05 October 2013

What's the Big Deal about Methylation?! Update of the popular MTHFR blog post...


Do you have a genetic defect in the MTHFR gene??

Maybe you've have a family history of heart attack or stroke... maybe you've suffered through multiple miscarriages.  Or maybe you struggle with chronic migraine headaches or irritible bowel syndrome or depression.  Perhaps your child or a sibling has autism.  What do all these things have in common?  Well, these are just some of the conditions liked to a faulty enzyme called MTHFR.

What's up with MTHFR?

MTHFR stands for methyl-tetrahydrofolate reductase, an enzyme that is responsible for the process of methylation in every cell in your body.  MTHFR is a common genetic variant that causes this key enzyme in the body to function at a lower than normal rate.  This can lead to a variety of medical problems.  Although there are over fifty known MTHFR variants, the two primary ones are called C677T and A1298.  Your doctor can order a blood test to determine if you have these genetic variants. Better yet, you can order a complete genetic profile yourself through 23andMe.

What's the big deal about methylation?

Methylation is a core process that occurs in all cells to help your body make biochemical conversions.  When people with genetic mutations is MTHFR are exposed to toxins, they have a harder time getting rid of them which can cause some very serious illnesses.  The methylation process 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
The 677T variant is most commonly associated  with early heart disease and stroke and the 1298C variant with a variety chronic illnesses, but either anomaly can cause a wide variety of health problems.  The MTHFR anomaly is reported out as heterozygous or homozygous.  If you are heterozygous that means you have one affected gene and one normal gene.  Your enzyme activity will run at about 60% efficiency compared to a normal.

If you are homozygous or have 2 abnormal copies, then enzyme efficiency drops down to 10% to 20% of normal, which can be very serious.   The worst combination is 677T/1298C in which you are heterozygous to both anomalies.  Many chronic illnesses are linked to this anomaly.   Fibromyalgia, irritable bowel syndrome, migraines, chemical sensitivity, frequent miscarriage and frequent blood clots are all conditions associated with MTHFR anomaly.  For a great diagram of more methylation related health problems, check this out:

MTHFR Related Health Problems 

Glutathione is the body's primary antioxidant and detoxifier.  One of the ways that MTHFR gene mutation can make you susceptible to illness is by lowering your 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 conditions that may be associated with MTHFR gene mutations

  • 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


Treatment for MTHFR

Fortunately, you can easily be tested for the MTHFR mutation.  If you find out that you have one or more of the gene mutations, you can supplement with methyl-folate  and methyl B12, the active forms of these B vitamins.   You can also supplement with liposomal or acetyl-glutathione, the end product of the 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 Methyl Guard Plus and 5-MTHF 1mg and 5mg.

There are prescription medicines, that also contain methyl-folate: Deplin, MetanX, CerefolinNAC are a few.   Methyl B12 can also be given as shots, nasal sprays, and sublingually.  The intramuscular shots are by far the most effective method and must be prescribed by your physician.  The choice of nutrients will vary from patient to patient and should be done under a doctor's supervision.  There is a bell-shaped optimal curve so you may not feel well with too much or too little of the appropriate supplements.   Other B vitamins, such as riboflavin and vitamin B6 also play an important role.  As you may have surmised, this can be quite complex and I suggest you find a functional medicine trained physician to help you sort through your needs for the different nutrients if you have a chronic health condition related to the gene mutations.  It is not uncommon for patients with these genetic polymorphism's to be very sensitive to supplementation.

Patients who I recommend be screened for MTHFR mutations:

  • Mood disorders: depression, anxiety, irritability, mood swings, bipolar
  • 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 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 are interested in knowing more about your genes, the 23andme gene test will be the best $99 investment you've ever spent !

More reading

23andMe Gene Test
Holistic Primary Care 
Genetics Home Reference
Molecular Biology of MTHFR
Genetics of Homocysteine Metabolism
Homocysteine and MTHFR mutation
LiveWello Gene app


  1. I am very much in agreement here, the one area I wonder about is the use of NACL as a GSH precursor. It has shown to be not very effective.My research has led me to γ-glutamylcysteine found in undenatured whey.http://www.tennishealth.biz/glutathione.htm

