If you’ve been giving yourself headaches by trying to understand diagrams like this, I think I can help you.
I spent years thinking I would never understand all this methylation stuff. I read online forums full of people who seemed to know what they were talking about, yet who made me hopelessly confused.
I wanted to understand it, because incorrect methylation can cause a wide range of serious medical conditions. It seems to be a particular problem among people with chronic Lyme disease, autism and CFS.
I suddenly realised I was approaching it the wrong way. I am a professional researcher. I had no excuse! After studying peer reviewed medical research, I feel ready to summarise this methylation business quite simply.
May I first make it absolutely clear that I am not a doctor or a scientist, this is not medical advice, and I am not taking any responsibility if I have got any of this wrong!
Let’s get started
Here’s my own methylation diagram:
You may notice I have removed a few details to make it clearer. Don’t worry, we’ll add them back as we go along.
What is methylation for?
Methylation of toxic heavy metals, such as mercury and lead, makes them water soluble. This means they can be excreted out of the body in urine.
Parts of the DNA in living cells are methylated. In humans, 60% to 90% of the DNA needs to be methylated.
* Methylation makes embryonic stem cells differentiate irreversibly into different types of body tissue.
* It suppresses the expression of harmful stretches of DNA that have found their way into human DNA over time, such as endogenous retroviruses and mutations.
* Methylation is very important in neural development and it appears to be essential to long-term memory formation.
The Wikipedia article on DNA methylation gives more detail on this and cites a lot of original research sources.
Abnormal DNA methylation (hypermethylation and hypomethylation) is associated with cancer. In particular, a lower level of white blood cell DNA methylation is associated with many types of cancer. In most types of cancer there is hypermethylation of tumor suppressor genes and hypomethylation of oncogenes or cancer-causing genes.
The cells lining blood vessels must be methylated to repair them, and undermethylation results in cardiovascular disease and hardened arteries. This condition has been correlated very closely in many medical research papers with high homocysteine.
Two types of white blood cells (monocytes and lymphocytes) must be methylated. Under-methylation in these cells leads to excessive blood clotting, causing thromboses and strokes. It also leads to impairment in the functionality of aspects of the immune system dependent on these cells, though more research is needed to understand this properly.
What happens when your body is not methylating efficiently?
You will accumulate abnormal levels of toxic heavy metals which are found in food, vaccinations and the environment.
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.
You may have blood which clots rapidly, and therefore develop thromboses or strokes.
You are likely to suffer memory impairment and may have a range of other neurological problems.
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. Folic acid (in the right form) is essential for methylation, and lack of folic acid in pregnant women has long been known to result in brain and spinal abnormalities such as spina bifida. After birth, this 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.
Why is it a cycle?
Most scientists talk simply about methylation, but Amy Yasko coined the term “methylation cycle.” She wanted to highlight the fact that homocysteine (bad) must be recycled, and a problem in the recycling of this harmful substance can result in a shortage of methionine (good), and thus problems in the rest of the methylation processes.
A good analogy would be traffic flowing around a roundabout. An obstacle in any of the roads leading off the roundabout, or anywhere on the roundabout, will results in traffic jams ALL AROUND the roundabout.
So far, so good: yet the roundabout she seems to have used as her model is this one!
What happens when you don’t recycle homocysteine back to methionine?
You can see from my diagram above that the methylation cycle has two halves.
One part (pink) methylates the things listed above. To do so it starts with methionine (an amino acid which you get from the protein foods you eat) and, once it has done all this methylating, it has given away its methyl group molecules, and you end up with homocysteine – a different type of amino acid.
The second part of the methylation cycle (blue) recycles this homocysteine back to methionine by adding methyl group molecules back onto it.
High homocysteine levels mean that somewhere in this recycling half of the methylation cycle, something is not working well. You may have genetic polymorphisms that mean you produce less than adequate amounts of the enzymes needed, you may have a deficiency in one or more of the nutrients those enzymes need to do their jobs, or you may have other factors that are suppressing production of those enzymes (this is what people mean when they talk about altered gene expression).
