MTHFR debunked

This interesting article explains in detail many of the wrong assumptions of the so-called "MTHFR-experts". It shows why some of their assumptions are based on facts almost pulled out of thin air. And it raises the question of how they can be sure about suggesting supplements based on single mutations. We look at the science behind it. One assumption among "MTHFR-experts" is that homozyguous mutation in MTHFR C677T results in activity reduction of 70% of this single SNP (single nucleotide polymorphism), and that is far from proven. Another assumption is that the same mutation results in folate deficiency, and that is far from the truth in most cases. You should also read our BLOG-post "Methylfolate - the "suicidal" nutrient (don't believe the hype)". Some even recommend multi-vitamins, eating folate-rich foods or even take folate supplements, and that could make things even worse due to high folate level in these. Folate is not better than folic acid, and methylfolate is just slightly better. The assumption that one "cannot" convert folic acid, and only convert naturally occurring folate, is totally wrong. Too much of any of these (even methylfolate) could be a problem, but not for these reasons. Detoxing also seem to be a focus, but why not address the cause of the problem, which is poor methylation, by taking SAMe and cofactors instead of a bunch of alternative detoxing activities only? Of course, living a healthy lifestyle is also important. Besides, MTHFR does not mean that you are undermethylated (even if most maybe are), you could also be overmethylated (even if that is more rare), and that results in diametrically different symptoms and needs. "MTHFR-experts" might give you the impression that MTHFR mutants is one homogeneous population with the same "disease", and that taking a genetic test will give you many answers. What they don't tell you is that it just gives you a lot of questions and confusion. This makes you more susceptible to their easy or complex explanations and recommendations since they are the "experts", and if you have that single mutation everything can be "explained".

The exact number of genes in the human genome is not even found yet (estimates at the time being around 20,000), and we all have thousands of mutations (heterozygous or homozygous). One mutation does not at all mean the gene/enzyme is not working at all! The efficiency of the one SNP is reduced, but maybe not as much as some would like you to think. We are all different and that is a good thing. Variation is crucial for health and evolution, and most mutations have advantages as well as disadvantages making us all different in some way or another. Even identical twins who shared the same DNA at conception will have different genes (mutations) at birth and even develop differences later in life. This is called epigenetic changes (gene expression), and it turns out that methylation plays one of the most important roles in this:
“In general, methylation tends to inhibit or prevent gene expression, and the absence of a methyl mark tends to promote expression. Once established in the womb, the marks are firmly in place and usually persist throughout life. Environmental insults can produce deviant marks in the womb or later in life. Although the technology for reversing deviant bookmarks is still unavailable, effective therapies for treatment of many epigenetic disorders are known today. For example, many paranoid schizophrenics exhibit excessive dopamine activity that can be normalized by Vitamin B-3 that uncoils DNA to increase gene expression of DAT proteins (comment: this is the case for overmethylation). In another example, methionine and SAMe act as serotonin reuptake inhibitors by compacting chromatin to reduce production of SERT transport proteins. (comment: this is the case for undermethylation)”. 

Every “MTHFR-expert”, and also other good neutral sources, claiming that enzyme activity is reduced by up to 70% (only when you are homozygous for MTHFR C677T, and much less when heterozygous) all use as evidence this article written in 1994 (or links referring to it):
The fact is that the level of enzyme activity reduction is not proven with certainty, and could be far from accurate or even very wrong due to some very special conditions during the experiment. Even if it was true/accurate it should not scare you if only one SNP is reduced by 70% - you still have many other SNPs working at 100%, and supplementing with only methylfolate and too much of it could make things even worse especially if folate level is high to begin with. It is also mentioned in this article from 1994: “Large case-control studies are required to evaluate the frequency of this genetic change… and …Well-defined populations need to be examined, as the limited data set thus far suggests that population-specific allele frequencies may exist” (and while we are waiting for these studies, it is still used as proof).

In this study there were only 5 people who were homozygous for MTHFR C677T who were chosen from another study with vascular diseases, and another 7 individuals from another group (total 12 individuals). That is very few! In the “normal” group (no mutation in MTHFR C677T) there were only 19 individuals, and in the heterozygous there were only 9 individuals! The very low number of individuals is only one of the factors contributing to the uselessness of this study. At least one should question why the number 70% is used uncritically without mentioning the limitations in this study.

There are also other very important sources for errors:
1. The conditions: they did not measure MTHFR activity inside the human body, but the DNAs were expressed in E. coli (bacteria) to yield protein, and in addition to that the extracts were heated to 46 degrees Celcius for five minutes, and as they say “the expression experiments were not designed to measure differences in specific activity before heating, since variation in efficiencies of expression could contribute to difficulties in interpretation” and “It is possible that the mutant protein has increased stability in E. coli, or that inclusion bodies in our extracts contributed to differences in recovery of properly-assembled enzyme.”
2. How the selection was done. For instance it is not sure at all that homozygous mutation in it self increases the risk for elevated homocysteine levels which again increases risk for vascular diseases - we will get back to that. Other scientific data from Walsh Research Institute - using a much larger database of more than 30,000 individuals (might be much higher now), shows that elevated homocysteine is more common with overmethylation and that usually homocysteine is low with undermethylation regardless of individual mutations. This could mean that most individuals in this study were actually overmethylated, and therefore also depressed in folates (as confirmed by the study itself):
This makes the selection very unusual, since MTHFR mutation tends to slow down the methylation cycle. Besides, undermethylation is much more common than overmethylation.
The headline for the article is “Mutation in MTHFR as candidate genetic risk factor for vascular disease”, however they say “…our experiments do not directly address the relationship between this change and vascular disease. Nonetheless, this mutation represents a diagnostic test for evaluation of MTHFR thermolability in hyperhomocysteinaemia”.

