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.

Read the full article: CookChildren's Checkup Newsroom

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