MTHFR: What the Bleep is It?

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• WTF is MTHFR?
• What's the Fuss?
• Should I Get Tested? What Tests?
• Should I Test and Treat My Kids?
• Epigenetics – Looking at the Bigger Picture

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If you've heard of MTHFR and have no idea what it is and feel like you should, of if you've discovered that you have this genetic change and are shaking in your boots, this article will help clear up your concerns and give you clear guidance on how to handle it for your best health. Wow, if ever a gene is having its day in the sun it’s the MTHFR. My Facebook Live on the topic drew 20,000 views in 2 days. I get questions about this popular topic from most of my patients, and emails about it regularly. I’m not quite sure how MTHFR became so famous – perhaps it’s the humorous acronym (look at it long enough if your brain doesn’t automatically fill in the missing letters), the popularity of 23andme genetic testing, or the very real risks it carries. But clearly, there are a lot of questions about it. And it’s an important gene, with significant consequences for some who have it.

In this article (and in the audio recording of the Facebook Live event, which you'll find posted below if you prefer to listen), I’m going to explain what MTHFR is, why it’s important in your body, what it means if you have the genetic change, whether and how to get tested if you don’t know if you carry it, what to do if you do. Hopefully I will also dispel your worries, because this is a very manageable issue with straightforward prevention steps you can take.

WTF is MTHFR?

The MTHFR gene provides the code for a specific set of instructions your body uses to make an enzyme called methylenetetrahydrofolate reductase – yes, a mouthful – so we all call it MTHFR.

Wait, what’s a gene? And what’s an enzyme? Let’s review these concepts first.

Genes, which are made up of DNA, are the basic units by which heredity happens – that is, the transfer of your genetic blueprint from your parents to you. They are present in all of your cells (except your red blood cells), and provide your body with the instructions for assembling all of your basic structures via protein formation. The Human Genome Project estimates that we humans have somewhere between 20,000 and 25,000 genes, each of which is made up from a few to thousands of sequences of the genetic building blocks called nucleotides.

Each of us is gifted with two copies of every gene, one copy of each inherited from each of your biological parents. These pairs are called alleles, and we all have basically the same number of genes, coding for the same proteins, with variations in some genes that give us our unique height, eye color, and other “traits.” We also have basically the same genes that program our biological functions, but even there, we can have variations. The most obvious differences occur when there are serious genetic variations that can occur by accident or damage in the reproductive process and lead to birth defects or diseases.

We also can have less serious variations in the sequences of our genes, whereby one of the smallest particles that make up our DNA, the nucleotides, gets dropped or swapped one for another, in one of the alleles. These changes are called SNPs, short for single nucleotide polymorphisms. However, unlike genetic defects that lead to diseases, the SNPs associated with the MTHFR gene don’t automatically cause disease or medical problems- they are changes that are modifiable with lifestyle and nutritional approaches that I’ll share with you in this article so you can prevent problems.

Enzymes are substances that “catalyze” reactions – which means they cause a chemical reaction to happen, for example, the formation or breakdown of proteins to make the structures that perform most of the functions in your body. MTHFR is an enzyme necessary for a number of important chemical reactions, as you’re about to discover.

What's the Fuss?

MTHFR is involved in a series of chemical reactions necessary for your body to properly use folate (vitamin B9) and, as part of a multistep chemical sequence, transforms a by-product of this process, homocysteine, which has been associated with intravascular inflammation and most of the medical problems associated with MTHFR SNPs, into the amino acid methionine, an important building block in protein formation and required for the formation of S-adenosylmethionine (SAM-E), a universal methyl donor for almost 100 different substrates, including DNA, RNA, hormones, proteins, and lipids. What's a methyl donor? It's a carrier that contributes a methyl group (unromantically, a carbon atom attached to three hydrogen atoms), to a biological reaction in your body.

Methylation is a process whereby one molecule passes a methyl group to another molecule,  a process that occurs in your body millions of times each minute. Methylation is responsible for genetic expression – activating (turning on) and silencing (turning off) specific genetic sequences. When a gene sequence is turned on that should be off, or turned off that should be on, the consequences can be serious – for example, cells are programmed to die when they are damaged – a process called apoptosis – if the sequences in this process are altered, damaged cells may, instead of automatically self-destructing as they are supposed to, continue to replicate. Another term for excessively replicating damaged cells? Cancer. Which is why MTHFR SNPs are associated with possible increased risk of cancer.

