The MTHFR polymorphism

This is one of the polymorphisms that can impede the human body’s ability to methylate correctly. MTHFR stands for methylenetetrahydrofolate reductase, but a lot of people tend to insert a different collection of vowels into MTHFR and produce another name for this mutation!

Which mutations are we talking about?




These are the polymorphisms which Genetic Genie will report on if you upload your DNA analysis from 23andme to them.

At least 40 mutations in the MTHFR gene have been identified, and this is an area of ongoing research in the medical community. To find out about other polymorphisms, I suggest looking at SNPedia, an online database which gathers and indexes new genetic research.


The MTHFR gene provides instructions for making an enzyme called methylenetetrahydrofolate reductase.

Three enzymes change folic acid from the form in which we eat it, into the form in which our body can use it.

1. First, dihydrofolate reductase (shortened to DHFR) changes reduces dihydrofolic acid into tetrahydrofolic acid. These are both forms of folic acid.

2. Next, serine hydroxymethyltransferase (SHMT) changes tetrahydrofolic acid into another intermediate substance called 5,10-methylene THF.

3. Finally, methylenetetrahydrofolate reductase (MTHFR) changes 5,10-methylene THF into the ready-to-use form of folic acid, called levomefolic acid, or 5-methyl tetrahydrofolate, or 5-methyl THF, or 5-methyl folate.

These names do not exactly roll off the tongue, so when bigpharma company Merck created a useful version in tablet form, they invented the trademark name Metafolin, which is widely used in online discussions of methylation by laymen (or laywomen) like me. It is licensed to various nutrient producers so you can find a range of different brands.


The form of folic acid (vitamin B9) which we get from vitamin supplements is called pteroyl-L-glutamic acid. I have read some articles claiming it is identical to the form found in foods, and other claims that this form is very rare in foods and that dihydrofolic acid is the “natural” form usually found in food.

Both of these claims have been made in peer-reviewed medical literature and I have no idea which is actually correct – I think it is simply a matter of opinion. 

What does this do normally?

Folic acid, once activated, is used by other enzymes to change homocysteine (an amino acid) into methionine (another amino acid). This methionine is used, along with other nutrients, to “methylate” our own DNA, and toxins which need to be excreted.

In other words, it performs indispensable actions in our bodies, including regenerating our own body cells. This means we need this enzyme if we are going to repair our body tissues properly.

I have written in detail about homocysteine and methylation in a previous post called Methylation for Dummies. Look at the section “What is methylation for?” 

What does this polymorphism cause?

This polymorphism means your MTHFR enzyme is slow at methylating (in other words, activating) folic acid into a usable form.

About 30% of the population has a heterozygous (mild, from one parent) MTHFR  polymorphism and about 30% has a homozygous (severe, from both parents) polymorphism.

The latest research indicates that people with a milder polymorphism have about 70% of the MTHFR action they need, and those with the severe form have only 30% of what they need.

The health implications for this are many and varied, but the aspect most thoroughly researched in conventional medicine is that upon cardiac health. This polymorphism leads elevated levels of homocysteine, and this is well-proven to cause hardened arteries (atherosclerosis), heart disease, heart attacks, thromboses, and strokes.


You may very gradually develop signs of cardiovascular disease such as abnormal blood pressure, enlarged heart, orthostatic intolerance, chest pain or postural orthostatic tachycardia syndrome. However, many people have no indication of problems at all until they suffer a heart attack.

People with the more severe polymorphism have been found, consistently, to have dangerously hardened arteries before they were even out of their teens.

Follow this link for a long page of references to peer-reviewed scientific research.

You may also develop any of the following problems:

You will accumulate abnormal levels of toxic heavy metals which are found in food, vaccinations and the environment.

You are likely to suffer memory impairment and may have a range of other neurological problems.

If you are pregnant, the folic acid you take to protect your unborn baby from spina bifida may have limited effectiveness. Folic acid (in the right form) is essential for methylation, and lack of folic acid in pregnant women – which results in inadequate methylation of nerves – has long been known to result in brain and spinal abnormalities such as spina bifida and anencephaly.


Children with autism have been found to have brain abnormalities which may derive from inadequate methylation of nerve cells during critical stages of brain development in early childhood. After birth, the neural methylation process continues to be vital in the development of baby and toddler brains.


You will be at increased risk of cancer.

You may be susceptible to a wide range of chronic inflammatory illnesses, including some autoimmune conditions. This derives from inadequate methylation of monocytes and lymphocytes. So far a definite link has been established between under-methylation of these cells and the development of autoimmune diabetes and systemic lupus erythematosis.

You are likely to have a weakened immune system and be unable to sustain a strong immune defence against infections.

