- 1 MTHFR mutation may increase the risk of cardiovascular disease and vitamin B deficiencies
- 2 What about other disease states and disabilities, like cancer and hypothyroidism?
- 3 MTHFR symptoms of a problem
- 4 Folic acid is a problem, L-Methylfolate (5-MTHF) is an alternative
- 5 Folic acid, MTHFR and pregnancy Active folic acid is highly protective against Neural Tube Defects.
- 6 MTHFR diet and nutrition recommendations
- 7 MTHFR in the medical community
- 8 How and where to get an MTHFR test
- 9 The Bottom Line
Hacking Nutritional Support for Methylation
Here are some of the important ones that you can get through diet and, for some, you might need add some supplementation.
For folate, eat uncooked green vegetables, and for you beef liver lovers, it’s the top source. Folate requires active transport across the intestinal mucosa, so if you have IBS or other gut problems, you might not be absorbing enough. http://lpi.oregonstate.edu/mic/vitamins/folate
Vitamin B12 (aka cobalamin) is the yin to folate’s yang – both are required at a critical point in the methylation cycle. If you’re a vegetarian, you will need to supplement regardless of genetic variants because it is found in highest quantities in animal products. Some supplements use cyanocobalamin, but if you have the MTRR genetic variant, you might want to consider methylcobalamin if your blood levels stay low after supplementing.http://lpi.oregonstate.edu/mic/vitamins/vitamin-B12
Vitamin B6 in it’s coenzyme form is involved in more than 100 enzyme reactions, mostly concerned with protein metabolism. Pyridoxal 5′ phosphate (PLP) and pyridoxamine 5′ phosphate (PMP) are the active coenzyme forms of vitamin B6. PLP is involved in the metabolism of one-carbon units, carbohydrates, and lipids. Tuna is the best source, followed by spinach, cabbage and bok choy. Go easy on the cooking since prolonged heat can degrade B6. Inflammation can lead to low B6 levels. http://lpi.oregonstate.edu/mic/vitamins/vitamin-B6
Mind your zinc levels. I could do a whole separate post on the role of zinc in immune health! Oysters, red meat, sesame and pumpkin seeds and lentils rank highest as food sources, but phytates bind zinc and will limit it’s absorption from grains, legumes, nuts and seeds. Another reason to soak them before using. GI disease, diabetes, and liver disease can decrease zinc absorption. http://lpi.oregonstate.edu/mic/minerals/zinc
Choline is not a vitamin, but considered an essential nutrient. Humans only synthesize a small amount, so we all need to bump our dietary or supplement intake. If you don’t consume or supplement enough folate, the body draws on choline to recycle homocysteine, reducing the amount that can be used to produce phosphatidylcholine, and essential to keep your cell membranes fluid and functional. Shrimp, eggs and scallops top the list of food sources. If supplementing, the best type of choline is up for debate. You can search APOE4.info for those discussions. Citicoline is recommended by Dr. Bredesen for the ReCODE protocol.http://lpi.oregonstate.edu/mic/other-nutrients/choline
Consider using a nutrition tracker, like MyFitnessPal or Chron-o-meter, for a short while to see if you are getting enough micronutrients. They can be tedious to use, but eye-opening. And make sure to test your blood levels and see if you are within range before deciding to supplement. In addition, prescription drugs, other supplements and aging can impact your ability to absorb and utilize vitamins. If you’re looking for specific foods that can boost specific nutrients, I like to use http://www.whfoods.com/.
And lastly, if you go back to the large Seeking Health diagram, you can look for other co-factors that could potentially be tweaked.
Hacking Genetic Variants
Supplementation might be needed with some of these genetic variants. Work with your doctor to get the appropriate labs done, and always start with low doses and work up to a level that works for your target range. For that reason, I do not recommend amounts because they should be based on your individual needs, except for a comment on where to start with methylfolate, mostly driven by personal experience. Some doctors may suggest higher doses, so I’m suggesting a starting point.
