Making Sense of MTHFR Polymorphisms

Heart attack and stroke. Multiple miscarriages. Chronic migraine headaches. irritable bowel syndrome. Depression. Autism.

What do all these common but seemingly disparate diagnoses all have in common? They’re just some of the conditions linked to a faulty enzyme called MTHFR (methyl-tetrahydrofolate reductase). It’s a safe bet that most of the disorders we see in a typical primary care practice are related to methylation deficiencies resulting from variants in the genes coding for MTHFR.

What’s up with MTHFR?

Although there are over fifty known MTHFR polymorphisms that can affect the amount and activity of this vital enzyme, the two primary ones we need to think about are called C677T and A1298. These are the most common genetic variants that cause MTHFR to function at a lower than normal rate and thereby slow the methylation process in tissues throughout the body.

  • Methylation is a core process that occurs in all cells. It is responsible for:
  • Cellular Repair: synthesis of nucleic acids, production and repair of DNA and mRNA.
  • Detoxification and Neurotransmistter Production: interconversion of amino acids.

Healthy Immune System Function: formation and maturation of red blood cells, white blood cells & platelet production.

MTHFR-VitB12When people with mutations in MTHFR are exposed to environmental or food borne toxins, they have a harder time getting rid of them, which can cause some very serious illnesses.

The 677T variant is most commonly associated with early heart disease and stroke. The 1298C variant is linked to a wider variety of chronic illnesses, but either anomaly can cause health problems.

If someone is heterozygous for one of these, his or her MTHFR enzyme activity will run at about 60% efficiency compared to someone without these polymorphisms.
If someone is homozygous, then enzyme efficiency drops down to 10% to 20% of normal, which can be very serious.

The worst combination is 677T/1298C in which someone is heterozygous for both anomalies.

Many chronic illnesses are linked to this “double whammy.” Fibromyalgia, irritable bowel syndrome, migraines, chemical sensitivity, frequent miscarriage and frequent blood clots are all conditions associated.
MTHFR-Related Health Problems

Glutathione is the body’s primary antioxidant and detoxifier. One of the ways that MTHFR gene mutation can increase susceptibility to illness is by compromising the ability to make glutathione. People with MTHFR anomalies usually have low glutathione, which makes them more susceptible to stress and less tolerant to toxic exposures.

Accumulation of toxins in the body and increased oxidative stress, which also leads to premature aging.

Some other conditions that may be associated with MTHFR gene mutations include:

  • Autism
  • Addictions: smoking, drugs, alcohol
  • Down’s syndrome
  • Frequent miscarriages
  • Male and female infertility
  • Pulmonary embolism and other blood clots
  • Depression and anxiety
  • Schizophrenia
  • Bipolar disorder
  • Fibromyalgia
  • Chronic Fatigue Syndrome
  • Chemical Sensitivity
  • Parkinson’s disease
  • Irritable Bowel Syndrome
  • Stroke
  • Spina bifida
  • Migraines
  • Hyperhomocysteinemia
  • Breast cancer
  • Atherosclerosis
  • Alzheimer’s
  • Multiple Sclerosis
  • Myocardial Infarction (Heart Attack)
  • Methotrexate Toxicity
  • Nitrous Oxide Toxicity

Treating MTHFR Polymorphisms

It is easy to test for the most common and problematic MTHFR polymorphisms. Many functional diagnostic labs offer tests, and the information can be extracted from consumer-facing genomic tests such as 23andMe.
If someone has one or more of the problematic mutations, you can supplement with methylfolate and methyl B12, the active forms of these B vitamins. You can also supplement with liposomal or acetyl-glutathione, the end product of the MTHFR-mediated biochemical pathway.

Glutathione is poorly absorbed, so either the liposomal form or a precursor, called n-acetylcysteine (NAC) may be used. Some of my favorites are Thorne Research’s Methyl Guard Plus and 5-MTHF 1mg and 5mg.

There are also prescription medications that contain methyl-folate: Deplin, MetanX, CerefolinNAC are a few. It’s also possible to give methyl B12 via intramuscular injection, as a nasal spray, or sublingually.

The intramuscular shots are by far the most effective method, but have obvious limitations in terms of routine use and patient compliance.

Other B vitamins, such as riboflavin and vitamin B6 also play an important role in the care of patients with MTHFR polymorphisms. As you may have surmised, this can be quite complex, and it is important to keep in mind that it is not uncommon for patients with MTHFR polymorphisms to be very sensitive to supplementation.

Who Should Be Screened?

  • I recommend testing for MTHFR mutations in all patients with:
  • Mood disorders: depression, anxiety, irritability, mood swings, bipolar symptoms
  • Infants and children of parents with MTHFR mutations
  • Family members related to someone with MTHFR mutations
  • Infertility and Pre-conception care: test both man and woman
  • Elevated folate (not processing to active 5-MTHF due to inability to methylate)
  • Elevated homocysteine (due to low active 5-MTHF and methylcobalamin)
  • Elevated s-adenosylhomocysteine (due to low active 5-MTHF and methylcobalamin)
  • Elevated serum cobalamin (due to inability to methylate cyanocobalamin to methylcobalamin)
  • Elevated methylmalonic acid (due to methylcobalamin deficiency)
  • Patients with complex chronic “syndromes:” IBS, multiple chemical sensitivity, fibromyalgia, Down syndrome, chronic fatigue syndrome
  • Neurological disorders: Multiple sclerosis, Autism, Alzheimer’s, Epilepsy, Parkinson’s
  • Cancer: family history of cancer or undergoing cancer treatment
  • Cervical dysplasia
  • Cardiovascular risk: family history of strokes, embolisms, heart attacks, clots, hypertension
  • Birth defects: cleft palate, tetralogy of Fallot, spinal bifida, midline defects
  • Drug sensitivities: methotrexate, anti-seizure meds, nitrous oxide, anesthesia.

If you start looking for these polymorphisms, it’s very likely you will find them. This will open new opportunities to minimize risk and truly optimize patients’ health through safe and effective nutrition-based interventions.


Jill C. Carnahan, MD, ABFM, ABIHM, practices functional medicine with her medical practice partner Dr. Robert Rountree, at Boulder Wellcare and Flatiron Functional Medicine, in Boulder CO. Dr. Carnahan is board certified in both Family Medicine and Integrative Holistic Medicine. She founded the Methodist Center for Integrative Medicine in 2009 and worked there as Integrative Medical Director until October 2010. She completed her residency at the University of Illinois Program in Family Medicine at Methodist Medical Center and received her medical degree from Loyola University Stritch School of Medicine in Chicago.

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