A Pediatrician Goes In-depth Into MTHFR

MTHFR Gene Mutation Testing: Helpful or “Hypeful”

There are certain posts that we write that are guaranteed to cause a reaction…vaccines, raw milk and essential oils are some of the ones that have really brought on the comments. The usual comments don’t surprise me…from “you don’t know what you’re talking about” to “but ____________ really worked for me and my family.”

But, I try to not to worry too much and I try to do my research to present to you the best possible information available, ignoring whatever the response might or might not be.

I suspect the topic of MTHFR gene mutations will soon be added to my list of topics that bring on controversy because a consistent response to the other hot topics is…“But, what about people with MTHFR gene mutations?”

So, you might call MTHFR mutations the controversial topic of the controversial topics…the uber-controversy…or meta-controversy.

What is the MTHFR enzyme?

MTHFR (or 5,10-methylenetetrahydrofolate reductase for long) is an enzyme that, according to the American College of Medical Genetics and Genomics practice guideline on the topic, “catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-5-methyltetrahydrofolate, the primary circulatory form of folate, and a cosubstrate for homocysteine remethylation to methionine.” Easy, right?

MTHFR is an enzyme. An enzyme is a substance that speeds up chemical reactions. Enzymes help almost every chemical reaction in our body. The efficiency of an enzyme can be sped up or slowed down by many different factors. MTHFR matters because the last product in its pathway, methionine, is converted to another product that can donate something called methyl groups. Methyl groups can be donated to many different parts of the cell and play an important role in the function of DNA and proteins.

What happens if MTHFR doesn’t work?

In instances when mutations in MTHFR cause the enzyme activity to be severely impaired, it can lead to elevated level of an amino acid (the building blocks of protein) called homocysteine. Buildup of this amino acid may increase the risk of blood clotting and heart disease.

Recent studies have cast doubt on this association and have shown that treating the elevated levels of homocysteine may not decrease the incidence of heart attacks but we know that homocysteine does activate blood vessels and make them more likely to form clots. Mutations that do not affect homocysteine level have not been proven to cause disease. Many variations exist at the gene level which do not appear to affect the activity of the enzyme. Without further confirmation that these cause problems, they should probably be thought of as normal variations (like eye color).

Studies have attempted to link mutations in MTHFR to over 600 different medical conditions. There have been 1000s of publications and no doubt more that went unpublished. Yet, only one condition has been definitely shown to be an increased risk in children with MTHFR mutations: women with a variant known as C677T have a slightly increased risk of delivering a child with a neural tube defect (like spina bifida).

Individual studies have shown other associations but, for each condition, there are conflicting studies that argue against MTHFR being a cause.

At this point, the American College of Medical Genetics and Genomics does not recommend routine testing of MTHFR for patients with blood clots, for women with recurrent pregnancy loss or for any other condition.

So, what’s all the buzz about?

There are a handful of doctors and naturopathic providers out there recommending MTHFR genetic testing for just about any condition under the sun. They generally recommend testing and then having the genome analyzed by a second company (often this second company is run by or provides financial kickbacks to the referring provider). After this, the treatment plans often involve supplements and other therapies. These treatments can be very expensive.

The providers of these services often tout their extensive research. The research may include some of the scientific studies that have suggested a link between MTHFR and the condition at hand, but they often ignore the other published evidence (often of stronger quality) that fail to show the same link. Other research published on their websites show collections of anecdotal stories, even down to the level of collections of blog posts, which report improvement in symptoms after having completed MTHFR testing and diet or supplement modification.

What are others saying?

As I mentioned before, the American College of Medical Genetics and Genomics practice guideline does not recommend MTHFR testing for evaluation of increased blood clotting, recurrent pregnancy loss or at-risk family members despite the fact that these are the most plausible diseases which would be caused by MTHFR mutations. No other medical societies have endorsed MTHFR mutation testing.

I think the most telling evidence comes from this post and summary of the topic from the 23andMeBlog. 23 and Me is a company that offers the genome sequencing (for $149) which is necessary for starting the workup for MTHFR mutations. So, they have 149 reasons for you to want to investigate your MTHFR status. But, what is their summary?

“Based on the existing data, scientists at 23andMe have concluded that people should not interpret their genotypes at the common MTHFR variants as having an effect on their health. In order for a connection between a genetic variant and a health condition to be considered real and clinically meaningful, well-run scientific studies need to show convincing and consistent evidence for that association.”

So, if no diseases have been definitively proven to be caused by MTHFR mutations, no major medical society endorses MTHFR evaluations and the company that can sell you the evaluation says it’s not worth it…maybe we should really think twice before going down this pathway except in very specific cases.

Your questions:

Does having a mutation on the gene for MTHFR absolutely mean that you will have problems because of it?

Unfortunately, it’s not that straightforward. Variations on the gene are very common. I have seen figures up to 40-60% to have some type of change. But, those changes do not necessarily mean that a person will have increased risk of disease because of them. Many of these changes could be (and probably are) normal variants. Based on our current knowledge, if levels of homocysteine are normal, it does not appear that the mutations are clinically significant.

Think about something like eye color. Around 55% of the population have brown eyes, but that doesn’t mean that everyone else will have poor vision. How do we test for vision? With a vision test, not by checking the genes for eye color.