Start any B supplementation regime with methyl-B12 first, especially if your labs show low B12 status. This avoids a potential “methylfolate trap” where methylfolate can’t get converted due to lack of B12. For more on that, see http://www.ncbi.nlm.nih.gov/pubmed/16445837.
Use a methylated version of folate. This allows you to bypass the less efficient process of converting dietary folates to their active form. Too much methylfolate is a problem, too, so start low (400 mcg/day or less), and go up slowly. Side effects of too much methylfolate include irritability, insomnia, anxiety, headaches, migraines, palpitations, sore muscles and achy joints. If you feel any of these symptoms after taking folate, try taking 50-100 mg of niacin as nicotinic acid. Niacin is broken down by SAM, so it’s a good way to use up excess SAM (from excess folate).
It is also important to use methylfolate with MTHFR variants because there is competition between “active” folate and “inactive” folic acid. So, it’s best to avoid vitamins or processed food products with folic acid.
A Perspective on Systemic Nutrition and Nutritional Genomics
“Dietary folate and folic acid supplements compete with L-methylfolate at the blood-brain barrier. Unmetabolized folic acid is unable to cross the blood brain barrier and may become bound to folate binding receptors on the membrane, blocking absorption of the active form, L-methylfolate (Zajecka, 2007.)”
Avoid Nitrous Oxide gas at the dentist. This study shows that patients with a homozygous MTHFR 677C>T or 1298A>C mutation are at a higher risk of developing abnormal plasma homocysteine concentrations after nitrous oxide anesthesia. http://www.ncbi.nlm.nih.gov/pubmed/18580170
Avoid Methotrexate. The analysis highlighted a significant association of 677C>T polymorphism with overall MTX toxicity, hepatotoxicity, hematological toxicity, and neurotoxicity. It also revealed an association with MTX toxicity in patients with rheumatoid arthritis. http://www.ncbi.nlm.nih.gov/pubmed/22143415
Avoid Lamisil. “It was later noted that Lamisil’s mechanism of action interferes with cells’ methylation cycle, which we suspect compromises cellular function in people with the methylenetetrahydrofolate reductase genetic mutation.” https://www.ncbi.nlm.nih.gov/pubmed/25929315
Check for hypothyroidism. In hypothyroid conditions, the hepatic activity of MTHFR is decreased. http://www.ncbi.nlm.nih.gov/pubmed/16335688
Other Genetic Hacks
With the remaining genetic variants, I have not found many direct studies testing specific treatments. So, if you want to treat any of the following, here’s a starting point and feel free to check the Seeking Health diagram for other substrates and co-factors and go from there. N=1!
Test your folate, B12 and zinc levels. Supplement as needed to get within range.
Take care using methotrexate for rheumatoid arthritis if you have the A2756G G variant. This genotype was associated with MTX-induced accelerated rheumatoid nodulosis (MIARN). (http://www.ncbi.nlm.nih.gov/pubmed/17611986)
You might want to look at B12 metabolism genes, too, such as transcobalamin II (TCN2), which is essential for the uptake of vitamin B12 from the intestine. With variants, sublingual B12 might work better to bypass intestinal absorption.
TRANSCOBALAMIN-II VARIANTS, DECREASED VITAMIN B12 AVAILABILITY AND INCREASED RISK OF FRAILTY
Common variants of FUT2 are associated with plasma vitamin B12 levels
All humans have the same set of genes. Our differences come from the tiny variations in those genes.Those variations influence not only in how you look or behave different to others… But in how your body reacts differently to external factors. Especially how it reacts to the foods you eat and lifestyle you live.
Some have issues that increases their risk of Alzheimer’s disease, known as APOE4.
This is because we all have certain genetic variations or “defects” that can influence how we metabolise and use certain nutrients.
One of the more common and potentially dangerous variations is known as an MTHFR mutation.
This gene variation can impact how well your body metabolises folate and folic acid. Both are forms of vitamin B9, required for numerous critical bodily functions.
