Category Archives: MTHFR

MTHFR C677T Superpower: Prostate Cancer Protection.

There could be benefits of MTHFR C677T mutation. Who knew? © Patrimonio Designs Limited | Dreamstime Stock Photos

There could be benefits of MTHFR C677T mutation. Who knew? © Patrimonio Designs Limited | Dreamstime Stock Photos

I am so happy to report that the MTHFR C677T mutation now comes with a superpower, and it’s prostate cancer protection.  It’s not quite X-Men worthy and I have to admit mind control might be a bit cooler, but protection against one of the most common forms of cancer is nothing to scoff at.

The association between MTHFR mutation and prostate cancer has been unclear, with some studies showing increased risk, some studies showing no change and some showing decreased risk, so the information can be difficult to wade through. A recent research study conducted in Shanghai and published in Scientific Reports shows that C677T polymorphisms, whether they are homozygous or heterozygous, are actually protective against prostate cancer although they are quick to say that this study was conducted on the Han Chinese population in Shanghai and that the results may be different for different ethnic groups.

The study shows that intracellular homocysteine levels are slightly elevated when the C677T mutation is present and that elevated homocysteine actually helps to encourage damaged cells, such as precancerous and cancerous cells, to die off the way they should, rather than proliferating into full blown cancer. In unfortunate news, a recent meta-analysis published in Genetics and Molecular Research, showed that this association may not exist in caucasian males and that in this population C677T mutation may not have any effect on prostate cancer. Interestingly, this same meta-analysis showed that the A1298C mutation might have a slight protective effect against prostate cancer in European males.




The most important thing to remember, is that almost every mutation that exists in humans or animals has a double edge – it often has some drawbacks, but typically benefits too or the members of the population with that mutation would die out.  MTHFR seems to be, if anything, becoming more common so I suspect in years to come we will find many other benefits associated with it.



Am I Overmethylated? MTHFR Questions.

Overmethylated vs. undermethylated seems to be one of those things that everyone defines a different way, so let’s talk about it and see if we can bring some clarity. The terms overmethylation and undermethylation make the most sense to me as the Walsh Research Institute uses them.  These are general physical tendencies based on the sum of your genetics, nutritional status and body burden. There isn’t one gene or genetic defect alone that can account for them – so just because you have an MTHFR C677T mutation doesn’t actually mean you’re over or under methylated (although it would be one factor that might push the balance to undermethylation).  Dr. Walsh describes one’s methylation status as being like a tug of war between opposing factors. Many of those are genetic and some are nutritional or environmental.

Overmethylation MTHFR

This is less common than undermethylation. According to Dr. Walsh’s research, 70% of the population are normal methylators, 22% are undermethylators and 8% are overmethylators. Overmethylation in this context means that the methylation cycle as a whole is sped up, or downstream reactions that use SAMe (the ultimate product of the methylation cycle) are compromised in such a way that there is too much SAMe floating around wanting to methylate something.

  • Clinically overmethylators are more likely to have agitated or anxious conditions. Frequently panic or anxiety attacks (64% of panic/anxiety clients at the Walsh Research Institute), paranoid schizophrenia (52% of paranoid schizophrenic clients at WRI were overmethylators), ADHD (28%), behaviour disorders (23%), depression (18%). Depression  can occur in under, normal or over methylators but 18% of depressed clients of Dr. Walsh are overmethylators.
  • Mutations most likely to contribute to overmethylation are AGAT, GAMT, CBS and MT. MTHFR mutation usually pushes towards undermethylation (but I myself am compound heterozygous MTHFR and an overmethylator) Remember that the presence of one or more of these mutations isn’t enough to say if you’re an over or under methylator. The combination of all of your genetic factors as well as your nutritional state must be taken into account. The best way to determine is through symptoms and traits.
  • Other contributing factors are impaired creatine synthesis. This is because Approximately 70% of the SAMe from the methylation cycle is used by creatine synthesis, so if this is impaired the SAMe is used more slowly. This can be due to genetic factors (AGAT or GAMP) or due to deficiencies of arginine or glycine. Also impaired cystathione synthesis, or other polymorphisms in methyltransferase SNPs that account for the rest of the SAMe use.
  • Overmethylation leads to excessively high activity of dopamine, norepinephrine and epinephrine in the brain.