The best article on the web about what happens when you have too much homocysteine is on the Life Extension Foundation website. It summarises a large array of peer reviewed medical research, all of which is cited in the bibliography. I strongly recommend this article, which is so clearly written it is a joy to read.
How does the body change homocysteine to methionine and vice versa?
Now we can add a little more detail to our diagram.
Enzymes that methylate DNA, heavy metals etc
N.B. This is not a complete list, just an introduction to some of the more thoroughly researched polymorphisms.
MTRR = methionine synthase reductase
This changes hydroxycobalamin (= hydroxy B12) into methylcobalamin (= methyl B12) and, in so doing, it also changes methionine into homocysteine as a by-product.
Vitamin B12 which has been methylated in this way can be used for methylating DNA, toxic metals etc. This process changes it back into hydroxy-B12. It can be recycled infinitely.
COMT = catechol-O-methyltransferase
This carries out part of the process of breaking down certain neurotransmitters and catecholamines, including dopamine, epinephrine (= adrenaline) and norepinephrine (= noradrenaline). These neurotransmitters are essentially what create much of your personality, as they create your mood and emotions, inhibition of behaviours and ability to control the temper, and planning, short-term memory and abstract thinking.
People with a COMT polymorphism are slower than average at breaking down these neurotransmitters.
Normally they are balanced. Adrenaline, for example, causes a rush of excitement and stimulation to deal with a crisis, known as the “fight or flight” response. Dopamine, on the other hand, brings about the relaxed, warm fussy feeling people enjoy after a good, hard session of exercise: the word “dopamine” is derived from the same linguistic root as “dopey”. One is never supposed to have high levels of both of these neurotransmitters at the same time.
Imagine a child at school with a COMT polymorphism which makes him slow at clearing these substances out. He is full of dopamine, so he has immense difficulty concentrating and he appears to be making no effort. His teacher tells him off, frightening him and provoking a major adrenaline rush. Now the child is full of both adrenaline and dopamine, to he feels tired and wired both at once.
The commonest symptom of both children and adults with this problem is mood swings and extreme irritability.
Enzymes which recycle homocysteine back to methionine
N.B. This is not a complete list, just an introduction to some of the more thoroughly researched polymorphisms.
DHFR = dihydrofolate reductase
This changes reduces dihydrofolic acid into tetrahydrofolic acid. These are both forms of folic acid.
The form of folic acid (vitamin B9) 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.
SHMT = serine hydroxymethyltransferase
This changes tetrahydrofolic acid into another intermediate substance called 5,10-methylene THF.
MTHFR = Methylenetetrahydrofolate reductase
This 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 this 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.
BHMT = betaine homocysteine methyltransferase
This changes homocysteine into methionine.
It takes trimethylglycine (=betaine) + homocysteine, and produces dimethylglycine + methionine. Most research on this enzyme comes from Amy Yasko’s clinical observations, not from peer reviewed medical research.
MTR = 5-methyltetrahydrofolate-homocysteine methyltransferase
This converts homocysteine back to methionine as well.
It takes 5-methyl folate (metafolin) with homocysteine, and produces methionine and tetrahydrofolate (THF) which is “ordinary” (inactive) folic acid.
According to Amy Yasko, the MTR polymorphism is an upregulation, meaning the enzyme is over-active and uses up too much methyl B12. I cannot find any peer-reviewed medical research which verifies this.
CBS = cystathionine beta synthase
This is something like a major road off the methylation cycle “roundabout.” Instead of recycling homocysteine to methionine, it turns it into cystathionine. Cystathionine is converted in sequence by various enzymes and this process is called the trans-sulfuration pathway.
Various parts of the body need to be sulfated, but this is a topic for a separate blog post.
Polymorphisms in enzymes in this pathway will cause intolerances to sulfites, sulfates or other forms of sulfur.
