MTHFR debunked

This fascinating 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 homozygous mutation in MTHFR C677T results in enzyme activity reduction of 70%. This exact number is far from proven. Besides, the very uncertain underlying scientific findings of activity reduction is even misinterpreted to the claim that 70% less methylfolate is produced! There are more than 100 SNP locations in MTHFR. MTHFR consists of about 600 amino acids and is a relatively large enzyme. 677 and 1298 are just two of these locations (SNPs) that are thought to be more significant than others, but "MTHFR-experts" seem to convince us that these two SNPs in MTHFR are the only ones there are (OK, they are considered the two most important locations, but...). Consider this fact when you look at a "genetic report" showing only locations 677 and 1298. If you have a mutation in one (or both) of these two, you still have around 100 MTHFR locations that might work at 100% efficiency if there are no SNPs in these. Or you might have mutations in many of these locations not showing in the genetic report.

Another assumption from the "experts" is that the same mutation results in folate deficiency, and that is far from the truth in most cases (based on the alternative fact that you produce up to 70% less methylfolate when you have a double C677T mutation). If you read on, you will find the underlying scientific findings the "experts" use does not prove that at all. You should also read our BLOG-post "Methylfolate - the "suicidal" nutrient (don't believe the hype)." Some even recommend multivitamins, eating folate-rich foods or even take folate supplements, and that could make things even worse. 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 entirely wrong. Too much of any of these (even methylfolate) could be a problem, but not for these reasons. Detoxing also seems 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 under-methylated (even if most maybe are), you could also be over-methylated (even if that is rarer), and that results in diametrically different symptoms and needs. "MTHFR-experts" might give you the impression that MTHFR mutants are 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 simple 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 enzyme might be 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 distinct 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:
http://www.walshinstitute.org/epigenetics.html
“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 the 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 over-methylation). 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 from 1994 (or links referring to it):
http://digitalcommons.unl.edu/cgi/viewcontent.cgi?article=1123&context=lawfacpub
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 extraordinary conditions during the experiment. Even if it was correct it should not scare you, since you still have many other locations in MTHFR enzyme and other enzymes working at 100%, and supplementing with only methylfolate and too much of it could make things even worse especially if folate level is high. They also mention that 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, some still use it as proof).

In this study, there were only five people who were homozygous for MTHFR C677T chosen from another study with vascular diseases, and another seven individuals from another group (total 12 individuals). That is very few! In the “normal” group (no mutation in MTHFR C677T) there were only 19 people, and in the heterozygous group, there were only nine individuals! The low number of people 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 critical sources of errors:
1. The conditions: they did not measure MTHFR activity inside the human body. 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. 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 (comment: or perhaps the other way round), or that "inclusion bodies" in our extracts contributed to differences in recovery of properly-assembled enzyme.”
2. The selection. For instance, it is not sure at all that a homozygous mutation (in it self) increases the risk for elevated homocysteine levels which again increases the 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 over-methylation and that homocysteine usually is low with undermethylation regardless of individual mutations. This could mean that most persons in this study were over-methylated, and therefore also depressed in folates (as confirmed by the study itself):
http://www.walshinstitute.org/biochemical-individuality--nutrition.html
This makes the selection very unusual since MTHFR mutation tends to slow down the methylation cycle. Besides, there are three times as many under-methylated people than over-methylated ones in the total population. Therefore the selection might be unusual in that regard also.
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 hyperhomocysteinemia”.

Even if MTHFR activity is lower (although not as much as 70%), that does not at all mean that the enzyme is not working at all, and one is 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 extremely rare (only about 50 cases worldwide). It is much more likely that you win first prize in the lottery, and you would also have serious problems that would be discovered without a general screening of MTHFR) and caused by mutations resulting in (perhaps) 0–20% residual enzyme activity:
https://www.ncbi.nlm.nih.gov/pubmed/20356773
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). Several mutated genes 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 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 extraordinary 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.

Some general studies are suggesting an 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:
https://www.ncbi.nlm.nih.gov/pubmed/25591425

As this article from American Heart Association suggests:
http://circ.ahajournals.org/content/132/1/e6
“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 present, such supplementation with folic acid, vitamin B6, or vitamin B12 for primary prevention of heart disease is not recommended. Similarly, treating patients with elevated homocysteine and cardiovascular problems 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 the two MTHFR mutations 677&1298 only 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 many genes are 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”.
https://www.ncbi.nlm.nih.gov/pubmed/18670064
“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 prove that homozygous C677T results in elevated homocysteine (and that is not what they claim in this study either):
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC507663/
“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. A 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 over-methylators as data from Walsh Research Institute shows).

Besides, why would people with homozygous MTHFR C677T have a 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 a significant risk factor as regarded in the 90s).  


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  • Ted Hu on

    There are exceptions to rule like cerebral folate deficiency. Whereby increasing both folinic and or methylfolate dose may be required to overcome.

  • A on

    The articles on MTHFR are very interesting and informative. I recently had lab work on… Edit: Name and the rest removed and question moved to the appropriate place – NEW Help Center (F.A.Q): https://www.vitacure.me/apps/help-center


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