The MTHFR brouhaha

This has gone far enough.

The benefit and activity of folic acid / folate progresses through a metabolic pathway known as the methylenetetrahydrofolate reductase (MTHFR) pathway. Mutations occur in this gene, which are passed from parent to offspring.

If you inherited one mutated gene, you are heterozygous for the MTHFR defect. This altered gene is called a polymorphism or SNP. The scientific term for the condition isMTHFR C677T.

If you inherited the defective gene SNP from both parents, you are homozygous, and if ignored, the defect will likely increase your risk for a number of vascular, neurolgic, and metabolic diseases including type 2 diabetes. The homozygous MTHFR polymorphism is also associated with risk for disorders as widely varied as autoimmune disease and certain types of cancer.

REF: Eur J Med Genet. 2015 Jan;58(1):1-10. doi: 10.1016/j.ejmg.2014.10.004.

Methylenetetrahydrofolatereductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases.

Liew SC1, Gupta ED2.

A genetic test can tell you if you have one or two SNP’s of the MTHFR gene, and quite frankly, I don’t see this as a big deal for most people. That’s because the defect is rather easy to overcome. The SNP essentially reduces (not prevents as some claim) the metabolism of folate or folic acid to methyltetrahydrofolate. This is known as a methylation step. Thus, someone with the MTHFR polymorphism will have a hard time methyating folate, and that has consequences, the most immediate being a buildup of homocysteine in the blood.

Of course, homocysteine can be measured on a routine blood test, and if elevated, steps can be taken to restore it to normal. This includes supplementation with vitamins B6, B12, and folic acid. Obviously, someone with the MTHFR polymorphism will have greater success with a form of folic acid that is already methylated. At the health food store, you would look for a product with names like, 5-MTHF, L-Methylfolate or Metafolin.

Women of childbearing age need to be aware of their folate status because of the association between low folate and birth defects. Even women with one copy of MTHFR mutation (aka heterozygous) should probably use methylated folic acid.

You’re probably getting that nutragenomics– the intersection of genomics and nutritional biochemistry – is expanding, and offering important new insights to clinicians and researchers. And in any emerging science, there’s bound to be some confusion. What chafes my fanny is when people intentionally confuse the issue by making stuff up.

Q: Why would anyone do that?

A: The answer to that question has to do with the axiom “knowledge is power.” Someone with information that you need has power, especially if the information concerns your health. So there’s no shortage of people making stuff up in order to sell a product, gain subscribers or just feel important.

In this case, it’s the “You have a genetic defect. The sky is falling” blather that is exploding on the internet. In the last month, scores of women have contacted me – almost in a panic – because they were found to have the MTHFR polymorphism. Especially worrisome is that they were told to assiduously avoid any nutritional product containing folic acid, because the unmethylated compound would be extremely harmful.

People have sent me links to a video by a naturopath named Ben Lynch, which contained outlandish nonsense. He claims that folic acid is dangerous because it is “man-made” and has to be converted in a multi-step process before the body can use it. O.K. So does the folate you get from your spinach. All forms of folic acid are converted to dihydrofolate (dihydrofolic acid), tetrahydrofolate (tetrahydrofolic acid), and other metabolites, which have a variety of biological activities.

There are thousands of studies showing myriad beneficial effects of folic acid (FA) supplementation, but Lynch claims that FA somehow “blocks” receptors so that naturally occurring dietary folate can’t get into the cell. He specifically emphasizes how dangerous FA supplements are for pregnant women, when the data clearly shows that FA supplements reduce oxidative stress, reduce risk for miscarriage, and numerous birth defects including cleft lip, cleft palate, Neural Tube Defects (NTDs) and heart defects.


1. J Obstet Gynaecol. 2015Feb 18:1-4.

Impact of iron and folic acid supplementation on oxidative stress during pregnancy.

Lymperaki E1, TsikopoulosA, Makedou K, Paliogianni E, Kiriazi L, Charisi C, Vagdatli E.

2. Sci Rep. 2015 Feb17;5:8506. doi: 10.1038/srep08506.

Maternal folic Acid supplementation and the risk of congenital heart defects in offspring: a meta-analysis of epidemiological observational studies. Feng Y1, Wang S1, Chen R1,Tong X2, Wu Z1, Mo X1.

3. Oral Dis. 2015Mar;21(2):240-7. doi: 10.1111/odi.12256. The role of folic acid to the prevention of orofacial cleft: an epidemiological study. Figueiredo R, et al.

4. Wolff T, Witkop CT, Miller T, Syed SB (2009) Folic acid supplementation for the prevention of neural tube defects: an update of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 150: 632–639.

5. Christiansen M, Garne E (2005) Prevention of neural tube defects with periconceptional folic acidsupplementation in Europe. Ugeskr Laeger 167: 2875–2876

6. Folic acid: influenceon the outcome of pregnancy. Theresa O Scholl andWilliam G Johnson Am J Clin Nutr May 2000 vol. 71 no. 5 1295s-1303s

Then, Lynch expands on this delusion, stating that supplementing with folic acid while breast-feeding will create serious growth and development problems for the child; that mothers are effectively “stunting future generation with folic acid.”

In support for this bizarre statement, he claims to have “paper after paper on this.” I searched MEDLINE, PUBMED and EMBASE databases and found none. Instead, there is an abundance of evidence in support of folic acid supplementation. In one study conducted with women undergoing in vitro fertilization (IVF) the MTHFR polymorphism disadvantage was overcome simply by doubling supplemental folic acid from 400 mcg to 800 mcg per day.

REF: GeburtshilfeFrauenheilkd. 2014 Sep;74(9):845-851. Folate Metabolism andHuman Reproduction. Thaler CJ.


1. Int J Vitam Nutr Res. 2012Oct;82(5):342-7. doi: 10.1024/0300-9831/a000129. Vitamins for the first 1000 days: preparing for life.

Elmadfa I, Meyer AL.

2. J Nutr Metab.2012;2012:470656. Epub 2012 Sep 13. Folate intake and markers of folate status in women of reproductive age, pregnant and lactating women: a meta-analysis. Berti C1, Fekete K,et al.


1. Extraordinary claims require extraordinary evidence, and so far, I can find no support for the anti folic acid diatribes that are bouncing around the health care arena. If you have inherited one MTHFR mutation (heterozygous) you may be at increased riskfor disorders associated with folate deficiency. Probably best to supplement with a methylated folic acid product like 5-MTHF, available in pharmacies and heath food stores.

2. If you inherited the MTHFR gene mutation from both parents (homozygous) it is important for you to use a methylated folic acid supplement, and measure homocysteine and plasma folate every year at your annual physical exam.

3. When someone tells you that the MTHFR polymorphism requires you to carefully avoid all products containing folic acid (multivitamins and other nutritional supplements, protein bars and most baked goods), smile and politely ask for references from the biomedical literature. If they provide any, please forward to me so I can update this NOTE.


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