What is Methylation?


Methylation regulates the switching on and off of our genes and silences viruses. When functioning optimally, methylation keep the less desirable genes switched off, such as those that cause birth defects, cancers and auto-immune disease for example, while allowing the switching on of genes that helps our body systems to run effectively. We call this gene expression.

The process of methylation, if working properly, is what keeps us healthy. Without methylation we cannot survive as methylation contributes biochemically to who we are, what we look like, how we act and is also central to our physical, mental and emotional wellbeing.

We go about our day to day lives usually never being aware of these processes, but meanwhile this process is making, maintaining and repairing our DNA, which is our genetic coding.

We can get an ‘epigenetic’ effect whereby how we chose to live our lives can have an effect on our gene expression and it is these events, stressors and loving care that help either support or hinder the natural process of building and repairing our body.

In this article I will be covering the following topics:

  • Introduction to methylation
  • What is methylation
  • Testing for methylation
  • Biochemistry of UNDERMETHYLATION
  • Biochemistry of OVERMETHYLATION
  • Things that can affect methylation
  • Methylation impairments
  • What is homocysteine?
  • Causes of Elevated Homocysteine
  • Risks Associated With Elevated Homocysteine Levels
  • What is the hereditary predisposition MTHFR?
  • Symptoms of MTHFR gene copying errors
  • Anemia, DNA, and Folate
  • Methylmalonic Acid (MMA)
  • Folates, folic acid and unmethylated folic acid (UMFA)
  • Dangers of UMFA
  • Supplementation to support under or overmethylation

More about methylation

Methylation begins with a what is termed a ‘methyl group’ which is basically a carbon and three hydrogen atoms joined together and this group is then transformed to another compound.

An analogy would be a work place where one person passes an envelope containing a group of objects to another person, who then has the job of making those bits into another component, which is then passed onto someone else to finish the job to have a completed job order.

There are certain points within the methylation cycle where each has a particular task to  begin, carry out and finish the job. In other words each part has its role and ‘job description’ to complete the project.

Our nerve functions is highly dependent on proper methylation as each nerve requires the proper nerve insulation just like the wires in our house or car otherwise it will be like exposed wires and this can lead to symptoms of physical, emotional or behavioural changes. Methylation switching on and off of genes also control the production and breakdown of neurotransmitters which are our chemical messengers in the brain and nervous system as well as in the gut and many other places of importance.

The nervous system communicates with immune cells, so a faulty methylation process can lead to immune imbalances, which can turn a simple cold or flu into pneumonia or and auto-immune disease. An efficient methylation system will create an efficient communication system to sound the alarm bells of immune invaders. Methylation also immobilise fats and cholesterol so they can be removed by the body without clogging up arteries and organs, so improving methylation cycles can help the body to naturally clear cholesterol and fats that would otherwise lead to heart attacks, high blood pressure, diabetes and fatty liver disease.

There are so many other things that methylation supports such as hormones, regulating oestrogen and testosterone as examples, but also thyroid hormones, adrenal hormones and the list goes on.

Methylation regulates histamine levels which is why someone who gets allergies we call an under-methylator, because the body is unable to break down the histamine. Histamine is hormone that is often over expressed in cases of allergies, eczema, asthma and even anaphylactic reactions.

To summarise, methylation is involved in many of our most vital bodily functions, by offering support and/or managing, such processes as:
1) Detoxification
2) Controlling inflammation
3) Maintaining DNA
4) Immune function
5) Energy production
6) Mood balancing

Some of the conditions linked to poor methylation include but not limited to; cardiovascular disease, cancer, diabetes, neurological conditions, autistic spectrum disorders, chronic fatigue syndrome, Alzheimer’s disease, miscarriages, fertility, and problems in pregnancy, allergies, immune system, digestive problems, mood and psychiatric disorders as well as the aging process.

Tests for methylation (under and over)

Whole blood histamine (an important protein involved in many allergic reactions), Basophil count (a type of white blood cell), zinc and copper levels, homocysteine, and heavy metal and mineral balances.

The common biochemistry of UNDERMETHYLATION is:
1. High blood histamine
2. High basophil count
3. Low plasma zinc
4. Elevated serum copper
5. Low homocysteine
6. High heavy metals
7. Low levels of the neurotransmitters serotonin, dopamine and norrpinephrine.

As proper methylation is a major factor in the production of serotonin, dopamine, and norepinephrine in the body, undermethylation can lead to a depletion of these three essential neurotransmitters and can also result in some of the following characteristics – phobias, delusional behaviour, obsessive compulsive disorder (OCD), frequent headaches, denial of illness and non compliance, difficultly with transitions, seasonal allergies, high achiever, a strong will, highly motivated, addictive behaviour, calm demeanour with high inner tension, social isolation and sparse hair growth.

