It is well established in the scientific literature that the enzyme methylenetetrahydrofolate reductase (MTHFR) plays a variety of essential roles in the body. The abbreviation “MTHFR” is gaining attention due to a common genetic mutation that alters normal DNA methylation function and subsequent metabolic pathways. Under- and over-methylation, along with other epigenetic factors, may be a key variable in the pathogenesis of various diseases and conditions that your patients may be suffering from.

The MTHFR enzyme interacts with the nutrient folate, also known as vitamin B₉, to regulate intracellular folate level for the synthesis and methylation of DNA. In this cycle, MTHFR is critical for the production of S-adenosyl-l-methionine (SAM), the universal methyl donor, as well as the conversion of homocysteine back to methionine. However, a mutation in the MTHFR gene has been linked to a number of symptoms and associated illnesses. For example, the single nucleotide polymorphism (SNP) C-to-T substitution at nucleotide 677 is a common contributor to developing hyperhomocysteinemia. Chronically elevated homocysteine is a major culprit in cardiovascular disease and has been shown to be a probable trigger in chronic migraine sufferers. Elevated homocysteine increases oxidative stress and contributes to a decrease in SAM levels. 

According to NIH, between 30-40% of Americans may have a mutation at gene position C677T. Both undermethylation and overmethylation may be a result of this genetic polymorphism. Unfortunately, genetic testing alone cannot identify under- vs. over- methylators, therefore systems and symptomology review is needed in addition to testing interpretation.

Aside from hyperhomocysteinemia, C677T or A1298C MTHFR variant mutations are associated with an increased risk of other conditions including cardiovascular and thromboembolic diseases such as stroke, blood clots, and heart attacks, ADHD in children, pregnancies with neural tube defects, depression, anxiety, diabetic neuropathy, nerve pain, glaucoma, migraines, schizophrenia, and colorectal polyps. A recent updated meta-analysis in the journal Medicine found a significant association between the MTHFR C677T variant and lung cancer susceptibility in Chinese people. Keep in mind that the research around MTHFR is still evolving. If your patients experience any of those symptoms or conditions, a MTHFR mutation may be the cause and thus genetic testing may be worthwhile to rule out.

A review published in early 2019 in International Journal of Molecular Science provides evidence to support that the MTHFR genetic mutation play a significant role in cognitive loss and late-onset Alzheimer’s disease (AD) due to hyperhomocysteinemia and other dysfunctional metabolic pathways. When SAM levels are reduced, DNA demethylation occurs resulting in the overexpression of genes linked to AD pathology. The researchers emphasize the importance of supplementing with B vitamins in those with MTHFR variants. Additional B vitamins are essential coenzymes for homocysteine to convert back to methionine. Other than folate, pyridoxine (vitamin B₆) and vitamin B₁₂ (methylcobalamin) nutritional deficiencies may also contribute to increased levels of homocysteine. 

A previous article explains how the human GI tract has a limited ability to convert synthetic forms of folate, folic acid, into the bioavailable form 5-methyltetrahydrofolate (5-MTHF) and why patients may consider avoiding folic acid supplementation and processed foods fortified with folic acid. High dose folic acid supplementation can mask vitamin B₁₂ deficiencies. Avoiding processed foods that are fortified with folic acid and switching to a plant-based diet full of foods rich in dietary folate - such as spinach, turnip greens, lentils and asparagus - is a safer and natural alternative and can be quickly utilized by the body. When supplementing, choose high-quality B-vitamins in their coenzymated form, either individually or as a B-complex supplement that includes active 5-MTHF and choline to support methylation.