It's 2024 and our understanding of the genome has changed so much since my first MTHFR post in 2010. I thought it was time for a deep re-write to reflect the changes in how I view this now famous genetic variant.
So, What is MTHFR?
Let's cut straight to the chase.
MTHFr is the acronym for an enzyme called Methyl-Tetra-Hydro-Folate-Reductase.
This enzyme's job is to activate folate (aka vitamin B9) by attaching a methyl group to it. A "methyl group" is a single carbon atom with 3 hydrogens attached. It sort of looks like a Mickey Mouse head (a big ball with 3 small balls attached). That little methyl group is needed for a LOT of body processes. So getting it where it needs to be is pretty important.
When people talk about "having MTHFR", they are talking about having a subtle variant of the MTHFR gene that makes a slower enzyme.
Note:
Everyone has 2 copies of the MTHFR gene
There are lots of variations of that gene, most don't matter
There are 2 common variations that matter when the system is under stress
If you have 1 or more copies of slow MTHFR, you still make the enzyme, and the enzyme still works, it just has a slower "top speed" than average
Details for the science nerds like me
Every enzyme (or protein or communication molecule) has a gene that holds the code to make it. The gene is named for the thing it makes. So the MTHFr enzyme is based on the MTHFr gene code. All enzymes, including MTHFr, are made by a 3-D printing process inside our cells. The "printers" are cell structures called ribosomes. The ribosomes read genetic code. Based on what is in that code, they assemble all of the essential proteins, enzymes, and communication molecules for our body.
The MTHFr gene has 20,373 base pairs, and those base pairs are the code for the 656 amino acids that make up the MTHFr enzyme. The shape of an enzyme is determined by the order of the amino acids that makes it up. The order of amino acids is determined by the exact genetic code it was printed from.
There is a "default" gene code for every protein and enzyme called the wild type. Any change to that code is called a variant. A change at a single base pair is called a SNP. Any change in the code for a gene makes a change in the shape of the final molecule. Depending on the location of the change it might or might not alter function.
If you want a closer look at this, you can check out this post about gene SNPs, and this post about the mRNA Covid vaccines to learn how the 3-D printing process works.
Types of MTHFR
There are hundreds of known variations of the MTHFR gene. The vast majority make changes in areas of the enzyme that do not matter. Around 30 of those variants can change the function of the MTHFr enzyme. Most of those are extremely rare, but there are 2 variants that are very common that also have the potential to change function. Approxmately 40% of the population has at least one of these common variants. When people talk about "having MTHFR" they are talking about these 2 variants.
The 2 most common MTHFR variants
You have 2 MTHFr genes (one from each parent). Each one could could have the "wild" code or a "SNP" variant. SNP variants are designated by a number, the number indicates the location on the gene. The 2 most common variants (that have been researched the most) are at the 677 and 1298 locations.
Location 677
The "wild" type is C, the variant is T.
SNP at this location
leads to amino acid change (alanine to valine) at location 222 of the enzyme.
makes an enzyme that is less effective when hot
make an enzyme that dissociates from its riboflavin co-factor 3x faster than usual
is more affected by low folate levels
is more likely associted with high homocystiene (vascular inflammation, cardiovascular disease, clots and strokes)
is more highly associated with neural tube defects
Impacts
No Variant (both genes wild: C677C)
enzyme has average top speed
Single (one SNP: C677T):
Called "single, heterozygous"
Enzyme system top speed is 30% slower than average
Enzymes produced by this verison of the enzyme are 60-70% slower, but since half of the enzymes are printed from the other copy, assuming that copy is "wild", you only get half of that impact.
Double (both genes have SNP: T677T)
Called "double, homozygous"
No normal speed enzymes being produced
Enzyme system top speed is 70% slower than average
Location 1298
The "wild" type is AA, the variant is C.
SNP at this location
leads to amino acid change at location 429 of the enzyme
does not change heat staibility
has less impact on homocystiene
has less association with neural tube defects
DOES affect conversion of BH4 which is the first step in the pathways for building neurotransmitters and nitric oxide.
