Methylation and Folate
What is methylation?
Methylation is one of the most important series of chemical reactions in the body. It is involved in repairing our DNA and protecting it against toxic damage, it helps control hormones, reduces homocysteine levels, a compound that damages blood vessels. Methylation supports detoxification, aids the nervous system and helps maintain inflammation plus many other important body reactions. It plays a key role in the production of glutathione (our body’s most potent anti-oxidant) that protects body cells against damage caused by free radicals or reactive oxygen species (unstable molecules) and the ability to neutralize toxins such as pesticides and heavy metals.
It helps support the body in a number of ways especially in preventing:
Degradation of the myelin sheath surrounding nerve cells commonly diminished in some individuals with autism
Dysfunctional immune T helper cell activity against pathogens (bad bugs) and an increased T helper cell response against food and environmental allergens
Methylation supports the production of CoQ10 required in optimizing mitochondrial energy production
Methylation supports the production of hormones and neurotransmitters such as dopamine, serotonin, melatonin, nor epinephrine and epinephrine
The methylation cycle starts with the amino acid, Methionine, derived from dietary protein and is found in foods such as animal protein, broccoli, turnips, sesame seeds and asparagus. Methionine is converted to S- Adenosyl Methionine, (SAMe) requiring magnesium to do this. SAMe is anti inflammatory amino acid which helps support the immune system and produces dopamine, serotonin and melatonin. Dopamine is important for focus, concentration, short term memory, emotional stability, organization, vestibulo-visual interaction, coordination and affects the levels of the stress hormones epinephrine and nor epinephrine, serotonin is supportive of mood and is known as our happy hormone and is also required for the contractions of the gut and melatonin is important for sleep.
SAMe in the methylation cycle produces homocysteine with the aid of vitamin B6. If levels of homocysteine (a protein that is damaging to our body) becomes too high it is then converted back to methionine using an enzyme called methionine synthase (MS) which requires 5-methyl-THF, derived from Vitamin B9 or folate and its production is governed by the C677T MTHFR gene and involves Vitamin B12. If C677T MTHFR is defective this conversion of folate to 5-methyl THF will not occur and subsequently an impaired conversion of homocysteine back to methionine results leading to high and damaging homocysteine levels in the blood system.
It is estimated that approximately 40% of Americans have a defective C677T MTHFR gene (heterozygous meaning 1 copy of the mutation or homozygous meaning 2 copies of the mutation) which may not strictly be inherited but as a result of toxic damage or epigenetic changes to the MTHFR gene and switching it off. The good news is that this gene may be switched back on with appropriate nutrient interventions including vitamin B9 or folate as 5 –MTHF, vitamin B12 (as Methylcobalamin), Magnesium and betaine as TriMethylGlycine (TMG). It is also important to remember that in order to produce glutathione, homocysteine must go through a series of reactions known as transulfuration. This is also commonly impaired in individuals with autism, ADHD and ADD and requires B6 (as P5P), Betaine (as TMG), the amino acids cysteine, glutamine and glycine, magnesium and potassium.
How to test for C677T MTHFR gene mutation?
A simple genetic blood test will identify a heterozygous or homozygous C677T MTHFR gene mutation. It is advised that homocysteine levels are also checked.
If a C677T MTHFR mutation is present limit folic acid rich foods in the diet and foods fortified with folate as this form of folate cannot be utilized and stop taking supplements with folic acid in them as processing of folic acid to 5-Methyl THF is impaired.
Nutrient Recommendations for supporting methylation and C677T MTHFR mutations: Please seek guidance from your health care professional.
Methylfolate as 5-MTHF
Vitamin B12 as Methylcobalamin
Betaine in the form of TMG
Magnesium
Amino acid complex containing methionine, cysteine, glutamine, glycine
SaMe (may be supportive if homocysteine levels are low)
In addition to the above the following nutrients are involved in transulfuration which reduces homocysteine to make glutathione:
Vitamin B6 as Pyridoxal-5-phosphate (P5P)
Potassium
N-Acetyl cysteine (not to be used in individuals with autism with a Candida sp. overgrowth as it may encourage the proliferation of Candida)
If I asked you which of these vitamins was found naturally in food, folate or folic acid, would you know the answer?
If not, you’re in good company. Medical professionals, nutrition experts, and health practitioners frequently mix up the two, simply because the terms are often used interchangeably.
Many health professionals would even argue that folate and folic acid are essentially the same nutrient. While folic acid is often considered to be a supplemental form of folate, there is an important distinction between these two different compounds. For women past childbearing age, and for men in general, excessive doses of the synthetic form of this nutrient are not necessary, and may even be harmful.
What’s the difference between folate and folic acid?
Folate is a general term for a group of water soluble b-vitamins, and is also known as B9. Folic acid refers to the oxidized synthetic compound used in dietary supplements and food fortification, whereas folate refers to the various tetrahydrofolate derivatives naturally found in food. (1)
The form of folate that can enter the main folate metabolic cycle is tetrahydrofolate (THF). (2) Unlike natural folates, which are metabolized to THF in the mucosa of the small intestine, folic acid undergoes initial reduction and methylation in the liver, where conversion to the THF form requires dihydrofolate reductase.