    If this reminds you of you, you could be overmethylated. A photograph of Robin Williams taken by Michael Dressler in 1979, later used as a cover photo for Time magazine to highlight Williams.

    If this reminds you of you, you could be overmethylated. A photograph of Robin Williams taken by Michael Dressler in 1979, later used as a cover photo for Time magazine to highlight Williams.




  • Symptoms and traits of overmethylation include:
    • High anxiety
    • Sleep disorder
    • High energy, restless, must move and fidget
    • Verbose or talkative
    • Often high artistic or musical ability
    • Antihistamine intolerance (makes anxiety or restlessness worse)
    • Overly empathetic with others
    • Non-competitive in sports
    • Tendency towards food and chemical sensitivities
    • Less likely to have seasonal allergies
    • Histamine Intolerance (or HIT – this is essentially a food sensitivity to high-histamine foods)
    • Low libido
    • Dry eyes and mouth
    • Adverse reaction to SSRI drugs, SAMe or methionine (typically all make anxiety or depression much much worse.
    • An easy way to picture this type is by using Robin Williams as an example.

Is Overmethylated the Same as Over-supplemented?

No, although it seems that in a lot of popular literature on the subject people use the term interchangeably. So often you’ll see someone say that you might  be “overmethylated” if you are taking too much 5-MTHF or SAMe.  I feel that these are different things entirely.  If you have a tendency to be overmethylated then certainly you would probably feel worse taking something like SAMe, but even without that you are still an overmethylator (in my opinion).  Likewise taking too much 5-MTHF, doesn’t make you suddenly “overmethylated” it just means you’re taking too much.

Okay! I’m Overmethylated. Now What?

Interestingly the best way to balance the consequence of overmethylation, is still 5-MTHF.  This seems strange, because it is also the answer if you’re’ undermethylated, but the effects are actually coming from a different mechanism. Folate actually reduces activity at serotonin, dopamine and norepinephrine synapses. 5-MTHF is the active form of folic acid, and you can also get it from foods, especially if you have some trouble taking the supplement.  Trouble taking the supplement is surprisingly common, although I think less common clinically in overmethylators (in my experience) than in undermethylators. Niacin or niacinamide can also be helpful for overmethylators as they quench some of the excessive methylation. Again, start slowly.

I Want to Start Taking 5-MTHF. How Do I Make This Easy?

Any time you start taking 5-MTHF, or increase your dose, there will be an adjustment period.  Here’s a whole post on it.  Just remember, start with a low dose and increase really slowly. This is changing the way your neurotransmitters work and doing some heavy detox work, so it’s vital not to overdo it because that is crazy-making. Start low and go slow.



Methylfolate Makes Depression WORSE! How Is This Possible?

Finding out you have an MTHFR mutation can be exciting, in it’s own strange way, because all of a sudden there is hope that you can actually help yourself and fix how you’re feeling, so it really feels like being kicked in the gut if you start taking 5-LMTHF and the methylfolate makes depression worse.  Have no fear, there is an explanation and also some possible solutions. Read on my friends.

Methylfolate makes depression worse! Don't worry - there is a solution. Great photo by © Philippe Ramakers | Dreamstime Stock Photos

Methylfolate makes depression worse! Don’t worry – there is a solution. Great photo by © Philippe Ramakers | Dreamstime Stock Photos

Why Does Methylfolate Make Depression Worse?

We recently talked about the terms “undermethylated” vs. “overmethylated” and although there aren’t great lab tests to show your status, typically you can determine your general tendency through their symptom picture.  Depression, however, can be ambiguous because it can happen in people who are undermethylated, overmethylated or people with totally normal methylation.  Although having the MTHFR mutation pushes many people into the undermethylated category, having the mutation itself isn’t enough to tell you if you’re under, over or normal. I myself am a compound heterozygous MTHFR mutant, but happen to have other genetic factors that make me an overmethylator – go figure.




5-L methyltetrahydrofolate (5-LMTHF) is suggested for everyone with a methylation issue – over or undermethylators.  It’s the first line of defence because it can actually help both groups to balance their methylation in different ways.  Also for depression specifically, folic acid or 5-LMTHF supplementation can be extremely helpful even without a known methylation issue because folate deficiency is a common cause of depression – so really for most people folate is beneficial. There is one group, however, who doesn’t respond well at all that that is undermethylated people with depression.

