MTHFR is an enzyme that allows folate (vitamin B9) to support the cellular process of methylation, which is important for the synthesis of creatine and phosphatidylcholine, the regulation of gene expression, neurotransmitter metabolism, and dozens of other processes. There are two common polymorphisms that decrease its activity, A1298C and C677T, with C677T having the stronger effect. Genetic decreases in MTHFR activity are associated with cardiovascular disease, neurologic and psychiatric disorders, pregnancy complications and birth defects, and cancer.
While discussions of these polymorphism tend to focus on supplementing with methyl-folate, this should only be a small piece of the puzzle, and may be unnecessary in the context of a diet rich in natural food folate. The bigger pieces of the puzzle are restoring choline, creatine, and glycine.
In this episode, I describe how the methylation system works, how it's regulated, and how it's altered with MTHFR variations. I then use this to develop a detailed dietary strategy and an evaluative strategy to make sure the dietary strategy is working.
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Show Notes for “Living With MTHFR”
00:35 Cliff Notes
12:15 Introduction of Living with MTHFR
13:05 Bird’s eye view of methylation & MTHFR
14:25 How to know if you have MTHFR
17:00 Prevalence (these are really common)
20:30 This is not a genetic disease: this is a variation in metabolism
21:10 Health Associations
23:00 Mechanisms of what MTHFR does
31:35 Methylation system as a whole (methyltransferases)
36:50 How the system is regulated
56:05 Two Addenda: COMT and Agouti Mouse Study
01:00:10 Mechanistic impact of polymorphisms (% down in enzyme activity)
01:04:45 It’s not all about 5-methyl folate
01:05:35 You can restore normal flux
01:08:45 Compensate with choline
01:15:30 Glycine Buffer
01:16:42 Why upping Methionine and SAMe is bad idea
01:19:00 Dietary Strategy – Basic Objectives
01:35:45 Reiterate problem with methionine/and SAMe in context of meat for creatine 900-1200 mg choline
01:41:40 The evaluative strategy
01:42:00 StrateGene Report
01:43:55 Homocysteine, methionine and glycine
01:46:36 HDRI methylation panel
01:47:35 Folate in plasma and FIGLU
01:49:40 Other tests of interest
How to Know If You Have an MTHFR Mutation
I recommend getting 23andMe Health and Ancestry and then running your raw data through StrateGene.
A Dietary Strategy for MTHFR Polymorphisms
1) Get the RDA for folate from non-fortified whole foods.
- For adults and children 14 years and older, the RDA is 400 micrograms, except that it is 600 for pregnant and lactating women, regardless of age.
- For children, the RDA increases from 65 micrograms in the first six months, to 80 in the second six months, 150 for 1-3-year-olds, 200 for 4-8-year-olds, and 300 for 9-13-year-olds.
- Feel free to use (as an adult, not for children), 400 or 600 micrograms per day of a methyl-folate supplement, providing you are adding it to a folate-rich diet rather than using it to replace food folate. I recommend Jarrow Methyl Folate based on cost, dose, and the fact that it is otherwise the same high-quality product as sold by other manufacturers in more expensive, higher-dose supplements.
2) Consume at least the RDA for protein.
- The RDA for protein is 0.36 grams per pound bodyweight.
- Most people need more than this for other reasons, such as optimizing body composition, preventing loss of lean mass during weight loss, reaching satiety to manage energy intake, or reaching athletic goals. You may need one gram per pound body weight or more, depending on your goals, but the RDA is adequate to support the methylation pathway.
3) Get 3 grams of creatine per day.
- 1-2 pounds of muscle meat or fish (but not organ meats, eggs, dairy, or plant proteins) will supply on average 3 grams of creatine.
- Large volumes of muscle protein may be undesirable for someone with an MTHFR mutation because it could exacerbate the loss of glycine.
- Alternatively, you can supplement with 3 grams of creatine (or 5, if you wish, the standard maintenance dose for athletes). I'm currently using Optimum Nutrition Micronized Creatine Powder.
4) Consume 900-1200 mg/d choline.
- This can be obtained by eating 4-5 egg yolks per day.
- You can substitute 100 grams of liver for two egg yolks.
- You can meet this choline amount by eating a very large volume of low-carbohydrate plant foods. See Meeting the Choline Requirement for more details.