Unfortunately, a fault in this metabolic cycle is linked to many serious health problems (3).
This article describes the MTHFR mutation and explores what implications it may have for your health and diet.
Note that each section in this article has a ‘summary’ box (like this one) to save time.
What is MTHFR, the MTHFR gene, and MTHFR mutation?
MTHFR, short for Methylenetetrahydrofolate Reductase, is a very important enzyme in the body.
It’s necessary for Methylation to occur, a metabolic process that switches genes on and off, repairs DNA and many other important things.
This is a diagram of how complex it is, but you only need to see the final step.
Without the enzyme activity of MTHFR, methylation of folate and folic acid cannot occur properly.
Put simply, the MTHFR gene triggers the production of MTHFR enzymes.
Think of the gene as the flower, the enzyme as the honey-bee, and active folic acid as honey.
Without flowers, there will be no honey-bees. Without honey-bees, no honey is created.
Roughly 30-50% of us carry a mutation in the MTHFR gene, passed down from our parents.
The two main functional mutations (also known as polymorphisms) of the gene are MTHFR C677T and MTHFR A1298C (3).
Specifics aside, these genetic mutations are collectively known as MTHFR mutations.
They can be like a “defect” which limits production of your MTHFR enzymes.
Most people with a mutation remain unaffected and do not experience symptoms.
However, for some, enzyme efficiency can drop down to between 30-70% depending on the variant of mutation (4).
MTHFR mutation may increase the risk of cardiovascular disease and vitamin B deficiencies
Those with an MTHFR mutation are at risk for poor MTHFR enzyme efficiency.
Consequently, folate and folic acid cannot be efficiently converted into their active form, known as 5-MTHF or L-methylfolate. Therefore those nutrients can’t perform one of their key functions: breaking down (recycling) Homocysteine.
Homocysteine is an amino acid thought to damage the lining of your arteries and other cells of the body. It is naturally formed in the body, but gets broken down (recycled) by 5-MTHF.
It has also been linked with a wide range of other health problems including macular degeneration, Alzheimer’s disease, hearing loss, and cancer.
A lack of active folic acid (alongside a low folate diet) can also lead to a Folate Deficiency, which has major health implications on its own.
Therefore, those with a “bad” MTHFR mutation are at an increased risk for health problems if the issue is not addressed and their diet is not rich in folate.
Summary: Those with an MTHFR mutation may be predisposed to increased levels of homocysteine, a strong risk factor for cardiovascular disease. They are also more likely to develop a folate deficiency if their diet is not rich in folate.
What about other disease states and disabilities, like cancer and hypothyroidism?
Considering that genes are influenced by our diet and environment, many studies are also able to find a link between MTHFR and a particular disease process or disability.
This ranges from cancer risk to autoimmune diseases and more; however it’s difficult to pinpoint an MTHFR mutation alone as a direct risk factor.
Take thyroid hormone, for example, which appears to help regulate conversion of vitamin B2 (17). Vitamin B2 is crucial in the methylation of folate (more on that below), so we can make the assumption that those with hypothyroidism (an under active thyroid) and an MTHFR mutation are high risk. It could be true, yes, but it’s still just a theory.
The reality is that overall evidence for these health claims are hypothetical, and MTHFR mutations are unlikely to be a direct causal factor. Innocent until provenguilty.
Summary: MTHFR could very well contribute to or exacerbate heart disease and folate deficiency, but this is due to excessive homocysteine. The mutation itself is unlikely to be a direct cause of certain disease states or disabilities.
MTHFR symptoms of a problem
If you believe you may have an MTHFR issue, there is no way to know for sure without getting tested (more on that below).
In saying that, there are some trending “MTHFR symptoms” among those with a defect that warrant an MTHFR test:
- High homocysteine levels: Caused by poor methylation. Those with potentially “severe” mutations should check homocysteine with their doctor.
- Folate deficiency: A deficiency in folic acid (folate) could be linked to MTHFR and is worth checking out. Common symptoms include extreme fatigue, light-headedness, and forgetfulness.