Let me clarify – anyone starting 5-LMTHF for the first time, or even increasing a dose, may notice some side effects for the first few days.  Starting to methylate differently can be messy and so this first few days isn’t enough time to know if you actually have a bad reaction. This is why we talk so much about starting with a low dose and easing your way up. If you’ve started with a low dose and you’re easing into it, but your depression gets worse and stays worse beyond the first week or so, then chances are you have undermethylated depression. This means methylfolate, folic acid and even folate rich foods are probably always going to make your depression worse.    Here’s why:

The link between Methylfolate and Serotonin

This is complicated because typically boosting your methylation cycle also helps your body to make more neurotransmitters via BH4 (we don’t need to go into it, but if you want a refresher you can read about it here). So 5-LMTHF is supposed to fix depression by boosting levels of serotonin, dopamine and other key neurotransmitters.  The problem is that 5-LMTHF, folic acid and folate all have a second effect on neurotransmitters, which is to depress serotonin through an epigenetic mechanism.

Epigenetics is essentially the study of how external factors (like nutrition, stress, oxidative damage, etc…) influence the way our genes express themselves. Folate and folic acid, according to the Walsh Research Institute, have an epigenetic effect on the SERT transporter.  The SERT transporter helps to reuptake serotonin after it’s been released. SERT is the target for many pharmaceutical antidepressants (SSRIs, or Selective Serotonin Reuptake Inhibitors). SSRIs work because they interfere with SERT and so serotonin stays active longer, which means you get more benefit from this happy neurotransmitter. Methylfoate, folate from foods and folic acid, while they increases serotonin production through BH4, also increase SERT via an epigenetic effect.  This means they help your brain to clear out serotonin faster, thereby reducing the amount of serotonin that is available for you to use. Essentially this makes folate the anti-anti-depressant.  Sigh.

As a brief reality check – Walsh Research Institute is convinced this is happening (see the link to their presentation above), many MTHFR websites are convinced this is happening, and it certainly explains a lot of what I’ve seen clinically, but for whatever reason I can’t find any published research that says definitively that this is happening so please take this with a grain of salt.

Methylfolate Makes Depression Worse For Me – Now What?

Don’t worry – you have a couple of options.  If you’re sure this isn’t just your body adjusting to methylfolate (the symptoms last beyond the first week of moderate supplementation) then it’s time to check to see if you fit the profile of an undermethylator. If that sounds like you, and your depression is getting worse, then let’s look at your choices.

  • SAMe – Ultimately the end product of the entire methylation cycle is SAMe, so it can be a helpful work around for people who can’t take 5-LMTHF.  This is where all that methylfolate is going and although it doesn’t entirely cover the necessity for methylated folate, it does help with the depression. This is partly because SAMe is a very slow acting serotonin reuptake inhibitor – just like the pharmaceutical drugs only much less powerful. As with any methylation issue, start with a low dose and work your way up.
  • Methionine – This amino acid is a direct precursor to SAMe in the body, and uses the MATI/II enzyme (coded by the gene of the same name) to go through the conversion.  Because this turns into SAMe it can be a much more cost effective way to get the same benefits, which again is as a slow acting serotonin reuptake inhibitor.  The only situation in which that isn’t going to be helpful is if your MATI/II gene has an issue or something is interfering.  Most people find methionine to be effective though, so this can be a far less expensive solution. Again, start with a lower dose and work your way up.
  • St. John’s Wart – This has nothing to do with methylation, only with serotonin.  Happily, St. John’s wart shows similar effectiveness to SSRI medications for major depressive disorder, with significantly fewer adverse events.  Here’s the research study, from the Annals of Family Medicine that compares St John’s Wart (referred to by it’s latin name, hypericum) with SSRIs and other anti depressant medications as well as placebo. Go nature!

It should be said that while SAMe and Methionine will help to augment the methylation cycle, they still aren’t providing folate of any kind, so they won’t protect against the more folate dependent issues like neural tube defects in babies and issues with pregnancy and fertility.  If you have undermethylated depression and are considering getting pregnant it is vital to work closely with a doctor who can help you to get the folate that you need and also help you to offset the depressive symptoms that might come with that. Even though methylfolate makes depression worse,  in pregnancy it might still be necessary so please consult a physician.