  2. Great explanation and introduction, Dr. Jill!

  3. Hi - a friend who is also a hospice nurse suggested your blog when I told her I was trying to do some research before our 7yr old daughter possibly has to have a tonsillectomy. Long story short - I am compound heterozygous (C677T and A1298C) for the mthfr mutation. We found out after on 2nd son was stillborn 6wks before his due date. Fast forward 10yrs and I've had 2 DVT's, a large post op clot form in my abdomen and a stroke after our 5th child was born ( I did lovenox injections for all our pregnancies after losing our son) The stroke was 10wks post partum / 1 week after stopping the lovenox. After the last clot in my arm 2yrs ago my doctors and I decided that warafin was now needed and I take 12.5mg daily. Our oldest son is also positive for the mutation and had a strokes after each open heart surgery to correct transposition of the great arteries. He currently takes 800mg of folic acid daily. Our daughter just saw the hematologist at our children's hospital - she has tested positive for the Lupus Anticoagulant and well as Antithrombin III Activity and MTHFR . At our initial appointment her doctor said that the MTHFR deficiency doesn't cause any concern with the majority of hematologists - I'm not sure I agree and given my history and the fact that I had so many tests done after our loss and also after the CVA that I can't imagine that they've missed something - what are your thoughts? We've put our daughter's surgery on hold and will be consulting w/ her regular pediatrician regarding the chronic strep and how else we can deal with this..her surgeon has tried to reassure us that she will be fine and he plans on a 3 day admission vs. an out patient procedure.. but my husband and I are just not comfortable with having her undergo the surgery with all this new information. At a bit of a loss with all of this - any input would be appreciated.

  4. Hi Anonymous - sorry to hear your complex story of health issues. I suggest you contact my office or find a functional medicine doctor in your area to help you and your family.
    Dr Jill

  5. Hi Dr.Jill,

    After getting a very high reading on my serum B-12 and being told it is probably from my diet when I have been diagnosed with autoimmune gastritis and Hashimoto's< I was wondering if something was going on. I also have not been able to get out of the active stage of mono for 2.5 years. I thought I didn't have enough stomach acid to kill the Epstein Barr virus, but when I got my second high B-12 reading yesterday, I suspected there was more going on than just low stomach acid. In fact this result is contrary to low stomach acid and the inability to absorb B-12. I suspect I have an MTHFR gene defect on some level and would love to get this tested. I went to the 23 and me Gene Test website and it appears their tests for this have been temporarily discontinued. Where else might I find this test? Could my PCP who is a DO and forward thinker order this test through Quest or Labcorp? Or should I just assume I have it and start treatment myself?


    Scared and confused but happy to have possibly stumbled upon an answer

  6. You can still get 23andme raw data and easy for any physician who knows SNPs to help interpret. I recommend still getting that test done and finding a functional medicine doctor in your area....

  7. Hi Dr Jill, My son of 5 years old has a mutation on MTHFR i.e.
    MTHFR C677T genotype homozigote. At the date when I made the genetic test ( about one year and 1/2 ago) I made also homocisteine test and folates , which were OK.
    My son is in spectrum , he has a easy form of autism,
    We are making progress with ABA Therapy, I also gave him, that time Methyl B12 but I did not see any improvement , he became more agitated. so I had to gave up givind him MethylB12.
    From our dr from my country ( Romania- Est Europe) the answer is that this mutation has nothing to to with autism. I am desperate to take my son out of the spectrum and I do not know how to use some suplimments in ord to help him being health.
    Thank You

  8. Hi Monica - please find a functional doctor who is in your area or willing to consult by phone (www.functionalmedicine.org) as this is very complex and they can help you by doing testing to determine his toxic load, gut health and nutritional needs to better guide supplementation.
    Dr Jill

  9. Hello, would you agree that there are some people who cannot tolerate methyl b12 and would be better off using either Adeno or Hydroxy....or both? Great Post :)

  10. Yes, indeed. If a patient has high NO levels, best to use hydroxyB12. Low MMA, then adenoB12. I still use more methylB12 than anything else, however :-)

  11. Dear Dr. Jill,
    Thank you for being what you are - highly trained professional in your area of expertise, open minded and straight forward medical practitioner.
    I come from Bosnia & Herzegovina - South East Europe, and with multiple medical issues, which seam to be correlated with each other, but so far no medical professional (local and elsewhere) could figure them all out and put a puzzle together for one reason or another, which is not the subject I would like to comment hereby. However, I wish to ask you several questions, and would highly appreciate your straight forward reply or replies.
    1. What is the usual bodily temperature or environmental temperature that renders MTHFR enzyme of C677T heterozygous mutation thermolabile and inactive? In that sense, can a prolonged exposure to high environmental temperature, for instance in sub-Saharan Africa, influence the above and cause the enzyme inactivity?
    2. Does MTHFR play any role in metabolism of estrogen in male population? If yes, can a shortcoming expressed in MTHFR heterozygous C677T mutation cause a build up of estradiol in male population over extended period of time, which in turn activates hyper production of serotonin but also hyper metabolism of the same by having increased the production of 5-HIAA, deficiency of Niacin (vitamin B3), and a subsequent mixed hyperlipidemia of typical shortage of HDL but highly elevated LDL and Tryglicerides?
    The above stated is just a fragment of the whole picture, as I do have more impairments with amino acids and vitamin co-factors pointing to the same cause.
    Regardless of whether your opinion would differ from what I asked and state above, your reply will be highly appreciated.
    Best regards

  12. Hi Nedzad, the human body highly regulates intracellular pH and temperature to such an extent that the enzymatic activity should not be affected by external climate to a large degree. However the stress of external heat or cold, starvation or other factors on the body could certainly influence enzymatic activity. Methylation is intricately connected to sulfation and glucuronidation which aid in processing and elimination of estrogen metabolites in both men and women.