- Had a miscarriage: Many alternative practitioners recommend testing for MTHFR mutations if you have had one or more miscarriages.
- Longstanding gastrointestinal issues: Such as irritable bowel syndrome, but this is just a theory.
- An autoimmune disease: Such as fibromylagia, although this is based more on anecdotes than solid science.
- Long history of anxiety or depression: Based more on anecdotes than solid science.
It’s important to note that an MTHFR mutation itself is not inherently dangerous… but any form of genetic variance has the possibility to affect your health.
Knowing what the gene is and how it could affect you is seen by many as beneficial.
Summary: There are some common trends among those who have an MTHFR mutation. If you experience any “MTHFR symptoms” it could be worthwhile getting tested.
Folic acid is a problem, L-Methylfolate (5-MTHF) is an alternative
This is a big problem for people who don’t metabolise folic acid well, whether from low MTHFR activity or another enzyme issue (11).
It becomes an even bigger problem when you consider the recommended daily intake for folic acid is 400 μg, yet unmetabolised folic acid already appears in the blood when we consume just 200 μg per day (12).
Unetabolised folic acid accumulating in the blood can potentially mask dangerous vitamin B deficiencies such as megaloblastic anaemia. However, claims it has other harmful effects are unproven.
prostate cancer too SEARCH
Fortunately there is an alternative
Aside from cutting your intake of fortified wheat flour (commercial bread), folic acid supplements can be replaced with the active form: 5-MTHF or L-Methylfolate.
5-MTHF is also better absorbed and interacts with fewer medications than folic acid (15).
So far the FDA and European Food Standards Agency have approved several products containing 5-MTHF. Some speculate it will soon replace folic acid as the protocol treatment (16).
There are some important factors to consider before taking 5-MTHF though. Namely your vitamin B12 levels (and a particular variation of vitamin B12) and risk of anxiety, bipolar or depression.
This is why guidance from a Dietitian or practitioner that specialises in this area is so important. I strongly recommend you read this guide before going further.
That said, if you choose to supplement I recommend this L-methylfolate (5-MTHF) supplement (disclosure: affiliate link). It contains 800 mcg of biologically active folate (5-MTHF) plus 1 mg of vitamin B12 (a necessary coenzyme).
It’s also gluten, dairy and soy-free for those concerned, but always check with your doctor before taking any new supplements.
Summary: Folic acid can be very problematic for some, particularly those with an MTHFR mutation. Those people should avoid fortified wheat flour and look to swapping regular folic acid supplements for 5-MTHF.
Folic acid, MTHFR and pregnancy
Active folic acid is highly protective against Neural Tube Defects.
However, a conventional folic acid supplement is likely not protective of your child if it remains inactivated in your blood stream.
That’s why testing for and flagging an MTHFR mutation could be especially useful for women of childbearing age.
Therefore, a more conservative and thoughtful approach to folic acid supplementation is warranted for those with MTHFR issues.
If you are planning to have a child, or less than 13 weeks after conception, supplementing with L-methylfolate (5-MTHF) instead of folic acid is an option. The supplement I recommend is listed in the section above, but always consult with your doctor first.
While you’re at it, you should be avoiding these 6 foods too.
Summary: Women with an MTHFR mutation who are planning to have a child or already less than 13 weeks pregnant should be supplementing with 5-MTHF rather than folic acid.
MTHFR diet and nutrition recommendations
The importance of folate cannot be overstated.
That’s why MTHFR symptoms warrant such concern in the first place.
While more folic acid (often a syntheticvitamin B9 compound) is not desirable, more folate (natural vitamin B9 compounds) certainly is.
This is especially true for those with an MTHFR defect as folate-rich foods naturally contain the active form of folate too.
Additionally, more folate in the diet means more opportunities to create the active form. The more lottery tickets you buy, the more opportunities you have to win the lottery.
The body easily recycles leftover folate into a harmless compound, whereas it cannot always do so with folic acid. Without getting into more chemistry, that is why folic acid can easily accumulate in the blood.