If This Sounds Like You, You Might be Undermethylated

MTHFR mutation discussions can quickly turn into Greek and the topic of overmethylated vs undermethylated MTHFR is one of the Greekest. It seems like no two resources on the internet are talking about the same thing when they talk about it and so overmethylation and undermethylation are strange, kind of meaningless words because at the end of the day it feels like nailing jello to a wall. So let’s see if we can sort some of this out.

Whose Idea Is This? I’m Following The Walsh Research Institute

The terms overmethylation and undermethylation make the most sense to me as the Walsh Research Institute uses them.  These are general physical tendencies based on the sum of your genetics, nutritional status and body burden. There isn’t one gene or genetic defect alone that can account for them – so just because you have an MTHFR C677T mutation doesn’t actually mean you’re over or under methylated (although it would be one factor that might push the balance to undermethylation).  Dr. Walsh describes one’s methylation status as being like a tug of war between opposing factors. Many of those are genetic and some are nutritional or environmental.

Undermethylation MTHFR

This is the most common state. According to Dr. Walsh’s research, 70% of the population are normal methylators, 22% are undermethylators and 8% are overmethylators. Undermethylation indicates that the methylation cycle as a whole is slowed down enough that the end product, SAMe, is typically inadequate and thus causes symptoms.

  • Clinically undermethylators are more commonly autism spectrum (98% of autism spectrum clients at the Walsh Research Institute), antisocial disorder (95% of antisocial clients at WRI were undermethylators), schizoaffective disorder (90%), oppositional defiant disorder (85%), anorexia (82%), and depression (which can occur in under, normal or over methylators but 38% of depressed clients for Dr. Walsh are undermethylators).
  • Mutations most likely to contribute to undermethylation are MTHFR (C677T especially, but also A1298C), MS, BHMT, MAT and SAHH. Remember that the presence of one or more of these mutations isn’t enough to say if you’re an over or under methylator. The combination of all of your genetic factors as well as your nutritional state must be taken into account. The best way to determine is through symptoms and traits.
  • Other contributing factors are histamine overload and protein deficiency, as well as frank deficiency of folate.
Highly competitive? You might be undermethylated

Highly competitive? You might be undermethylated




  • Symptoms and traits of undermethylation include:
    • Strong willed
    • Highly competitive at sports or whatever matters to them
    • Obsessive/compulsive tendencies
    • Addictive tendencies (more likely to be addicted with less exposure than a normal methylator)
    • High sex drive
    • Tend towards high accomplishment and usually a high achieving family
    • Appear calm and well controlled (possibly over-controlled) but inner tension is high
    • Greater likelihood of seasonal allergies
    • Higher fluidity of tears, saliva, etc…
    • Perfectionist
    • Less likely to be compliant with therapies
Addictive behaviour? You could be undermethylated. © Francesco Bisignani | Dreamstime Stock Photos

Addictive behaviour? You could be undermethylated. © Francesco Bisignani | Dreamstime Stock Photos

Is Undermethylated the Same as Under-supplemented?

No! Although it seems that in a lot of popular literature on the subject people use the term interchangeably. So often you’ll see someone say that you might still be “undermethylated” if you aren’t taking enough 5-MTHF.  I feel that these are different things entirely.  If you have a tendency to be undermethylated then certainly you will probably need to take 5-MTHF, but even once you’re taking enough you are still an undermethylator (in my opinion), you’re just taking the right protocol.  Likewise taking too much 5-MTHF, doesn’t make you suddenly “overmethylated” it just means you’re taking too much.

Okay! I’m Undermethylated. Now What?

Absolutely the best way to enhance the methylation cycle is by taking 5-MTHF, or 5-L methyltetrahydrofolate.  This is the active form of folic acid, and you can also get it from foods, especially if you have some trouble taking the supplement.  Trouble taking the supplement is surprisingly common, typically it is an adjustment reaction to actually enhancing the methylation cycle because this changes neurotransmitter levels, encourages detoxification and encourages more than 80 reactions in the body that are methylation dependent. So some adjustment reaction when you’re first taking 5-MTHF is normal and actually a good sign that things are changing in your body.   There is one BIG EXCEPTION TO THIS, and that is if you are undermethylated and have depression.