Doesn't bind SAMe as well which is the "off" switch - this means the enzyme sometimes keeps working past the point where it is useful or needed.
Impact
No Variant (both genes wild: A1298A)
enzyme has average top speed
Single (one SNP: A1298C)
Called "single, heterozygous"
Enzyme system top speed is 20% slower than average
Enzymes produced by this verison of the enzyme are 40% slower, but since half of the enzymes are printed from the other copy, assuming that copy is "wild", you only get half of that impact.
Double (both genes have SNP: C1298C)
called "double, homozygous"
No normal speed enzymes produced
Enzyme system top speed is 40% slower than average
Mixed (one 677 and one 1298 SNP)
This is called "compound heterozygous"
In this scenario both of your MTHFr enzmes will be slow in one way or the other.
This combination makes for folate and methylation cycles that are more sensitive to stressors than average, and you might see a little of the downside of both variants.
Depending on which set of SNPs is dominant, you can end up with a MTHFr system with a top speed that is 40-60% slower than average.
USUALLY if you have a mixed mutation you get one from each parent. But it is possible that Both mutations can exist on the same gene (you can get both mutations from just one parent).
Because of that, it is theoretically possible to end up with 3 or even 4 mutations.
We don't usually see this because it affects systems crucial for fetal development so much that these conceptions are rarely viable.
Why MTHFr can matter
The speed of the MTHFr enzyme determines the speed of activating folate
MTHFr enzyme converts folate to its final active form L-5-MTHF. Converting between the forms of folate is called the "folate cycle", and each conversion is done by an enzyme (which is based on a gene of the same name). The speed of this conversion is partially dictated by the genetic speed of the enzyme. If you have the "slow MTHFR" gene, then that enzyme will be limited in its top speed for converting folate to L-5-MTHF.
L-5-MTHF is a co-factor for a lot of other enzymes
In the Folate Cycle map above, you will see enzyme acronyms in green and next to those are vitamin and mineral cofactors in yellow. Every enzyme needs specific vitamins and minerals to function, those are called co-factors. L-5-MTHF is an essential cofactor for some enzymes (and all enzymes are important for something).
Folate has to be activated to be absorbed from the gut
A lage portion of dietary folates are in the THF form (see map above), and need to be converted to the L-5-MTHF form before they are absorbed. The MTHFR enzyme acts in multiple locations in the body: first it acts in the small intestine where it does the final conversion of THF into L-5-MTHF so we can absorb it. We also convert folates inside our cells and inside our mitochondria. So a slow MTHFr enzyme means not only slower activation of folate, but slower absorption of folate from our food. Some dietary folate in plant-based whole foods is already in the L-5-MTHF form. So eating a plant-rich whole foods diet or taking pre-activated L-5-MTHF as a supplement gets around slow conversion and the L-5-MTHF gets absorbed directly.
Folate receptors only respond to L-5-MTHF
Folate has to bind to a receptor on the surface of a cell to get absorbed into the cell (so it can be used by all the pathways that need it). Both folic acid (synthetic folate) and L-5-MTHF can bind to the receptors, but only L-5-MTHF can act at the recptor or get into the cell.
L-5-MTHF (methyl folate) is the transition point between the "folate cycle" and the "methylation cycle". Both cycles affect a LOT of really important processes in our bodies. See the list below for all of the things that depend on these 2 cycles.
Things affected by the Folate Cycle
Reminder: having MTHFR does not mean that this system doesn't work. Even if you have "double" MTHFr this whole cycle still runs. However having slow MTHFr enzymes can potentailly affect all of the things below.
