[Neurosciences/Junk Sciences] MTHFR, folate, folic acid, spina bifida, autism…..Oh my!

Lately a lot of media attention has been revolving about folic acid (or folate which is strictly the same I will explain to you later) and I have seen a lot of worried and less worried mommy bloggers panicking about folate or obviously making comments about being diagnosed with MTHFR mutation, that folic acid is not folate, that the former is the “all-natural” and the latter is not absorbed, that folate-supplemented food is “evil”.
Add to it the recent oral communication presented at the International Society of Autism Research (ISNAR) Annual meeting in Baltimore that suggested an association between excessive folate consumption and increased risk for autism (as reported by ScienceDaily here) that was blown out of context in mainstream media (because of course mainstream media has a fond for blowing up single studies and junk science as fact).
You have the perfect storm for a major sanitary disaster to happen and the right condition for quacks to prey on panicking expecting mothers.
I feel it is important that we desacralize and demystify the “folate/MTHFR” scare using science and facts to better understand folate and folic acid, the physiological function of folic acid, why folic acid is essential and have been added to wheat and corn flour and why you should not stop taking folic acid without recommendation of your physician and pharmacist.

1. What is folic acid?
Folic acid  is also known as folate or vitamin B9. Some people will argue that it is not the same molecule. The fact is folate=folic acid, even Sigma-Aldrich (one of the main chemical manufacturer for scientific research) agree on me with this term (Sigma-Aldrich technical data sheet can be found here). Both share the same chemical identification number known as CAS (CAS-59-30-3).
The only difference is subtle and has to do whether you are referring to the non-ionized form (folic acid) or the salt (or ionized form, folate) form of folate. To understand it, you have to have a basic in organic chemistry but if you remember your high school science class, you should be able to understand the chemical structure below.2000px-folat-svg
As you can see we have two carboxylic acid groups (COOH<->COO- + H+) and one basic primary amine (NH2 + H+ <->NH3+) that is conjugated with two neighboring secondary amines.
If you remember your chemistry class, carboxylic acids are what we call weak acids, same for amines (weak bases). Each weak acid and base has a particular  feature called the pKa value. This pKa value is important as  giving the properties of a pH buffer solution. When pH=pKa, we have a 50%/50% ratio between ionized and non-ionized form and this gives the buffer properties of a solution. Most biological solutions have a defined composition that results in a particular pH. Most body fluids (with some exception such as stomach), have a pH defined by various chemicals. In blood and tissular fluid, this pH is set at 7.4. You should go slightly below (pH=7.3) or over (pH=7.5) and you will enter into an acidosis or alkalosis situation that can kill you if your body does not remediate. This is why the idea of alkaline diet or trying to alkalinize your body with lemon juice (an acid made mostly of citric acid) is completely useless and based on junk science (I have been discussing this aspect of junk physiology in an earlier post).
The pKa of folic acid/folate is about 3.37. At intestinal pH (~5.5), you are roughly 2 pH units over the pKa of folic acid, that means 99% of folic acid will be under form of folate and will harbor its two carboxyl groups as COO-.

2. What is folate biological function?

Folate is actively transported from the intestinal lumen and converted into different metabolic intermediates but usually will end up as 5-methyltetrahydrofolate (5-MeTHF).

gr2b1

Like any vitamin, Vitamin B12 plays an important function as a co-factor. You don’t need much of it, but you need it to have some enzymes to work. Without it, enzymes cannot work and you may develop severe vitamin malnutrition. For instance, a lack of vitamin A (beta-carotenoid) is a important cause of Vitamin A deficiency resulting in children blindness in South East Asia (this is the raison d’être for the genetically-modified rice or “golden rice” that can provide a steady Vitamin A supply in the region). This is also the case for vitamin C (ascorbate), an important co-factor for prolyl-hydroxylase, an enzyme synthesizing collagen that form your connective tissue. Without it, you end up with scurvy.