I Want to Start Taking 5-MTHF. How Do I Make This Easy?

Any time you start taking 5-MTHF, or increase your dose, there will be an adjustment period.  Here’s a whole post on it.  Just remember, start with a low dose and increase really slowly. This is changing the way your neurotransmitters work and doing some heavy detox work, so it’s vital not to overdo it because that is crazy-making. Start low and go slow.

HELP! I’m An Undermethylator and I Have Depression.

My next post is going to be all about this because UNDERMETHYLATORS WITH DEPRESSION DUE TO LOW SEROTONIN CAN’T TOLERATE 5-MTHF, FOOD SOURCES OF FOLATE OR FOLIC ACID AT ALL. That’s a really big deal! Depression is typically characterized by low serotonin states and unfortunately 5-MTHF (or any folate or folic acid). The short explanation for this is that folate, 5-MTHF and folic acid all increase the activity of the transport protein that re-uptakes serotonin into the cell. Essentially this is the opposite of a serotonin reuptake inhibitor (like prozac), it’s a serotonin reuptake promotor – meaning it makes the serotonin you have far less effective because it clears it out more quickly. There will be a whole post on this – I promise!



MTHFR and depression – what is the link here?

MTHFR mutation is becoming kind of the “in” thing to have at the moment and it seems like everyone talks about MTHFR and anxiety, MTHFR and heart disease, MTHFR and depression. The question is, why does a gene for the enzyme that activates folic acid have anything at all to do with those things?  First off, if this sounds like gibberish, then here’s some background reading on MTHFR and on MTHFR and folate. Now – lets see if we can decode the link between MTHFR and depression, because understanding this can hopefully help a lot of people who are struggling start to regain some normal and some happy in their lives.

What is the Link Between MTHFR and Depression?

At the simplest most basic level, your body needs methylated folate (which is what you don’t make very well if you have the MTHFR mutation) in order to manufacture the neurotransmitters serotonin, dopamine, epinephrine and norepinephrine and also the neurohormone melatonin (which helps with sleep among other things). The methylated folate isn’t used directly for these neurotransmitters, but it helps to make something called BH4, or tetrahydrobiopterin if you want to be technical about it. BH4 is then used to help the neurotransmitters building blocks (which are amino acids) to be converted to the active neurotransmitters that your body uses for brain cell signaling.

This is the link between MTHFR and depression, in not so plain english. Great diagram from Dr. Rostenberg, in this post which goes into the subject in more detail. Dr. R was kind enough to give me permission to use this! http://www.beyondmthfr.com/mthfr-depression-folate-bh4-connection/

This is the link between MTHFR and depression, in not so plain english. Great diagram from Dr. Rostenberg, in this post which goes into the subject in more detail. Dr. R was kind enough to give me permission to use this! http://www.beyondmthfr.com/mthfr-depression-folate-bh4-connection/




Um… Still Not Following.

Right – so I honestly don’t think it is hugely beneficial when you’re trying to fix MTHFR  issues in yourself to actually dive too deep into the biochemistry of what is happening because it gets overwhelming really quickly.  Suffice to say that your body has trouble making neurotransmitters if it can’t make BH4 because there just isn’t enough methylfolate. When your body has trouble making neurotransmitters, then you can start to see symptoms including these.

Symptoms of Low Serotonin (Think Negativity and Anxiety):

  • Negative thinking – Pessimistic, cynical or distrusting thoughts.
  • Craving for sweets and starches – Bring on the bread. With a side of fries. These foods temporarily boost serotonin levels in the brain, so you might reach for these more frequently
  • Sleep trouble – You need to make serotonin before you make melatonin (your primary sleep hormone) so this can be a big issue.
  • Low self esteem – Serotonin is one of the chemicals that helps you to feel good about you. Without it, you might feel socially anxious, inferior, or incapable.
  • Anxiety – worry, apprehension, obsessive thoughts and panic attacks are all more likely when your serotonin is low.
  • Aggression – Violence, aggression and suicidal thoughts or actions (violence against yourself) are all symptoms of low serotonin.
  • Impulsive behaviour – Low serotonin can reduce your ability to control impulses.

