MTHFR testingThere are more and more practitioners using genomic testing these days. One of the most common SNPs tested is MTHFR, which stands for methyltetrahydrofolate reductase. This is a key enzyme in the methylation pathway. MTHFR is responsible for converting folate into its active state. The two main variants that are well understood and tested for are C677T and A1298C. The end result of having one of these SNPs is reduced enzyme activity and a reduced amount of useable folate. The prevalence for the presence of an MTHFR polymorphism is 25% for C677T and 25% for A1298C.

MTHFR is most commonly associated with homocysteinemia especially in conjunction with low B-vitamin status. This is associated with many cardiovascular disorders such as increased risk of atherosclerosis, stroke, abdominal aortic aneurysm, essential hypertension, and venous thrombosis. Other conditions associated with MTHFR polymorphisms are increased risk of diabetic depression, schizophrenia, autism, osteoporosis, certain cancers, and pregnancy-related disorders.


Effects of the MTHFR Polymorphisms:


C677T (-/-)A1298 (-/-)C677T (-/-)A1298 (+/-)C677T (-/-)A1298 (+/+)C677T (+/-)A1298 (-/-)
Normal enzyme activityNormal enzyme activity30-40% reduced enzyme activity30-40% reduced enzyme activity


C677T (+/-)A1298 (+/-)C677T (+/+)A1298 (-/-)C677T (+/+)A1298 (+/-)
50-60% reduced enzyme activity60-70% reduced enzyme activity60-70% reduced enzyme activity


The A1298C is associated with a decreased enzyme activity but not to the degree as the C677T mutation. In the C677T SNP, the enzyme activity is reduced by each mutant allele present. There are other MTHFR SNPs, however, they all don’t have an effect on the enzyme activity.

Lifestyle considerations:

  • Avoid smoking
  • Avoid excess coffee
  • Avoid alcohol
  • Exercise

Dietary Considerations:

  • Eat adequate folate-rich green vegetables
  • Mediterranean/Paleo Diet
  • Avoid foods fortified with synthetic folic acid (see unmetabolized folic acid below)

Unmetabolized Folic Acid

Natural folates are essential for our overall health and function. However, the synthetic form, folic acid, is used in fortified foods and most dietary supplements. Designs for Health does not use any folic acid in their line. Newer research has shown us that the increased intake of synthetic folic acid combined with many patients with MTHFR polymorphisms can lead to an accumulation of unmetabolized folic acid in the blood. Unmetabolized folic acid is associated with the development and progression of certain cancers. In addition, an excess of folic acid or unmetabolized folic acid can weaken immune function as well as impair natural killer cells.

Supplements Considerations:

It is important to note that there are many patients with MTHFR SNPs that do not have an elevated homocysteine level. Most people with MTHFR may need a separate folate (L-5-MTHF) if they require higher dosing. Most individuals will need 1mg or 5mg of L-5-MTHF. Patients with MTHFR have folate needs that vary quite of bit from patient to patient, so there will not be a one perfect product for them. How impaired the methylation is will be determined if the patient has a heterozygous, homozygous, or compound presentation. One patient may have a heterozygous SNP and only need 1mg of L-5-MTHF while another may have a homozygous C677T and need 5-10mg. Another patient may have one copy of A1298T and not need any more folate. Keep in mind some of these patients have developed compensatory ways to counter the SNP and may have sufficient folate.

When supporting methylation pathways, it is important consider synergistic nutrients in addition to folate and vitamin B12. Some of the toughest patients will not get effective lowering of homocysteine until choline is supplemented. Choline converts to betaine with the help of riboflavin and aids methylation in this step of the pathway. In addition, TMG (trimethylglycine) provides extra methyl groups. The most common block in the homocysteine pathway is the conversion of cystathionine to cysteine, which requires B6 to activate the cystathionine beta-synthase enzyme. Serine is also needed along with vitamin B6 to help convert homocysteine into cystathionine.

N-Acetyl-cysteine supports homocysteine metabolism by mobilizing homocysteine from its binding proetins (albumin). N-Acetyl-cysteine at 600 mg daily has been shown to reduce plasma homocysteine levels.

In addition, when using high doses of folate it is possible to have an imbalance of B12 as a result, so B12 may need to be assessed and supported. Also, at higher doses, low dose niacin should be considered since it requires a lot of methyl groups during its breakdown in the liver.

Other Testing for Methylation

Complete blood count – Simply looking at the mean corpuscular volume (MCV) can reveal if someone has a methylation problem. This is one of the first thing I look at. Large red blood cells (Folate or vitamin B12 deficiency) or anemia can be a sign of impaired methylation.

Plasma Homocysteine – Homocysteine is an amino acid produced as part of the body’s methylation process. The metabolism of homocysteine is highly dependent on in vitamin B12, folate, and vitamin B6. Deficiencies in any of these may be associated with elevated homocysteine levels.

Organic acid testing – Organic acids are products of metabolism that can identify nutrient deficiencies that typically preced any abnormal findings on a CBC or a comprehensive metabolic panel. . Methylmalonate (MMA) is a more specific test for a vitamin B12 insufficiency. A person’s levels may be elevated even if you have a normal serum vitamin B12 or homocysteine level. In addition, formiminoglutamate (FIGLU) is a functional marker of folate insufficiency.

By. Michael Jurgelewicz, DC, DACBN, DCBCN

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