The low activity of this enzyme in the human liver, combined with a high intake of folic acid, may result in unnatural levels of unmetabolized folic acid entering the systemic circulation.
Several studies have reported the presence of unmetabolized folic acid in the blood following the consumption of folic acid supplements or fortified foods. (3) Human exposure to folic acid was non-existent until its chemical synthesis in 1943, and was introduced as a mandatory food fortification in 1998. (4) Food fortification was deemed mandatory due to overwhelming evidence for the protective effect of folic acid supplementation before conception and during early pregnancy on the development of neural tube defects (NTD) in newborns.
Risks associated with excessive folic acid intake
While the incidence of NTDs in the United States been significantly reduced since folic acid fortification began, there has been concern about the safety of chronic intake of high levels of folic acid from fortified foods, beverages and dietary supplements. (5) One of the major risks associated with excessive intake of folic acid is the development of cancer. (6) In patients with ischemic heart disease in Norway, where there is no folic acid fortification of foods, treatment with folic acid plus vitamin B12 was associated with increased cancer outcomes and all-cause mortality. In the United States, Canada, and Chile, the institution of a folic acid supplementation program was associated with an increased prevalence of colon cancer. (7, 8) A randomized control trial found that that daily supplementation with 1 mg of folic acid was associated with an increased risk of prostate cancer. (9)
Researchers have hypothesized that the excessive consumption of folic acid in fortified foods may be directly related to the increase in cancer rates. Excess folic acid may stimulate the growth of established neoplasms, which can eventually lead to cancer. The presence of unmetabolized folic acid in the blood is associated with decreased natural killer cytotoxicity. (10) Since natural killer cells play a role in tumor cell destruction, this would suggest another way in which excess folic acid might promote existing premalignant and malignant lesions.
A high intake of folic acid might mask detection of vitamin B12 deficiency and lead to a deterioration of central nervous system function in the elderly.
In one study, consumption of folic acid in excess of 400 micrograms per day among older adults resulted in significantly faster rate of cognitive decline than supplement nonusers. (11) Another study found a higher prevalence of both anemia and cognitive impairment in association with high folic acid intake in older adults with a low vitamin B12 status. (12) As vitamin B12 deficiency is a common problem for many older adults, these studies suggest that high folic acid intake could cause serious cognitive consequences in the elderly.
Make it stand out
Despite the risks associated with high levels of folic acid intake, it is well established that adequate folate intake from the consumption of folate-rich foods is essential for health.
Folate aids the complete development of red blood cells, reduces levels of homocysteine in the blood, and supports nervous system function. It is well known for its role in preventing neural tube defects in newborns, so women of childbearing age must be sure to have an adequate intake prior to and during pregnancy.
Excellent sources of dietary folate include vegetables such as romaine lettuce, spinach, asparagus, turnip greens, mustard greens, parsley, collard greens, broccoli, cauliflower, beets, and lentils.
Not surprisingly, some of the best food sources of folate are calf’s liver and chicken liver.
You can supplement with folate if your dietary intake is inadequate. Look for products that contain the Metfolin brand, or list “5-methyltetrahydrofolate” or “5-MTHF” on the label. Avoid products that say “folic acid” on the label. Make sure to check your multivitamin, because most multis contain folic acid and not folate.
Women planning on becoming pregnant should consume between 800 and 1200 mcg of folate per day for several months before the start of pregnancy. Unless you’re consuming chicken or calf’s liver and substantial amounts of leafy greens on a regular basis, it’s difficult to obtain this amount from diet alone. If you’re pregnant or trying to get pregnant, I recommend supplementing with 600-800 mcg of folate per day, depending on your dietary intake.
Glutathione (GSH) is the most prevalent and potent antioxidant and detoxifier in the body.
Significant deficiency in glutathione is common in people with autism due methylation and transulfation ( a series of chemical reactions that make glutathione) gene defects and is increasingly being viewed and researched as a major factor in the condition.
The main functions and abilities of glutathione are as follows:
Binds to toxins making them more water-soluble and easier to eliminate
Powerful antioxidant that neutralizes damaging molecules called free radicals
Vital to cellular energy production by protecting mitochondria (power houses in each cell)
Supports production of lymphocytes (white blood cells)
Natural chelation agent, bonding with heavy metal molecules for elimination
Regulates protein bonds
Maintains integrity of the gut lining by neutralizing microbial toxins and stimulating immune function
Individuals who have genetic mutations with methylation such as hetero or homozygous mutations with MTHFR and transulfuration genes may not be able to produce sufficient glutathione via the methylation or transulfuration pathways and therefore supplementation of glutathione and using nutrients such as MTHF as a folinic acid supplement may be supportive.