Symptoms of Low Dopamine (Think No Motivation and No Reward):

  • Lack of Motivation – No real “reason” to do things that matters to you. This also shows up in difficulty getting going in the morning and outright fatigue.
  • Joylessness – Dopamine helps you to actually feel the positive effects of enjoyable things. Without it, everything is a little blah. You have a hard time experiencing pleasure.
  • Memory Loss – Forgetfulness, lack of focus and outright memory loss.

Symptoms of Low Epinephrine and Norepinephrine In the Brain (Think Get Up and Go Got Up and Went)

  • Mentally Worn Out – Mental energy is lacking. All mental effort feels like far too much.
  • Inattention – Can’t really focus on anything.
  • Lack of Excitement – Yeah. Another day in paradise.

The short version of all of this is that without MTHFR you have trouble methylating folate. Without methylated folate, your body lacks Bh4. Without enough BH4, you have low levels of these neurotransmitters and with low levels of these neurotransmitters, everything feels pretty yucky. Like sad, apathetic, anxious, joyless yucky. Is there hope? Hell yes! This isn’t the post for it, but here’s some info about finding the right dose of methylfolate for you, and here’s one about foods that are high in natural sources of folate. It’s a great place to start. Even if you have depression but haven’t confirmed that you have a MTHFR mutation this can be a really great place to start.



MTHFR Basics Podcast

This week I had the lovely opportunity to be on Blog Talk Radio with Erin Chamerlik, The Real Food Revivalist- see getbetterwellness.com. Her listeners wanted to know a little bit more about MTHFR mutation.  You can listen to the recording here:

MTHFR Basics Podcast with Dr. Amy Neuzil, ND on The Real Food Revivalist Show

Tune in now to listen to this MTHFR basics podcast.

Tune in now to listen to this MTHFR basics podcast.

Listen for answers to questions like:

  • What is the MTHFR mutation?
  • Is it Common?
  • What are the implications for fertility and mood?
  • What sort of testing is available for MTHFR?
  • How do you start supplementing with 5-LMTHF?
  • Doesn’t this have to do with detoxification too?

 



I hope you enjoy this free podcast and if you have any questions for me please feel free to post them as comments. 🙂



I Have MTHFR A1298C Mutation – What Does That Really Mean?

MTHFR mutations are just starting to be recognized as an issue and so more and more doctors are testing, but what happens if your doctor tells you that you’re homozygous for MTHFR A1298C? They might as well be speaking Greek! So here’s the skinny on what that really means. Also here’s a post about MTHFR mutation basic in general.

MTHFR A1298C Terminology Basics (or as basic as we’re going to get with genetics).

The simplest level of information here is just the plain genetics.  Here are some quick factoids to get us started:

  • MTHFR is the short name for the genes that code for the enzyme that changes folic acid to the active form that your body uses (the long name is methylfolate reductace).
  • 1298 is the marker for one particular MTHFR gene.
  • The official genetics labeling of this gene is Rs1801131. Sigh.
  • You get one copy of this gene from your mother and one from your father, so there are two possible copies that can be either “normal” or “mutant”
  • If you inherited one good copy and one bad copy that’s called “heterozygous A1298C”
  • If you inherited two bad copies (one from each parent) that’s called “homozygous A1298C”
  • A…C stand for the bases that you actually have.  A = adenine C = cytosine.  Bases are essentially the letters that spell out your genetic code.  There are four of them commonly (C, T, A and G).
  • When this gene is “normal”or “wild type” (I love that name) it looks like MTHFR A1298A.
  • Heterozygous mutations (one good copy and one bad) are MTHFR A1298C because there is one normal A and one abnormal C Also occasionally written 1298AC.
  • Homozygous A1298C (two bad copies) can also be written as C1298C (because there are two abnormal copies with C instead of A). Occasionally you’ll also see it written 1298CC

Phew! So the take-away there is MTHFR A1298C means you have at least one bad copy of this gene, and if it’s called homozygous, or C1298C then you have two bad copies.

How Much of a Problem Is This?

The MTHFR A1298C mutation is considered less serious than the C677T mutation because it seems to cause less impairment to actual methylation function than C677T.  That doesn’t in any way mean that it isn’t an issue. This mutation can still be a significant problem If you don’t have a good diet, don’t take supplements or burden your body with a lot of stressors like smoking, alcohol, drugs, sedentary lifestyle or high stress. If you get lots of dark green leafy veggies, legumes and other food sources of natural folate – see this post – then you’re probably already getting good methylfolate. If your diet isn’t up to scratch, then supplementation can be useful and here’s a whole post about that.