If this trans-sulfuration pathway is not working efficiently, you will also accumulate excess amounts of ammonia, hydrogen sulfide and alpha-ketoglutarate, which Amy Yasko and associates say leads to excitotoxicity – manifested by stimming in autistic children and a feeling of being “tired but wired” in adults. This is an anecdotal clinical observation rather than the conclusion of scientific research.
What can make the methylation cycle go wrong?
1. Polymorphisms that reduce the quantity or effectiveness of any enzyme involved in the cycle
2. A deficiency in any of the nutrients needed by these enzymes
3. A reduction in gene expression, which could be caused by drugs, infections or other environmental factors. This is an area of research and so far not much is known about this in relation specifically to methylation. It is known so far that antibiotics of the tetracycline-doxycycline-minocycline-lymecycline family alter gene expression extensively and consistently.
How common are methylation cycle polymorphisms?
A heterozygous MTHFR polymorphism is found in 30% of the population worldwide, and the more severe homozygous form (homozygous means you inherited the inferior gene from both parents, not just one) is found in 10%. This particular polymorphism is so far the one most intensively studied in the scientific community, as it directly causes a build up of homocysteine which has been proven to be the cause of hardened arteries and heart disease.
MTR polymorphisms are much rarer. A homozygous MTR A2756G polymorphism affects fewer than 1% of the population, for example.
There are scattered articles providing information on the prevalence of the other polymorphisms, but often they study a specific ethnic group, or a study population too small to extrapolate the data to the population at large. It does seem, however, that some of these polymorphisms are far from rare.
Why are methylation polymorhisms such a problem for some people?
The key factor for people with discernible methylation related symptoms appears to be the specific combination of polymorphisms they have. Most of the groups of enzymes involved in the methylation cycle do a job can also be done by a different set of enzymes – a plan B. The really important processes sometimes have a plan C as well. Someone who has a polymorphism in a plan A enzyme, another in the plan B enzyme and possibly one in plan C will logically be likely to suffer adverse effects. Someone who has a scattering of polymorphisms affecting different systems, but who can reliably fall back on plan B, may never suffer symptoms.
The sheer number of polymorphisms is also bound to be an important factor. As an example, my rudely healthy husband has two polymorphisms (vitamin D receptor and MTHFR) whereas I, with chronic Lyme disease (and CFS if you believe some of my past doctors), have 4 homozygous ones and 6 heterozygous ones.
Why is methylation important in Lyme disease, autism and CFS?
The symptoms of impaired methylation described above are common, perhaps universal, in people with autism, CFS and Lyme disease. People with these conditions who can pay for genetic testing always seem to find a range of genetic polymorphisms which will reduce the rate at which they produce enzymes that form the methylation cycle. So far there has been no population-wide research that has compared the rate of these polymorphisms in patients with these illnesses against the rate of polymorphisms in the healthy population.
Most people with Lyme disease, for example, felt perfectly fine before catching Lyme disease yet already had all these polymorphisms. It is possible that the Lyme disease itself triggered a change in gene expression which took their adequate (but less than ideal) production levels of these enzymes down below the “adequate” threshold.
How can you tell how well or badly you are methylating?
A blood test of homocysteine levels will highlight problems with recycling methionine back to homocysteine. If you start taking nutrients to help your methylating processes work better, you can repeat the test to monitor progress. Read the Life Extension Foundation article which discusses different levels of homocysteine.
A DNA test performed by 23andme (or some other companies) and then analysed by Genetic Genie will indicate if you have relevant DNA polymorphisms that will reduce your ability to make many of the enzymes which collectively form the methylation cycle.
Genova Diagnostics offers various test panels which monitor how your methylation processes are working. (I have no personal experience at all with this company.)
If you know of other tests that I have not mentioned here, please add a comment, and post a link if possible.