The common biochemistry of an OVERMETHYLATION is:
1. Low blood histamine
2. Low basophil count
3. Low plasma zinc
4. Elevated copper
5. Elevated levels of the neurotransmitters serotonin, dopamine and norepinephrine.

Overmethylation can cause some of the following characteristics – high anxiety/panic, poor achiever and low motivation, artistic/musical ability, low libido and overweight, easily frustrated, sleep disorder and paranoia, depression and self isolation, self mutilation and nervousness, tinnitus (ringing in the ears), food/chemical sensitivities, high pain threshold, past history of ADHD, hyperactive psychosis, grandiosity, nil family history, hirsutism and eczema/dry skin.

Things that can affect methylation

Lack of the necessary precursors such as:

  • methionine
  • choline
  • betaine
  • homocysteine

Lack of co-factors:

  • B12
  • Folate
  • Zinc
  • B2, B3 and B6

Enzyme polymorphisms (genes)

  • COMT

Methylation impairments

Impairment of methylation reactions could result in a condition of high levels of homocysteine known as hyperhomocysteinemia which can also be a marker of low levels of B12 and folate.

What is homocysteine?

Homocysteine is a chemical in the blood that is produced when an amino acid called methionine is broken down in the body. We all have some homocysteine in our blood, but high homocysteine levels, also called hyperhomocysteinemia, may cause irritation of the blood vessels which can increase the risk for hardening of the arteries which could eventually result in a heart attack and/or stroke, and blood clots in the veins, referred to as venous thrombosis.

Causes of Elevated Homocysteine

  • Deficiency of folate or B6 and B12
  • Kidney disease
  • Hypothyroidism
  • Medications such as methotrexate
  • Methylenetetrahydrofolate reductase (MTHFR) genetic fault
  • Psoriasis
  • Systemic lupus erythematosis

Risks Associated With Elevated Homocysteine Levels

  • Coronary artery disease
  • Heart attack
  • Stroke
  • Peripheral arterial disease
  • Venous thrombosis
  • Pulmonary embolism
  • Dementia
  • Neural tube defects in children

Let’s have a look at the main causes of elevated Homocysteine

If one of the causes of elevated homocysteine is MTHFR gene mutation, what does this mean?

What is the hereditary predisposition MTHFR?

Some people develop an elevated homocysteine level because of a genetic predisposition which then creates the methylation defect that affects the ability of the body to convert folate and thereby creating problems with regulating homocysteine levels in the body. We all have 2 MTHFR genes, one inherited from each parent for each of the two genes. Some people have a genetic mutation in one or both of their MTHFR genes. People with mutations in one MTHFR gene are called “heterozygous” for the MTHFR mutation, but if mutations are present in both genes, the person is said to be “homozygous” for the mutation.

The most common MTHFR mutation is called the MTHFR C677T mutation, or the “thermolabile” MTHFR mutation. Another common mutation is called MTHFR A1298C. To have any detrimental effect, mutations would usually be present in both copies of a person’s MTHFR genes. Even when 2 MTHFR mutations are present (eg, 2 C677T mutations, or one C677T mutation and one A1298C mutation), not all people will develop high homocysteine levels. Although these mutations do impair the regulation of homocysteine, adequate folate levels essentially “cancel out” this defect, especially if the folate is consumed from foods or the more active form of folate such as calcium folinate or better still is the 5MTHF.

Regardless of whether someone has an MTHFR mutation in both genes or not, the treatment for elevated homocysteine is the same—dietary intervention and supplementation with folic acid and vitamins B6 and B12. If supplementing, then the amount of each of these supplements should be adjusted on the basis of the degree of homocysteine elevation, not genetic status.

Symptoms of MTHFR gene copying errors

These can include fatigue, depression, cardiovascular disease, and other more vague complaints such as aches and pains and other symptoms.

A closer look into the world of B12 and folate:

There are two different co-enzyme forms of vitamin B12:

  1. Methylcobalamin
  • Used by the enzyme methionine synthase to turn homocysteine (HCY) into methionine (a methylation process).
  • Methionine is further converted to the important methyl donor, S-adenosylmethionine  also known as SAM or SAMe
  1. 5′-deoxyadenosylcobalamin
  • Used by the enzyme methylmalonyl-CoA mutase to convert methylmalonyl-CoA to succinyl-CoA.
  • Used by the enzyme leucine aminomutase to convert B-leucine into L-leucine and vice-versa.

