857.

  • Sawaengsri, H., Wang, J., Reginaldo, C., Steluti, J., Wu, D., Meydani, S. N., ... & Paul, L. (2016). High folic acid intake reduces natural killer cell cytotoxicity in aged mice. The Journal of nutritional biochemistry, 30, 102-107.

  • 9. Fisher, M. C., & Cronstein, B. N. (2009). Meta-analysis of methylenetetrahydrofolate reductase (MTHFR) polymorphisms a ecting methotrexate toxicity. The Journal of rheumatology, 36(3), 539-545.

  • 10.Friso, S., Choi, S. W., Girelli, D., Mason, J. B., Dolnikowski, G. G., Bagley, P. J., ... & Selhub, J. (2002). A common mutation in the 5, 10-methylenetetrahydrofolate reductase gene a ects genomic DNA methylation through an interaction with folate status. Proceedings of the National Academy of Sciences, 99(8), 5606-5611.

  • 11.Nazki, F. H., Sameer, A. S., & Ganaie, B. A. (2014). Folate: metabolism, genes, polymorphisms and the associated diseases. Gene, 533(1), 11-20.

FOR FURTHER INFORMATION, CONTACT:

Carolyn Ledowsky, Founder of MTHFR Support Australia

Carolyn Ledowsky is a naturopath, herbalist and nutritionist who has a Bachelor of Herbal Medicine, Bachelor of Naturopathy, Advanced Diploma of Naturopathy and Diploma of Nutrition, also having studied courses in genetics at Duke University and The University of Maryland in the US. Carolyn is a regular speaker at MTHFR events and provides both patient and practitioner training through her many webinars/presentations and online learning environments.

WEBSITES

MTHFR Support Australia is a dedicated clinic that specialises in addressing health issues associated with MTHFR genetic polymorphisms and methylation issues.


Juliana Kassianos