Finally: how to spot and avoid twaddle…
Crazy diagrams are often accompanied by comments which are poetic rather than scientific, such as
“Once long-closed metabolic pathways are reopened, the body may be unable to handle the accumulated toxins and will need detox support to deal with nasty symptoms.”
or “Trimethylglycine is the most powerful methyl donor and may be needed for those extreme under-methylators but beware, as it is very strong!”
The first comment is a surefire sign you are dealing with a quack. When something is helping your body, it does not make you feel worse before it makes you better. It just makes you better. Steer clear of snake oil!
The second comment comes from someone who just knows even less than I do about chemistry. Scientists do not talk about molecules being more or less “powerful”. Certain enzymes act upon certain substrates. They pull bits off molecules or stick bits on. That’s it. Trimethyglycine is a nutrient with three methyl groups on it, and some people have genetically impaired production of the enzyme needed to pull one of them off. This means it is not “powerful” for them, it is useless, and possibly harmful.
These are just examples, but the internet is full of writing about the methylation cycle which may have been science once, but has been retold and garbled into misinformation and nonsense. Be sceptical if you read anything that sounds sweeping and allegorical rather than scientific and specific.
I personally have issues with some other treatment approaches. Amy Yasko first realised people with autism apparently have all the symptoms of inadequate methylation, and she deserves great credit for that. The aspect of her therapy that I dislike is that she recommends not only the single nutrient you need to correct an enzymatic inadequacy, but a long list of different herbs and sometimes drugs as well. Why?
Taking herbs to improve the body’s methylation will not work, as these substances have no natural role to play in human biochemistry. Methylation is carried out by specific enzymes, each one using specific nutrients – it cannot be done in any other way.
…and how to find the truth
I started with peer-reviewed medical research published in reputable journals (excluding ones behind paywalls because I’m skint). I was surprised to find that some aspects of the methylation cycle, which are widely discussed among people whose lives are ruined by Lyme disease, autism or CFS, have absolutely no basis in objective scientific research at all – whereas others have been researched and verified very extensively indeed.
Then I moved on to analysing the evidence presented by Amy Yasko and her associates in the DAN (Defeat Autism Now) movement, reading as much as I could about their working theories based on clinical observation of their patients. Doctors usually let their personal bias affect their claims when they work this way, so information from this category has to be used more cautiously.
Sources and Further Reading
The best article on the web about what happens when you have too much homocysteine is on the Life Extension Foundation website. It summarises a large array of peer reviewed medical research, all of which is cited in the bibliography. It is highly readable and a very good place to start.
Wikigenes is a fantastic site which unifies masses of research on genes, enzymes etc. You can search any of the enzymes in this article, which will pull up a page of summarised research articles, with links to the full article.
Wikipedia article on methylation
Wikipedia article on DNA methylation
There are also Wikipedia articles on each of the enzymes listed in this article.
Amy Yasko’s treatment approach to methylation problems is explained in a free online book. She recommends a lot of tests and a very large amount of herbs as well as nutrients (an approach I personally disagree with).
The Heartfixer website explains a similar approach but gives a lot more scientific detail, and a therapy focused tightly on nutrients without additional substances (an approach I personally find preferable, and of course much cheaper!).
This article has links to lots of published research on DNA methylation.
A search on each enzyme in the SNPedia research database will produce a list of links to all the relevant peer-reviewed research on that enzyme available online free of charge. In the search box on this website you have to enter the abbreviated name (e.g. MTHFR) rather than the full name (methyl tetrahydrofolate reductase) – if you use the full name, it tells you there are no results.
This is the MTHFR page as an example. You have to click on the various SNPs (all possible known variants of the gene) to find the research specific to that variant.
This research article talks about some chronic inflammatory conditions related to abnormal methylation of monocytes and lymphocytes.
So far, this is the only actual peer-reviewed medical research paper I can find online about methylation impairments in autistic children:
IF YOU KNOW OF ANY ADDITIONAL RESEARCH OR USEFUL WEBSITES, PLEASE POST A LINK TO THEM IN THE COMMENTS SECTION. (Scroll down to the text box.)