In the case of 5-methylfolate (named mTHF in the graph below), it is a pivotal cofactor in several biochemical reactions as depicted below:
nrc3557-f3

mTHF carry a very important chemical called methyl (CH3-) group. This methyl is given to the homocysteine that becomes methionine, an important amino acid. This methionine can in turn serve as a co-substrate for methyltransferase to transfer such methyl into an another molecule. Why methylation matters? Because methylation is a key element of epigenetics (epi=over). Epigenetics is a branch of genetics that studies how living organisms can modify DNA without altering its sequences. Mutations affect the DNA sequences, epigenetic do not affect the sequences. It is the same than putting your smartphone into a lock position. If you don’t enter the password, it will remains locked.
It is a way for the living organisms to switch off certain DNA regions that they do not need anymore for their function. This explains why you have nerve cells, blood cells, muscle cells, bone cells despite having the same DNA sequence in all of them. This explains why some bees will become queen and the rest will remains workers, foragers or soldiers. This explain why your hair become grey over time.

Remember the methyl group that was for donation? Here we go, it goes into one nucleotides forming our DNA, cytosine. Once added, cytosine becomes 5-methylcytosine.

zakhari01

3. What about folate and spina bifida?

Now you may have heard about folate deficiency and spina bifida. Folate plays an important role during embryonic development, as it will serve as a co-factor for various enzymes responsible for the neural tube closure.
The neural tube is an important embryonic structure as it will give rise to the central nervous system. In particular, there is a step that is in crucial need for folate, it is the closing of the neural tube (step D) on both the rostral (head) and the caudal (tail) region, to close the brain and spinal cord. Folate deficiency impairs such closure and results in two dramatic and lethal congenital malformations: spina bifida and anencephaly.

 

tmp1411

Because such condition can be prevented by ensuring a minimum daily folate uptake, the Food and Drug Administration adopted the enrichment of wheat flour with folate in 1995.
As you can see, upon introduction of folate-enriched flour, we can see a net decrease in the number of cases of spina bifida:
usa_spina_bifida_rates

However, this public health intervention was missing an important population at risk for folate deficiency, the Latin-American community, as corn flour rather than wheat flour is their staple food. The recent FDA approval to enrich masa corn flour should help to reduce such levels.

4. MTHFR mutation: Fact or fad?

In recent years, we have seen a sudden urge in number of persons claiming to have an MTHFR mutation and claim all their issues related to such mutation including fatigue, dizziness and other ailments. The problem encountered is the recent development of genetic testing is a wild wild West in which modern snake oil sellers claim to have accurate genetic testing . Science-based Medicine has done an extensive job to debunk this fallacy and novel type of quackery currently flourishing.
To be concise, I will say that MTHFR polymorphism is not an important concern for most individuals. However, it can be a serious risk for mother to be and pregnant women as their MTHFR enzyme maybe working at slower pace than normal MTHFR and therefore impair proper methionine metabolism. Because patients become aware of such mutation only after having an history of miscarriage or abortion due to spina bifida or anencephaly diagnosis during ultrasound maternal screening and constitute only a small population (~10% of the US population), the supplementation with folic acid is an easier and safer intervention.
If you want to know more about MTHFR mutation, please visit the adequate page at the National Institute of Health (NIH).

5. Folate supplementation and autism risk: what you should know

Asia was reported in the news, a recent study presented in a scientific conference associated an excessive folate intake with an increased risk of autism. Let it be clear, this is an oral presentation presented in front of other scientists at the meeting. This has not been processed through peer-review yet. So we have a lot of unknown and in particular we have to assess the quality of the data.
I want to be clear about this: if you are pregnant and on folate supplementation, do not change your treatment without having your physician (real physician, not a DC or a ND. A real physician in a real hospital) or pharmacist recommendation. By stopping your folate supplementation, you are putting your pregnancy at risk to develop a spina bifida or anencephaly that so far exceed the risk of autism.
This is also a grim reminder on a lot of supplements prescribed by quack doctors and naturopaths may have not the quality control to ensure you receive the correct amount of folate supplementation and you may have a risk of overdosing on it. Do not consider such supplement harmless and ask your physician and pharmacists to direct you and counsel you for the right folate dosing and source.

 

 

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