In addition to these serious medical conditions, people who are unable to use dietary folic acid may feel very ill from taking ordinary folic acid supplements, or even from eating foods which are rich in folic acid. The inactivated folic acid seems to build up to toxic levels in the body, which is unable to excrete it fast enough. I have a heterozygous (mild) MTHFR polymorphism, yet I felt very ill indeed from taking just 400 microgrammes of ordinary folic acid a day.


Luckily, of all the possible polymorphisms affecting the methylation cycle, this is one of the simplest to treat.

5-methyl tetrahydrofolate, the activated form of folic acid which the MTHFR enzyme generates, can be bought as a supplement from various producers. It was invented by pharmaceutical company Merck and is licensed to various supplement manufacturers.

I have personally used the Solgar and Metabolics brands and I have found them both to be very good.  I am sure there are other good brands also available. Only buy a product with “Metafolin” on the label to make sure you are getting the right thing.

What dosage do you need?

Most practitioners advise taking between 400mcg and 800mcg daily. If your diet is already rich in folic acid, adding a high dose supplement will worsen the problem of accumulated, unused folic acid. I have been in this situation and it made me feel poisoned. I cannot think of any way to describe it other than to say I felt as if I needed to vomit out of every part of my body.

Your dose must be balanced with your dietary folic acid intake. If you have a heterozygous MTHFR polymorphism then you can make use of a limited amount of dietary folic acid. In this case, it would make sense to start with a lower 400mcg dose of metafolin and see how you get on. You may feel fine. If you have a more severe, homozygous polymorphism then you may well need to restrict your intake of foods rich in folic acid and take a higher dose supplement.

Having said this, it is all variable depending on your actual gene expression. My polymorphism is heterozygous yet I do have to restrict my dietary folic acid, otherwise I begin to feel very ill indeed. If you need to reduce folic acid intake, this site gives a useful guide to the foods richest in folic acid.

According to Amy Yasko, another variable , which may affect the dose you can handle, is your COMT gene status. There is no peer-reviewed medical research verifying or testing her theory, and she has published no research on it, but her theory goes like this: High levels of L-methylfolate can put a burden on people with COMT V158M and H62H polymorphisms, because they have a hard time breaking down neurotransmitters including adrenaline and noradrenaline. Methyl donors like L-methylfolate can elevate adrenaline and lead to anxiety and panic attacks in these people.

Again, it all depends on individual gene expression. I have both these polymorphisms yet, on a daily dose of 800mcg of metafolin, I have no panic attacks and feel perfectly calm. Or perhaps her theory is simply wrong.

Beware of folinic acid

I have seen discussions of methylation in which Folinic Acid is advocated as an alternative supplement to deal with the MTHFR polymorphism. Folinic Acid has to be converted into 5-methyl tetrahydrofolate by the MTHFR enzyme. If you have the MTHFR mutation, it will not help you at all. There is no reason for anyone with methylation problems to take this supplement. When I ill-advisedly took it, I became extremely ill. My body could not use it at all and it rapidly built up to toxic levels.

Useful links and sources

This concise page on MTHFR contains a great deal of useful cautions and usable advice regarding the MTHFR gene and is essential reading.

Genetics Home Reference summarises and links to some of the most important research into this gene.

A good source of all the newest research is the website MTHFR Research which is dedicated exclusively to the MTHFR mutation. I find the articles on this site varied in style and quality – use your own judgement. I consider the peer-reviewed medical research to be very reliable.

The great and highly readable article Homocysteine Reduction explains homocysteine in detail. It summaries a large amount of scientific research.

SNPedia is a database which links to all known research available online regarding the human genome. This is the MTHFR page.


Please note, I am not a doctor and this is not medical advice. I am a patient with this mutation and this is all based on internet research. 

3 thoughts on “The MTHFR polymorphism

  1. hey again !
    great page:)

    has methylation supplementation helped you with you symptoms? in which way and which symptoms have improved? which supplements did you take for your gene def and which tests did you get done?

    are you not scared of doing something wrong? its so complicated !
    how do you know that certain sups caused yu to feel sick, in cfs/lyme symptoms fluctuate so much day by day- i can never tell what is causing it.

    want to start methylation protocol
    : how do i do it ??

    which tests do i need to get done to start ?
    -23andme gene test?
    -hair ?? for lithium ?? yasko keeps saying knowing your lithium is mega important before adding b12
    -i want to know if i have high ammonia (feel tired and wired and overstimulated in the brain (neurotoxicity NMDA overstimulation ) — which tests for that ??

    which sups can i start while waiting for the tests ? short cut meth cycle ??

    thANK YOU


    1. The tests to do are 23 and me, then go to the genetic Genie website and enter your results there.
      This tells you what is based on peer reviewed medical research, which the Yasko love of lithium isn’t.
      I had a lot of improvement in energy and also found when I get a cold it lasts a week instead of two months.
      It is definitely worth doing.
      Genetic Genie tells you the supplements you need, but maybe I should write a blog post with a list to make it clearer? That is going on the to do list!


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