Methylation is also essential for detoxification processes to occur properly, and is necessary for the production of glutathione, one of the most important natural detoxification agents in our body. Thus the combination of decreased detoxification in our current environment with over 80,000 circulating chemicals, few of which have been tested for human safety, presents a potentially greater challenge and risks to the health of individuals with MTHFR SNPs, especially C677T.

Further, properly functioning MTHFR is also necessary for the utilization of vitamin B12, and MTHFR SNPs have been associated with vitamin B12 deficiency. Vitamin B12 is required for proper red blood cell formation, neurological function, and DNA synthesis.

While there are at least 40 variations in the MTHFR genes, the two that at this time we know carry the most significance for human health and potential disease are the MTHFR genes known as A1298C and C677T. Because we have one copy of each from each of our parents, we can have one or two variations in either. In fact, SNPs are incredibly common – about 30-45% of the population has one SNP in one or the other, and 10% of us have two variations in one or the other.

If you have one change in either gene, this is referred to as your being heterozygous for the SNP (often notated as +/-); if you have two changes in either gene, you are considered homozygous for that SNP (often written as +/+). So you can be either +/- or +/+ for A1298C, and/or +/- or +/+ for C677T.

One or even two changes in A1298C usually doesn’t usually lead to any health or medical consequences, though it merits awareness, while changes in C677T can, with two changes presenting the greatest likelihood of potential risk. Emphasis on the word potential – which I’ll come back to shortly.

Medically, because of the importance of adequate amounts of circulating folate, because of the potential harms of excess circulating homocysteine, and the hazards of methylation not properly occurring, the MTHFR C677T SNP has been associated with increased risks of the following:

• Vascular disease, high blood pressure, heart disease, cognitive dysfunction and dementia (including Alzheimer’s)
• Clotting disorders leading to excessive clotting (also increasing dementia and stroke risk)
• Glaucoma
• Depression, anxiety, and psychiatric disorders, as well as decreased response to antidepressant medications
• Fertility problems, miscarriage, Pregnancy Induced Hypertension (PIH), pre-eclampsia, and placental abruption.
• Intrauterine development of neural tube defects including anencephaly, spina bifida, and cleft lip and palate
• Vitamin B12 deficiency which can cause megaloblastic anemia, fatigue, weakness, constipation, loss of appetite, weight loss, neurological changes such as numbness and tingling in the hands and feet, difficulty maintaining balance, depression, confusion, dementia, poor memory, and soreness of the mouth or tongue.

Should I Get Tested? What Tests?

Conventional testing is readily available for the MTHFR SNPs themselves, and also for plasma homocysteine, B12, and folate levels. Any licensed provider can order these for you – though they are not necessarily all covered by insurance. Independent labs such as Genova and Doctor’s Data also offer these labs; I recommend reviewing your results with a knowledgeable medical practitioner before jumping to scary conclusions or jumping onto the high dose supplement bandwagon.

However, it’s very important to remember that the presence of an MTHFR SNP does not mean you are automatically at risk for any of the symptoms or conditions I’ve mentioned, and does not automatically mean you need supplementation to offset the potential risks. That’s all they are: potential risks. The presence of the gene alone doesn’t mean that the enzyme won’t function well. It can’t tell whether you personally are methylating well or poorly, for example, and whether you personally need additional support. And in fact, excess supplementation has it’s own risks!

In my practice, I check for the MTHFR A1298C and C677T SNPs themselves, along with testing for elevated homocysteine, and B12 deficiency in the following people:

• All women of childbearing age and specifically, all women trying to conceive, and women who have had a prior child with MTHFR-related birth defects or behavioral challenges or autism.
• Any patients with symptoms or a personal or family medical history that could be attributed to an MTHFR SNP, i.e., depression, heart disease, stroke, children born with neural tube defects, and any of the symptoms/conditions I’ve mentioned previously.
• Children with behavioral challenges or on the autistic spectrum (I check for SNPs, B12 levels, and elevated homocysteine).

So you’ve gotten tested and discovered that you have an MTHFR SNP and now you wonder what you should do. First – don’t panic! For one, just having the SNP doesn’t portend gloom or doom, and if you do have the SNP there are things you can do to protect your health.

Essentially, if you have the MTHFR SNP, you can’t get your folate into its methylated form, because your methylation pathway isn’t working, and then you can’t recycle your homocysteine back into methionine. It’s a bit like you need to get from Train Station A to Train Station C, but Station B is out of order. You need to hop a cab to get around the obstacle. Methylfolate is an already methylated form that allows you to bridge the gap without the functioning enzyme. From there, the rest usually takes care of itself. Read below for your specific needs.