Heterozygous MTHFR A1298C is thought to have mostly normal MTHFR activity  and homozygous MTHFR A1298C (C1298C) have about 65% normal activity (so 35% compromise). Normal activity refers to the way your body converts folic acid to 5-L-methyltetrahydrafolate (the active form) so that it can be used. Compromise in this case looks like a folate deficiency.

What Are The Health Risks of MTHFR A1298C Mutation?

According to SNPedia, which compiles research on genetics, A1298C mutants have been shown in at least one research study to have an increased risk for:

  • Midline defects such as:
    • Cleft lip
    • Cleft palate
    • Neural tube defects
    • Facial asymmetries
  • Cancers including:
    • Breast
    • Lung
    • Brain
    • Stomach
    • Head and neck
    • Kidney
  • Cardiac-related issues including:
    • Thrombosis (increased tendency to clot inappropriately)
    • High homocysteine levels (a heart risk)
    • Pre-eclampsia (dangerous high blood pressure in pregnancy)
    • Vascular dementia
  • Fertility issues including:
    • Multiple pregnancy loss
    • Low sperm count
    • Birth defects such as down syndrome
  • Neurological issues including:
    • Migraines
    • Autism
    • Alzheimer’s dementia
  • Mood and psychological issues including:
    • Depression
    • Anxiety
    • Schizophrenia

You’ll notice that this is quite a list, and it can be a little daunting to think about when you’re just learning about this. Most research doesn’t differentiate between the A1298C genetic variance and the C677T genetic variance so the list is the same for both mutations.  We assume the risk is lower with A1298C because the folate metabolism is less strongly impaired, but that might not be correct.

What Do You Do About This?

Compromise with the MTHFR A1298C gene can have severe consequences so it’s important to work on getting good sources of natural folate from foods, which is generally useable by mutants, or 5-MTHF (5-methyltetrahydrofolate) which is already methylated so the genetic compromise doesn’t matter.  As discussed in this article, I feel supplementation should be started slowly because for many mutants who haven’t had active folate very much in their lives it feels really strange when those active forms start showing up.  There can be quite an adjustment reaction  by your body.

Activated folate is used by your body to run enzyme pathways, to aid in some parts of normal metabolism, to help your body detoxify and even to methylate your DNA. The methylation cycle is also a big part of neurotransmitter manufacture, which explains the strong link to depression, anxiety, and mental disorders including addictions and even schizophrenia. If 5-Methylfolate  isn’t there then your body does maintains those functions as best it can, but the things your body can’t do start to pile up. Starting supplementation means your body can start digging in that pile to clear up high priority items.  This is exactly what we want, but if you start with high doses of a supplement then it’s a little like drinking from the firehose.  Kind of out of control and not very pleasant.

A great way to start if you’re unsure, is with a folate-rich diet.  I love this image because it kind of covers what we’re looking for.  Hint – think dark greens and beans. 🙂




Is folate in foods safe in MTHFR mutants? In these foods YES! For MTHFR C677T or MTHFR A1298C mutants. Thanks to exhibithealth.com for the great image.

Is folate in foods safe in MTHFR mutants? In these foods YES! For MTHFR C677T or MTHFR A1298C mutants. Thanks to exhibithealth.com for the great image.

Can Mutants Become “Normal”?

If you’re a mutant (like me) then you’ll always be a mutant, but it doesn’t have to matter. Essentially as long as you’re getting enough of the active form of folate and taking care of yourself for the other consequences of the MTHFR mutation then the mutation doesn’t have to matter.  If you aren’t taking care of yourself, then it matters a lot.

The bottom line is MTHFR A1298C mutations don’t have to mean anything at all as long as you supplement and have a good diet and lifestyle (here’s an article about a folate-rich diet for MTHFR mutants) I always suggest taking a little more care with yourself too.  There are known health risks for things like clotting, fertility and cancers so it makes sense to take some precautions.  Eat your fiber, do your exercises, get your sleep and generally treat yourself with high regard – shouldn’t we all anyway?