Anemia and Folate

Traditionally, B12 deficiency, normally resulting from the poor ability to absorb B12, but also from poor methylation, was diagnosed by finding abnormally large red blood cells. This sort of anemia has two names:

  • Macrocytic anemia – when the average volume of the red blood cells, known as the Mean Corpuscular Volume (MCV), is larger than normal
  • Megaloblastic anemia – when abnormally large red blood cells are observed under a microscope

The vitamin folate (aka folic acid) affects the anemia symptoms of B12 deficiency. Folate is needed to turn uracil into thymidine, an essential building block of DNA. DNA is needed for new red blood cell production and division. B12 is involved in this process because in creating methylcobalamin (used in the HCY to methionine reaction), B12 produces a form of folate needed to make DNA. If there is no B12 available, this form of folate can become depleted. Lack of Anemia Does Not Mean B12 Status Is Healthy. Traditionally, the existence of macrocytic anemia was relied on to indicate a B12 deficiency. However, neurological disorders due to B12 deficiency commonly occur in the absence of a macrocytic anemia.

Methylmalonic Acid (MMA)

The second coenzyme form of B12, adenosylcobalamin, takes part in the conversion of methylmalonyl-CoA to succinyl-CoA. When B12 is not available, methylmalonyl-CoA levels increase. Methylmalonyl-CoA is then converted to methylmalonic acid (MMA) which then accumulates in the blood and urine. Since B12 is the only coenzyme required in this pathway, MMA levels are the best pathology test indicators of a B12 deficiency.

High MMA levels can also (but rarely) be caused by genetic defects, kidney failure, low blood volume, gut bacteria changes, pregnancy, and thyroid disease

Folic Acid

FOLATES, FOLIC ACID, AND UNMETHYLATED FOLIC ACID are the different forms of folate. Found in leafy green vegetables, natural folates are the group name for related members of this B-vitamin family. The synthetic form, folic acid (FA), is used in fortified foods and most dietary supplements.

  1. Folate. This form of the vitamin is found in our green vegetables. If you eat about 1.5 cups of cooked greens three or more times weekly you will obtain enough natural folate to overcome almost any genetic copying defect.  Folate is also found in meats, eggs and other foods, but not as much.  Some folate can also be made in the intestinal tract.
  1. Folic acid. This is a synthetic form of folic acid that is widely used in B vitamin supplements. This form is not converted as well to the active form of the vitamin in people with the copying weakness (MTHFR gene defects) and so creates point 5 below.

  This is a supplemental form of folate that is well utilised by most with the copying defect mentioned above.

  1. Folinic acid. This is a supplemental form of folate that is well utilised by most with the copying defect mentioned above.

  This is also a supplemental form of folate that is well-utilised by those with the copying defect.

  1. Methyl folate. This is also a supplemental form of folate that is well-utilised by those with the copying defect.
  1. Unmethylated or unmetaboilised folic acid (UMFA).

With increased consumption of folate fortified grains and the popularity of vitamin supplements, many people are getting too much synthetic folic acid. Unlike natural folate, synthetic folic acid is processed very slowly in the body even at the Australian Recommended Dietary Allowance (RDA) intake of 400 mcg per day (for adults), UMFA can be found in the blood stream for extended periods of time. UMFA should be monitored for anyone who takes vitamins and/or consumes products with fortified enriched grains and cereals. Monitoring is also strongly recommended for women who are pregnant or who are trying to become pregnant. It has been known to increase the feelings of ‘morning sickness’, so nutritional supplements with folic acid are not advisable with those who have the MTHFR gene defects and preferably should use the more active forms.

What is the danger of too much UMFA?

  • Depressed immune function
  • Enhanced development and progression of certain cancers
  • Anaemia, poor cognition, and impaired memory especially with low B12 status

When folate is properly processed it can support the body with:

  • Making red blood cells
  • Proper nerve function
  • Bone health
  • Healthy brain and memory
  • Proper immune system function
  • Cell production, especially in skin and the digestive tract
  • Prevention of neural-tube defects (cleft lip and palate, spina bifida) in a developing foetus
  • Preventing miscarriage

Supplementation to support under or over methylation


Those with undermethylation often respond well to methionine, SAMe, 5HTP, calcium, magnesium, omega-6 essential oils such as borage and evening primrose oil, B-6, inositol, and vitamins A, C, and E, plus zinc, TMG or DMG. They should avoid supplements containing folic acid, but can tolerate the more active forms where there is MTHFR defect, especially if Homozygous for the defect.


This condition is the biochemical opposite of undermethylation. Those with overmethylation usually respond well to folic acid, B-12 (active forms), niacinamide (B3), DMAE, choline, manganese, zinc, omega-3 essential oils (DHA and EPA) and vitamins C and E, but should avoid supplements of methionine, SAMe, inositol, TMG and DMG.

In conclusion we have seen how methylation supports the body to detoxify as well as adjusts and rebuilds components needed for all bodily processes so also helps to control inflammation, maintaining good DNA transcription, support our immune and cardiovascular systems and provide us with the energy needed for our daily tasks and importantly also gives us a healthy brain and mood.