DNA synthesis which affects
New Cell production which affects
fetal development (leading to repeat miscarraige)
cleft palate and spina bifida
Intestinal lining turnover and repair
red and white blood cell production
wound healing
cancer (both too much and not enough methylation can be a cancer risk)
Neurotransmitter production
the whole cycle of neurotransmitter production is started by the same enzyme needed to convert folic acid to folate (DHFR)
Methylfolate is also a co-factor for neurotransmitter production
Ability to donate methyl group into the Methylation Cycle
Methyl folate activates B12 and Methionine by donating the methyl group
MTHFr can be rate-limiting for the methylation cycle (not enough L-5-MTHF can slow down the whole methylation cycle)
Things affected by the Methylation Cycle
The methylation cycle also impacts LOTS of body functions, and it all relies on being able to move a methyl group around. The Methylation cycle starts with L-5-MTHF donating its methyl group to B12 - which then donates it to Methionine which then hands it off to SAMe which gives the methyl group to more than 100 other enzymes. This affects:
Gene activation
methylation is what "turns on" or "turns off" genes
methyl groups bind to markers on genes to indicate if they should be "printed" or not
Cell membrane health and repair
The enzyme (PEMT) that makes phosphatidylcholine requires a methyl group
more than half of the methyl groups produced by the methylation cycle go toward making this enzyme
Energy production
Carnitine is essential to getting fatty acids inside the mitochondria so they can be burned as fuel
The enzyme that makes the pre-cursor to carnitine requires a methyl group
Neurotransmitter production and breakdown
COMT (catecholamine methyl transferase), SAMe, MTHF (L-5-Methylfolate), PNMT are all enzymes or cofactors needed to process neurotransmitters
challenges can be more common with 1298C variants
Homocystiene Levels
Homocystiene is the final product of the methylation cycle.
Elevated levels are associated with inflammation inside the blood vessels, which in turn increases the risk of cardiovascular disease, stroke, heart attack, dementia and more.
Low MTHF is one of the things that can raise homocystiene levels.
Elevated homocystiene is more common with 677T variants
Detoxification
glutathione production
affects detox of heavy metals and many chemicals
affects mitochondrial resillience during stress or illness
affects ability to balance oxidative stress with antioxidant activity
detoxification of most hormones and chemicals
lower detox capacity increases risk for a LOT of chronic health issues
this is part of why some people with MTHFR are so sensitive
Histamine breakdown
HNMT (histamine methyl transferase), MTHF (L-5-Methylfolate), and B12 are part of the primary histamine breakdown pathway
this is another reason why some people with MTHFR are so sensitive
Estrogen breakdown
COMT(catecholamine methyl transferase), SAMe and Glutathione all play a role in clearing estrogen from the body
Elevated estrogen ratio is a risk factor for several other conditions
Symptoms that can be associated with slow MTHFr genes:
To be clear, having MTHFR does NOT make these things happen, but if you have several of the things below, and what you have tried didn't work, MTHFR might be one of the underlying issues.
People with slow MTHFr genes can be fatigued, depressed and/or anxious and may have been feeling progressively worse over many years. Â They often have a strong family history of mental health issues, addictions, birth defects, stroke, allergies, and or cancer. Some people with MTHFr have "weird" responses to medications or treatments that seemed like they should work.
For many people, addressing slow MTHFr (or other related challenges) can be a "game changer" in their healing journey. Â Here is a short list of symptoms that can have MTHFr as a major contributor:
Choronic Fatigue
Anemia
Fibromyalgia
IBS
Allergies
Migraines
Anxiety / Depression
Focus and Attention
OCD and Addiction
Schizophrenia
Autism / Sensory Integration
Unusual response to medication or supplements
Slow healing
Higher risk of clots and strokes
Higher risk of Dementia
Why MTHFr matters (a little) less than we thought it did
It is not ONLY about the gene
Having the MTHFr gene does not directly cause any of the issues above. Those issues only arise in the context of stress on the system (emotional, biochemical, immunological, physical), and/or nutrient deficiencies.
Overclocking Capacity
Your enzyme systems do not run at "full speed" all day every day. Just because your car will go 100mph, doesn't mean that you drive it that fast all day. Usually you drive it at 25-50mph. Our enzyme systems are similar. We have more capacity than we use most of the time so that we can ramp up to full throttle when needed. In this context you can see that an enzyme that is 20--30% slower will not necessarily cause a problem on a day to day basis, but can be problematic under stress.