How do you check for MTHFR function? With homocysteine levels. It is possible that there might be other and better ways of testing for MTHFR function to be discovered, but I cannot find studies or recommendations for how to do so at this time.

Should vaccines be delayed or deferred in children with MTHFR mutations?

I can only find one study that looks at the relationship between vaccine side effects and MTHFR mutations. This study was looking at side effects of giving small pox vaccination in a population of ~125 patients. Those that had MTHFR mutations did show an increase in adverse events. The adverse events listed were both local (larger mark at the site) and systemic (fever, rashes and lymph node swelling). They did not report any further or long-term side effects.

I saw one of the major writers about MTHFR talk about how the mercury in vaccines combined with a patient with MTHFR mutations might have problem processing the mercury. The problem with that specific theory is that mercury is no longer included in vaccines except for multi-dose flu vaccines vials. For discussion of other heavy metals, see the question on the topic later.

I think it is very possible that, over time, we will discover that children may have differing responses to vaccines based on their genetics. The differences may be in side effects or effectiveness of the vaccines and will likely only affect an extremely small percentage of children. The problem is that we currently don’t have any information to inform those decisions. Further research is necessary and anyone who claims to know the secret link should have their claims evaluated with extreme caution. In addition, because differences in MTHFR genes are so common, it is hard to imagine that it will play a significant role in vaccine reactions. If they were, I would expect reactions to be much more common than they are.

Is there an association between MTHFR and autism?

There has been a few studies that have shown a connection between a slight increase in autism risk and a particular change known as C677T. A large study that combined the results of multiple studies (our favorite kind of study, known as a meta-analysis) showing something very interesting: “C677T polymorphism was found to be associated with ASD only in children from countries without food fortification.” The association between this mutation and autism disappears in countries where foods are fortified with folic acid.

There are no other significant studies that show a link between MTHFR and autism symptoms. While many of the MTHFR experts claim that high percentages of kids with autism have MTHFR mutations/variations, so do people without autistic traits. Proving it as anything more than coincidence would require that the number of mutations be higher in children with autism than neurotypical children.

Is there an association between MTHFR and processing toxins or metals?

This question is difficult to answer because the definition of what is a toxin is very hard to pin down. Pretty much anything we come into contact with can be a toxin if the exposure level is high enough. Almost every substance in nature is harmless if we aren’t exposed to too much. So, the ability to process toxins is vague and would be hard to define or study.

The discussion of metals is a little bit different. One of the most studied metals in association with MTHFR mutations is lead. One study suggested that moms who have mutations in the MTHFR may make their child more susceptible to developmental problems if they are exposed to significant amounts of lead before age 2. Other metals have not been studied as well although you could theoretically see how similar results might be obtained.

Can people with MTHFR mutations have trouble when they are given acetaminophen or other medications?

Acetaminophen causes depletion of glutathione which is an antioxidant that prevents protects damage to many parts of our cells. This has been implicated to cause a role in several different diseases-most commonly asthma and making asthma worse. Other studies have linked acetaminophen use to other problems, including use during pregnancy also causing autism. MTHFR mutations work on a related pathway and thus, people with decreased functionality of the enzyme could be at increased risk for these effects.

While firm treatment recommendations have not been changed as a results of these studies, I think it is prudent to decrease the use of and reliance on medications for most symptoms where possible. Some of the common scenarios where I see overuse of acetaminophen are: teething (kids don’t having teething symptoms for weeks), “low-grade” fevers and routine/scheduled acetaminophen after vaccines. I would be happy if my patients (MTHFR or not), never received treatment for these symptoms.

The most likely scenario where MTHFR mutations do have effects on the use of medications is in those conditions where treatment with parts of the same pathway are involved. Chemotherapeutic agents used for cancer and auto-immune disease (rheumatoid arthritis for example) often work on parts of the same pathway. We should use caution and continue to study the effect of MTHFR mutations in patients who need to receive these types of medications.

Is there a relationship between MTHFR mutations and tongue ties, stork bites, sacral dimples or other physical findings?

Yes, I’ve seen the graphic. But, is there a relationship between MTHFR mutations and tongue ties, stork bites, sacral dimples or other midline defects?

Stork bites are a common red mark found on the back of the neck. Sugar bugs are a prominent blue vein found on the nose. They have been a concern in Chinese medicine for ages and supposedly indicate a tendency towards a sensitivity to sugar. Tongue-ties are also fairly common and most are also normal variants. Sacral dimples are also a common finding. They are little bumps at the base of the spine, usually just above or in-between the crack of the bottom. They can be the mildest form of spina bifida. While most are not concerning, the doctor should look for the base of the dimple as well as the size and then be on the lookout for symptoms that could be signs of spina bifida.

I have searched the literature for any connected between these findings and MTHFR mutations. No studies exist. Because studies that fail to show a positive correlation are not often published, it is difficult to know if they have not been done or if they have been done, failed to show a correlation and thus were not submitted for publication.

What’s next for MTHFR mutations?

More research! We need to have more high quality studies performed before we can definitely say what the various mutations mean.

As with most findings from whole genome studies, because they only recently became available and cheap, we still need to learn what the various mutations mean. Only when we know what they mean can we reliably recommend treatment recommendations that make sense. Until then, recommendations will be based on theory alone and may or may not prove to be worthwhile. In fact, it’s often theoretical treatments that can end up being harmful.