Methylation Turns Good Genes On and Bad Genes Off

The topic of methylation has been gaining in popularity. As a result, there has been an increase in the number of practitioners using genomic testing in recent years. One of the most common SNPs tested is MTHFR, which stands for methylenetetrahydrofolate reductase. MTHFR is a key enzyme in the methylation pathway and 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 results of having one of these SNPs are reduced enzyme activity and a reduced amount of usable 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. Homocysteinemia is associated with many cardiovascular disorders such as increased risk of atherosclerosis, stroke, abdominal aortic aneurysm, essential hypertension, and venous thrombosis. Other conditions correlated 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 (-/-)
Normalenzyme activity Normalenzyme activity 30-40% reducedenzyme activity 30-40% reducedenzyme activity
C677T (+/-)         A1298 (+/-) C677T (+/+)           A1298 (-/-) C677T (+/+)       A1298 (+/-)
50-60% reduced    enzyme activity 60-70% reduced       enzyme activity 60-70% reduced enzyme activity

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

Lifestyle considerations:

  • Exercise
  • Avoid smoking
  • Avoid excess coffee
  • Avoid alcohol (destroys B Vitamins)

Dietary Considerations:

  • Eat an adequate amount of folate-rich green vegetables
  • Follow a 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, folic acid, the synthetic form, is used in fortified foods and most dietary supplements. Designs for Health does not use any folic acid in their supplement line. Newer research has shown us that the increased intake of synthetic folic acid combined 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, at 1mg or 5mg of L-5-MTHF. Patients with MTHFR have folate needs that vary quite a bit from patient to patient, so there will not be a one perfect product for them. How impaired the methylation is will be determined by whether 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 require 5-10 mg. Others may have one copy of A1298T and not need any more folate. Keep in mind that some of these patients have developed compensatory ways to counter the SNP and may actually have sufficient folate.

When supporting methylation pathways, it is important consider synergistic nutrientsin addition to folate and vitamin B12. In some of the toughest cases, the patient 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 vitamin B6 to activate the cystathionine beta-synthase enzyme. Serine is also needed along with B6 to help convert homocysteine into cystathionine.

N-Acetyl-cysteine supports homocysteine metabolism by mobilizing homocysteine from its binding proteins (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 vitamin B12 as a result, so B12 may need to be assessed and supported. Low dose niacin should also be considered with high doses of folate since this requires a lot of methyl groups during its breakdown in the liver.

Additional 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 things 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 precede 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.

For additional information on MTHFR, Folates, B12 and how I treat this problem with my patients, feel free to contact me at [email protected] or 619-231-1778