- You can supplement with phosphatidylcholine, but be careful of the labeling. Usually the supplement lists the phosphatidylcholine, and not the choline yield. A 420 mg capsule of phosphatidylcholine only provides 55 mg of choline, which means you'd have to take 22 capsules per day to get 1200 mg. On the basis of quality, soy-free status, and good feedback from others about the taste, I recommend Micro Ingredients Sunflower Lecithin. Although the choline content is not guaranteed, on the basis of this paper I recommend consuming four to five tablespoons per day to reach the recommended choline yield.
- If you find that memory loss, poor cognitive function, or weakness are your primary symptoms of concern, consider using alpha-GPC for your choline at the same dose. This form is more effective at converting to acetylcholine, a neurotransmitter involved in neuromuscular function.
5) Boost your glycine intake.
- At a minimum, use the skin and bones of the animals you eat. For example, eat chicken with the skin instead of without. Use the bones to make bone broth. If you eat canned fish, get the fish with edible bones.
- Consider supplementing with glycine. I recommend using between 1/2 serving and 3 servings of Vital Proteins Marine Collagen, on the basis that it has a much higher glycine content than beef hide products made by the same company or others with a similar devotion to quality and cleanness of source.
6) Be careful with SAMe. SAMe supplements support methylation, but MTHFR mutations increase the use of glycine to buffer SAMe levels, even when you don't have enough. While I do not make a blanket recommendation against supplementing with SAMe, I caution against its use in this context because it could aggravate the loss of glycine. If you use it, be careful, and consider monitoring your glycine levels (see recommended lab tests below).
Lab Tests Recommended for MTHFR Polymorphisms
1) Homocysteine. Available from LabCorp, Quest, and the Genova ION panel, aim to keep your numbers between 6 and 9, rather than the larger range on the report.
2) Plasma or serum folate. Available from Quest or LabCorp, aim to be in the normal range as listed. Avoid RBC folate unless you also corroborate it with plasma or serum.
3) Plasma methionine, glycine, and sarcosine. Available on a LapCorp amino acids profile, a Quest amino acids profile, a Genova ION panel, or a NutrEval, methionine and glycine should be toward the middle of the range rather than the bottom and sarcosine is best being as low as you can get it.
4) The HDRI methylation panel. Aim to keep 5-CH3-THF in the normal range. If it is specifically low while other folate forms are normal, this suggests your MTHFR mutation is impacting your methylation pathway negatively. The “extended” panel has methionine and homocysteine, but not glycine or sarcosine.
5) Other tests of interest. Serum creatine from Quest or LabCorp might be a good way of testing whether your MTHFR mutation is affecting your creatine synthesis if you are not supplementing. Aim to be in the normal range. The combination of creatine, creatinine, and guanidinoacetate (the direct precursor to creatine) from the same urine sample can be used to test problems with creatine synthesis. Unfortunately, these are only offered from labs looking for a genetic disorder, such as Mayo Clinic, Greenwood Genetics Center, and Baylor Genetics, and I'm not sure if they are easy to order for someone with no suspicion of a metabolic disorder or whether the reference ranges would be relevant for looking at the impact of an MTHFR mutation.
Posts and Episodes Related to “Living With MTHFR”
You Asked Me Anything About Methylation, Facebook Live, 06/25/16 | Mastering Nutrition Episode 17
Methylate Your Way to Mental Health With Dopamine | Mastering Nutrition Episode 43
Meeting the Choline Requirement — Eggs, Organs, and the Wheat Paradox | December, 2010 blog post
How to Get Enough Folate | Chris Masterjohn Lite
Folate: You Can Freeze Your Liver But Not Your Veggies | Chris Masterjohn Lite
Supercharge Your Folate With Pastured Egg Yolks and Sprouted Legumes | Chris Masterjohn Lite
Carbs and Sports Performance | Masterclass With Masterjohn Energy Metabolism Lesson 17
This discusses the role of creatine in energy metabolism.
Should We Avoid Animal Protein to Optimize Methylation? | May, 2015 blog post
Beyond Good and Evil: Synergy and Context With Dietary Nutrients | The first section of this December 2012 article on methionine, B vitamins, and glycine is very relevant.
Research Related to “Living With MTHFR”
Reed et al. Mathematical analysis of the regulation of competing methyltransferases. 2015.
Mudd et al. Methyl balance and transmethylation fluxes in humans. 2007.
Gregory and Quinlivan. In vivo kinetics of folate metabolism. 2002.
Bertolo and McBreairty. The nutritional burden of methylation reactions. 2013.
Brosnan and Brosnan. The role of dietary creatine. 2016.
Brosnan, et al. The metabolic burden of creatine synthesis. 2011.