Genomic and Epigenetic Balance
Genetic variations that do affect function tend to be balanced by complimentary variations in other genes. This is part of the evolutionary process. Our genes evolve as our environment does. Just because a gene is not "typical" (aka "wild") doesn't necessarily mean that it isn't good.
Many Roads to Methylation
There are several ways to get methyl groups into the methylation cycle. L-5-MTHF is naturally occuring in many foods and can be absorbed and used directly. Protien contains methionine which already has a methyl group. Tri-methyl glycine donates 3 methly groups to L-5-MTHF's one. Methylated B12 can donate methyl groups. All of these nutrients are readily available in a healthy whole foods diet and as nutritional supplements.
What we were wrong about
Becuase MTHFR is genetic, you should take supplemental MTHF and Methyl B12 every day for the rest of your life. (wrong!)
This seems logical and boy did it make sense when we first learned about MTHFr. The methylation cycle (and its many impacts) is extremely dynamic. As it turns out, you can over-do methylation pretty easily.
Too much methylation can disrupt the balance of gene regulation, allowing too many genes to be turned on (expressed / printed) or turning too many genes off. This can throw other systems out of balance. Overmethylation can be as much of a cancer risk as undermethylation. Because the folate and methylation cycles are complicated and affect so many things, sometimes supplementation with folates backfires and makes people feel a lot worse. Sometimes supplementation makes people feel a lot better for a few months, and then the benefit seems to fade.
A safer approach is to keep an eye on how you are feeling. If you do not have any signs that your methylation system is falling behind, then do not take supplemental methyl folate (unless you are trying to concieve, and then a Prenatal with methyl folate is always superior to one with folic acid).
When in doubt, there are now testing panels available to track the status of your whole methylation system. Testing every now and then can help you correlate how you feel to how your methylation cycle is running.
It is important to
learn what YOUR symptoms are when you are falling behind in methylation
learn what unique combination of supporting nutrients is best for YOU
AND
track your methylation status with homocystiene levels and/ or the occasional full methylation panels
New 2020's Rule: Do NOT take L-5-MTHF supplements just because you have the MTHFr SNPs. Treat only when you have symptoms.
Summary
Having the MTHFr gene does not cause problems for everyone, and for the people it does affect, it doesn't necessarily affect them all the time (this is really important). MTHFr is one piece of a really big, complex web of biochemistry. Environmental exposures, stress, other genes, other nutrients, inflammation, infections, oxidative stress, all play a big role in how all these systems work together.
I have seen people with "wild type" MTHFr who still have low methlation function and lots of the symptoms listed above.
I have seen people who have double MTHFr who are as healthy and happy as can be.
A stressed out person who has poor nutrition and a big environmental exposure can have MTHFr enzymes that work just as slowly as someone with a double mutation.... ermmm... and that can happen to all of us. Most people don't have optimally functioning MTHFr enzymes just based on our diet, lifestyle and environment (before you even get to the genetics).
Eating a plant-rich, organic, whole foods diet provides active L-5-MTHF directly, as well as providing the nutrients, antioxidants, flavonoids and fiber to support the whole system. When stressors kick in and you start to see some low methylation symptoms, you can reach for your best combo of methylated supplements to give yourself a little extra support.
As you can see, these systems are complex and dynamic and must be put in the context of your family history, your personal history, diet, lifestyle, exposures, stressors and more. If you are struggling with symptoms, or are concerned about how MTHFr (or other SNPs) might be affecting your health it is best to see a practitioner who really understands these systems and has extensive training in both healthcare and genomics. Please don't make health decisions based on the generic (and sometimes incorrect) advice in books, blogs, and social media.
If you would like to learn more about my MTHFr and Genomic offerings check them out HERE!
Thanks for reading!!!
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