I Have the SNP But Normal Homocysteine and B12 Levels, and No History of A Problem

If you have the A1298C SNP and no other issues or lab abnormalities, while technically current studies show no need for supplementation, I still recommend 400 mcg of methylfolate daily as it is protective, there's no harm at all, and we're still learning about the potential for these SNPs to be associated with disease.

If you have the C677T SNP, whether you are heterozygous or homozygous, and you have no other issues or lab abnormalities, I recommend a lifelong maintenance dose of 400 to 800 mcg of methylfolate daily depending on your family risk factors.

I Have the SNP and Am Trying (or Planning) To Conceive

In women of childbearing age, in order for folate (the naturally occurring form from plants), folic acid (the synthetic form), and methylfolate (the methylated form you need if you have the SNP) to have a protective effect against neural tube defects, it has to be taken during the first month of pregnancy – neural tube closure happens by 28 days of pregnancy – often before a woman even realizes she’s pregnant. Therefore, all women of childbearing age should be taking a supplement with 400-800 mcg of methylfolate specifically if she has the SNP or doesn't know, because the other forms will not only not provide her the form her body can utilize, but may actually be counterproductive. Then throughout pregnancy, the same dose should be maintained, and I go up to 1mg/day in women with a history of fertility challenges, miscarriage, or any of the pregnancy complications I mentioned above, or a child with any birth defects, behavioral challenges, or autism.

I Have the SNP, Elevated Homocysteine, Low B12, or MTHFR-Related Symptoms or Medical Issues

Here’s what you can do:

In my patients with elevated homocysteine I recommend supplementing with 800 mcg- 1 mg. of methylfoate daily, while trending homocysteine levels every 3-6 months until they are down to within normal range (< 8), and then staying on a lifetime maintenance dose of 400 to 800 mcg, unless additional dosing is recommended by your medical provider. If you are seeing a functional medicine practitioner, you may have been told you have elevated FIGLU – this is also a marker of trouble with folate metabolism, and is also suggestive of the need for homocysteine testing and methylfolate supplementation.

If your testing shows that you are low in Vitamin B12, you’ll want to make sure you’re getting ample sources of vitamin B12 in your diet, and supplement with methyl-B12 (methylcobalamine) as needed, however, without adequate methylfolate, you might not be able to utilize your B12 fully.

Sometimes, individuals struggling with depression need higher doses of methylfolate, even up to several milligrams daily, however, when exceeding 1 mg/day dosing I suggest working in conjunction with your medical provider. Over-supplementation of methylfolate can mask Vitamin B12 deficiency.

Histamine Intolerance and Methylated B Vitamins

For reasons beyond the scope of this article to discuss, individuals with Histamine Intolerance may find that methylated B vitamins act as a symptom trigger; in this case I supplement with SAM-E and trend homocysteine levels. If this is the case with you, I recommend working directly with a functional medicine practitioner experienced with histamine intolerance.

Should I Test and Treat My Kids?

As mentioned above, I test children on the spectrum and with significant behavioral issues for MTHFR, homocysteine, and B12. Otherwise, I don't routinely test kids under 2, or older kids. For kids that do test positive, and have medical issues, I supplement with 50-400 mcg of methylfolate depending on age, and I supplement with methylB12 accordingly. I recommend working with a functional medicine pediatric practitioner.

Epigenetics – Looking at the Bigger Picture

Geneticists have an expression: nature loads the gun, environment pulls the trigger. While having the MTHFR SNP may in itself inherently pose some risks that require you to supplement with methylfolate and methylB12, it’s important to also remember that just having the gene doesn’t necessarily increase your risks over the next person who doesn’t, and that we’re all at risk due to the overwhelming number of environmental toxins we’re facing in the setting of overall nutrient depleted diets. Skipping meals, skimping on veggies, and not getting enough phytochemicals in our diets, while also not getting enough sleep and being under undue stress and chronic overwhelm put us at just as much risk if not more, of health problems. And if you do have a genetic risk, you’ve got a double whammy.

So regardless of our MTHFR status, we all need to be mindful of supporting our elimination and detoxification pathways, avoiding the toxin exposures within our control in our diets, households, and body products, and leading healthful, mindful lives. Adding in a multivitamin with methylfolate, or supplementing a modest amount daily, is a safe and appropriate strategy even if you’re unable to get any testing and want to maximize your health protection.