Even if MTHFR activity is lower (not necessarily as much as 70%), that does not at all mean that the enzyme is not working at all, and one were not able to convert folate (as some misinformation out there from “MTHFR-experts” claims). One would simply not be alive if it did not work, and it happens more than a billion times per second for everyone regardless of MTHFR (the process is only a bit slower with some, and a bit faster with others depending on ALL genes active in methylation and also other nutritional and environmental factors).

Severe MTHFR deficiency however is more serious and is extremely rare (only about 50 cases worldwide - much more likely that you win first prize in the lottery - and you would have serious problems that would be discovered without general screening of MTHFR) and caused by mutations resulting in (perhaps) 0–20% residual enzyme activity:
If you are homozygous for only one of the two MTHFR genes you do not need to worry about that in it self, but you should look at the methylation cycle as a whole (if it is slow, fast or normal). There are several mutated genes that slow down the cycle, for instance: MTHFR, SAHH, BHMT, MS, MAT etc., and there are mutations in other genes that speed up the cycle: AGAT, GAMT, CBS, MT etc. It is still too early just by looking at the combinations of these and other genes to find out if you should supplement or not. It is better to look at symptoms or take a blood test measuring SAM/SAH.

You can still make sure sure the homocysteine level is not very high, but when undermethylated as most MTHFR mutants are, the homocysteine level is usually low (and it is more important, or at least beneficial to use the homocysteine actively in the methylation cycle). Some other studies suggest that homocysteine could be higher with homozygosity for the C677T (MTHFR 677C>T), and not with not heterozygosity. We will get back to these below, and there are sources of error and very special conditions, but anyway if homocysteine is higher with this mutation only, there are other vitamins that could alter homocysteine levels (like B6, B12 etc.) as found in the VITAcure Methyl Plus supplement.

There are some general studies suggesting association between the MTHFR polymorphism and elevation of homocysteine, but this seems like only in studies of indian population and not in western population, so other nutritional/environmental/genetic factors (or statistical errors) might be the cause:

As this article from American Heart Association suggests:
“Mild to moderate homocysteine elevations are common; extremely high homocysteine elevations are uncommon”
“If I Have Elevated Homocysteine, Should I Be Treated?
No. Although taking a daily supplement of folic acid, vitamin B6, or vitamin B12 can effectively lower blood homocysteine levels, such lowering does not lead to a decreased risk of cardiovascular disease, DVT, or PE. Therefore, at the present time, such supplementation with folic acid, vitamin B6, or vitamin B12 for primary prevention of cardiovascular disease is not recommended. Similarly, treating patients with elevated homocysteine and cardiovascular disease or DVT or PE is also not recommended.”
“In the United States, ≈20% to 40% of white and Hispanic individuals are heterozygous for MTHFR C677T…Although having a reduced enzyme function of MTHFR can lead to elevated homocysteine levels, it does not necessarily do so; many people have normal homocysteine levels” (comment: for this group there is no scientific proof indicating elevated homocysteine, quite the contrary according to sources above, and even if it was the case, the elevation is nothing to worry about).
“The presence of MTHFR mutations does not require any special treatment, such as supplementation with folic acid, vitamin B6, or vitamin B12, and no additional concerns arise.” (comment: looking at MTHFR mutations in it self has no meaning, you should look at your total symptoms etc., and perhaps you have a methylation imbalance (more likely) and because of that you are low in certain nutrients, then you should supplement with helpful nutrients to correct this imbalance. The imbalance could be due to many factors, genetics being one, and there are many genes playing a role in this (MTHFR genes are only part of the explanation). Nutritional and environmental factors could also explain imbalances (diet, stress etc.).

We mentioned some studies of homozygous MTHFR C677T. “MTHFR 677C>T polymorphism is the one most extensively investigated. However, the lack of homogeneity in the data and the high number of factors influencing plasma homocysteine concentrations remain conflicting. Moreover, studies on the evaluation of therapeutic interventions in improving the atherogenic profile, lowering plasma homocysteine levels, and preventing vascular events, have shown inconsistent results”.
“Hyperhomocysteinaemia is a multifactorial disease; smoking, coffee consumption, and lack of exercise can raise tHcy (Refsum et al. 1998; Nygard et al. 1997a; Nygard et al. 1998).”

Here is one Norwegian study it is often referred to (The Hordaland Homocysteine Study). It is an interesting study, but it does not actually prove that homozygous C677T results in elevated homocysteine (and that is not what they claim in this study either):
“From 1992-93, we screened 18,043 subjects, aged 40-67 yr, and found 67 cases (0.4%) with total plasma homocysteine (tHcy) > or = 40 micromol/liter. Compared to 329 controls, the cases had lower plasma folate and cobalamin levels, lower intake of vitamin supplements, consumed more coffee, and were more frequently smokers. Homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase gene was observed in 73.1% of the cases and 10.2% of the controls.”…
“We conclude that most subjects with hyperhomocysteinemia > or = 40 micromol/liter in the general population have the C677T mutation combined with low folate status. Daily supplement of low dose folic acid will reduce and often normalize their tHcy level.”
“Likewise, Jacques et al. (29) demonstrated that individuals who are homozygous for the C677T mutation have elevated tHcy only when the plasma folate is in the lower normal range(comment: that is usually more often the case with overmethylators as data from Walsh Research Institute shows).

Besides, why would people with homozygous MTHFR C677T have lower intake of vitamins, consume more coffee and more important: be more frequently smokers? And just THAT could be the whole reason for their vascular problems (first of all the smoking of course, and lack of exercise - coffee drinking is no longer significant risk factor as thought in the 90s).  

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