According to NutritionData, the best sources of folate per 100 g serving are:
Beans and lentils (~50% RDI)
Raw spinach (49% RDI)
Asparagus (37% RDI)
Romaine (Cos) lettuce (34% RDI)
Broccoli (27% RDI)
Avocado (20% RDI)
Oranges/Mangoes (~10% RDI)
(RDI = Recommended Daily Intake)
Studies have even shown that a folate-rich diet can match the homocysteine-lowering effects of either a regular folic acid or 5-MTHF supplement (16).
As though we needed any additional reasons to eat more vegetables and legumes.
The best sources of vitamin B2 per 100 gram serving are:
- Almonds (60% RDA)
- Beef and lamb (51% RDA)
- Oily fish (34% RDA)
- Hard boiled eggs (30% RDA)
- Mushrooms (29% RDA)
- Spinach (14% RDA)
- Natural yoghurt (~14% RDA)
The best sources of vitamin B6 per 100 gram serving are:
- Sunflower seeds (67% RDA)
- Pistachio nuts (56% RDA)
- Oily fish (40-50% RDA)
- Turkey, chicken, pork and beef (34-40% RDA)
- Bananas (18% RDA)
- Avocados (14% RDA)
- Spinach (~12% RDA)
If you are deficient in either of these nutrients, part of the folate metabolism cycle will break down.
What foods to avoid?
If you regularly take any of these, it is best to seek personalised health advice from your Dietitian or doctor.
Summary: Natural folate is a nutrient that we all need to eat more of… MTHFR defect or not. Vitamins B2 and B6 are also important given their role in folate metabolism.
MTHFR in the medical community
The medical community acknowledge the range of health issues linked with MTHFR mutations.
But as the current evidence is largely observational (cannot prove cause and effect), and in many cases inconsistent, their stance is:
“… there are very limited clinical indications for testing for the C677T and the A1298C polymorphisms in the MTHFR gene, and that testing is not indicated as a non-specific screening test in the asymptomatic general population.”
I agree that it’s unnecessary to test if you do not experience any cluster of symptoms mentioned above. Particularly high homocysteine and/or chronic folate deficiency.
Additionally, genetic testing is expensive.
The alternative is to have your homocysteine levels checked at the doctor. Levels within the normal range indicate no issues with folate metabolism.
Summary: The medical community does not recommend testing for MTHFR mutations for the general population, especially those without symptoms. Testing homocysteine levels is a more affordable alternative.
How and where to get an MTHFR test
If you still want to test for it, you must do a genetic test.
Most service providers can mail the testing kit out to you, so it remains non-invasive and you don’t have to go anywhere. Simply send back a saliva swab and await your results.
The largest and most reliable companies are 23andMe and Ancestry.com, who have millions of customers. These companies provide you with a huge amount of raw data and details about your ancestry.
You can order your own kit from their websites or here through Amazon(disclosure: aff link).
Just note that due to new FDA regulations, no genetic testing companies are allowed to interpret medical information up front.
The good news is it’s simple to upload you 23andMe or Ancestry.com raw data to other websites for detailed reports.
GeneticGenie.org (free) can check for MTHFR mutations. I also recommend Promethease.com, which gives you super-detailed and interesting health reports for $5.
Just remember to take your results ‘with a pinch of salt’, as many of the health suggestions are based on early stage research. If you can afford it, use NSGC.org to find a genetic counselor that can help accurately interpret your results.
If instead you choose to use your own local lab, ensure they test for the MTHFR C677T and A1298C mutations, which are the main ones. Not all labs do so make sure you ask first.
Remember that genetic testing is only a tool to support you in better health.
Having a genetic mutation does not necessarily mean it will affect you. In fact, it most likely won’t according the current stats.
As they say, “Genes load the gun, environment pulls the trigger.”
Always consult with a Dietitian or practitioner who can put your results into context. And eat more folate-rich foods… That goes for everybody.