    1. Dear Dr. Jill,
      Thank you once again for your understanding and efforts in your general, but yet so concise reply. It is well understood and received. However, there are many other studies to be done in my case to finally prove the exact cause and exclude other possibilities.
      Many thanks and best regards. God bless.

  13. About 1 year ago, I discovered that I am MTHFR, compound heterozygous. Through all the research and data I have read, I am convinced that MTHFR is the cause of all of my health issues. 1 month ago I weaned off all my meds, (except adderall and clonopin .5 at bedtime) and supplements (p5p, methycobalamin at bedtime because it makes me tired, methylfolate, calcium with d3, L-methionine 500mg,) obtain truly accurate lab results. I am aware of the risks, I am a Nurse, 51 years old. I have Hashimoto's, High Cholesterol, joint and muscular aches, ADHD, generalized anxiety disorder, vision changes, insomnia, menopause at 35 (ovarian failure, which I actually welcomed). I believe I have adrenal fatigue. (results pending). So far, here are my abnormal lab results. Lipids (T)=293, LDL=202.6, trig=47, HDL=81, B12= >1000, CK=154, TPO=105, Thyroglob ABs= <1, TSH, 25.70, FT4=0.67, T3 free= 27. CMP, all WNL, sodium low range normal, CO2, highest normal range. Also pending cortisol, saliva, VMA 24hr urine, copper, and heavy metals, Lyme, vitamin c, and d, cbc. If low adrenal function, etc.....what do I treat first? Historically, my ccholesterol is managed to a perfect range with 5mg crestor, but my muscles and joints ache. Prior to crestor, had side effects from lipitor and stopped. 3 weeks my cholesterol looked like it does now, on synthroid. Never pos lyme or any tick borne disease, tsh normal with 88mcg synthroid, but I feel like it doesnt do anything, for last 20 years. Since stopping synthroid, and crestor, lost 6 pounds, feel less anxious, but tired and lazy, otherwise feel good. If this is too much, I understand. Just wondering where to start 1st.

  14. Hi there, you need to find a functional medicine trained doc near you to help you navigate your health concerns by addressing and treating genetics, environment, infections, toxins and any other triggers and mediators affecting your health. I suggest searching by zip code at www.functionalmedicine.org. Warmest wishes for healing!
    Dr Jill

  15. Hi Dr Jill, I am 677T heterozygous, my cholesterol is 200, LDL is 140. I need to reduce these numbers, but have heard that cholesterol reducing protocols do not work if one is positive for the C677T heterozygous mutation. Is this correct?

  16. What protocol do you suggest for children that have one copy 677T and one copy of 1098? My daughter is 10 and want to avoid all the eventually detoxing and methylation issues. I hope to get in to see you myself but you are so good you are 18 months out! Thank you for the articles. I don't know why this isn't more well known to find a caregiver. I'm in the Denver area and would love another recommendation of someone who know about treating people who suffer from methylation mutations.

  17. Hi there, Unfortunately, there is no protocol. Treatment must be individualized ;-)

  18. Dr. Jill,
    Let me start off by saying I am adopted, and do not have any family history. :-) A year ago when I was 29 I had significant health issues including an ocular stroke. My cardiologist discovered around the same time I had a large PFO (Patent Foramen Ovulae) or an opening between the two sides of my heart. In June of 2014 I had an implant placed in my hear to close this opening. At that time, my cardiologist ordered extensive blood work and we discovered I am homozygous for the C677T mutation and negative for the A1298C mutation. My cardiologist said I needed to begin taking 1mg of folic acid daily and that was all I needed to do to address this mutation. I have been doing this for over a year and honestly have not felt "great" during this time. I have very low energy, anxiety, and am irritable. I take young living essential oils daily to help with the symptoms, but wondered if you had any insight on what else I could do. I have three beautiful, healthy daughters (1, 3, 6). I am assuming I will need to have them tested for this mutation. My cardiologist did not refer me to anyone to further investigate (functional dr, geneticist, etc.) which now seems questionable. Your input would be greatly appreciated!