Methylation 101


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Methylation.  What is it?  Who cares?

Well, I’m here to tell you methylation (methyl – A – shun) reactions are involved in some pretty important processes in the body.

For example, methylation is critical to in the citric acid cycle which is how we make fuel for our cells.  No fuel ultimately equals cell death.  Like I’ve often said, you can’t run a car on bad gas.  But when methylation is involved, you might EAT great….but because of gene mutations, you can’t transform the raw material well.    Ask anyone with fibromyalgia or chronic fatigue what their muscles feel like.  As your cells starve, they literally start tightening up – not unlike the process of rigor mortis.  As they starve, they affect other metabolic pathways downstream as well.

Methylation is also involved in protein synthesis, DNA replication, gene expression and more.  That doesn’t sound like a big deal if you aren’t fresh on your biochemistry but let me paraphrase for you.  Methylation is involved in cell life. Our body is in constant motion 24 hours a day, 7 days a week.

I bring this all up because in the last 1.5 years, research has EXPLODED regarding methylation and the MTHFR gene.  (Yup, MTHFR sounds like a dirty word but I didn’t make it up.)  Mutations come in all shapes and sizes and some don’t matter.  Eye color and hair color are different nucleotide sequences in the main gene.  For most of us, it’s not a big deal.  But mutations regarding methylation directly and indirectly affect our health.


Genes give instructions to enzymes and it can negatively or positively affect the speed of a biochemical reaction.  The bottom line is that a mutation in the MTHFR gene affects  MTHFR enzyme function  and changes the synthesis of 5-MTHF which in turn affects the remethylation of homocysteine to methionine.  If Homocysteine builds up, it’s considered a risk factor for cardiovascular disease.  If this cycle can’t go round and round, it also affects our production of SAMe which is related to mood disorders.  Because methylation turns genes on and off, mutations also affect cancers.  Downstream, methylation affects “activating” vitamin B12 as well as our ability to make Glutathione – the mother of all anti-oxidants.  There’s more but I think you’ll get the point.  For a really good time, check out this chart of metabolic pathways.

There are 4 possible mutations and each slows down the function of the enzyme. My analogy is that it’s like having a fatality accident on the freeway.  Not only does traffic slow down, it backs up.  Eventually it takes so long that everyone is directed to side streets.  They’ll get there but it’s a SLOW road.   Get it?  If the MTHFR gene and enzyme are slow, they back up, and because it’s such a popular thing in the body, their lack of performance affects others (glutathione, hormones via the COMT pathway, etc).

I mentioned hormones so let’s do another analogy since this affects sooo many of you.  Up ahead of the traffic accident/fatality are the estrogens, waiting for their raw material.  Because of the mutated MTHFR gene and hindered MTHFR enzyme, everything is slow and they don’t get their raw materials.    Another analogy would be a factory line.  A slow down in bottling makes the guys who want to box it all up slow down.   A definite hiccup in the system.

Specifics on the mutations

The two genes we know the most about so far are:

C677T and we’ll call it the “C” gene. The 3 options are:

  • no mutation (this is a good thing and they have full enzyme function)
  • 1 mutation which is called Heterozygous-C and enzyme function is reduced 40%.  This includes our ability to
  • 2 mutations which is called Homozygous-C and enzyme function is reduced 70%

A1298C and we’ll call it the “A” gene. Same options as above.

  • No mutation (a good thing with no effect on enzyme function)
  • 1 mutation is still called Heterozygous-A and enzyme function is reduced although no facts and figures seem to exist yet.  Clinically, I’ve seen plenty of these patients and thus we can say they aren’t at optimal wellness or function.
  • 2 mutations is called Homozygous (A) and enzyme function is reduced 40%.

A Compound Heterozygous status means one mutation on each the C and the A. Enzyme function is reduced about 70%.

Statistically, 30-40% of the population carries 1 or more mutations.  The May 2013 issue of Living Without magazine states that those with Celiac have a higher prevalence.  In my practice, because sick people hire me – not well people – every test but one has come back with at least one mutation.  And now that I know more, I realize that she only had the C mutation tested.  It’s quite possible she had one or two mutations on the A gene and it wasn’t tested.  She certainly fit the picture of a walking talking MTHFR.

Mutations on the “C”  gene are considered to be more serious in terms of cardiovascular disease risk via a build up of Homocysteine, but mutations on the “A” gene carry consequences as well.  The experts I know of – Dr. Bridgett Briggs (MD) and Dr. Ben Lynch (ND) – both present data as such.  Dr. Briggs has also said that even if a patient comes back negative for all the mutations yet has the signs and symptoms, she still treats and sees improvement.  It is thought that when we’re all done, we’ll be analyzing 24 mutations but we just aren’t there yet in the non-research world.

At this point, I can typically see all the seemingly unrelated signs and symptoms in a patient and tell them “we’re testing your MTHFR gene status not to see IF you have a mutation but to identify which one and how many”.  Seriously.

I have recently updated this page to reflect all of the health conditions a MTHFR mutation can relate to.  The list is tooo long to repeat so I HIGHLY encourage you to take a look at it.  The list of health conditions ranges from autism and ADD to migraines, to irritable bowel, to Cardiovascular disease, to depression and other mental health disorders, to any of the conditions associated with estrogen (PMS, irregular cycles, infertility, early hysterectomies, cysts…) to cancer (remember methylation is involved in DNA expression).  There are about 100 health conditions so far.

As I said, mutations in the MTHFR gene can affect anything and everything.  No doubt the MTHFR gene and its enzyme “talk” to other genes and so in person #1, it’s expressed as migraine headaches.  In person #2, it’s expressed as heavy periods.  Person #3, the unlucky soul, has migraines, heavy periods, and depression.

I have a mutation.  What now?

If a person tests positive for one or more mutations, the answer is a pretty easy fix.  “Activated folate” aka “L-5-MTHF” is given in place of folic acid.  Because of the mutation(s), the individual isn’t able to “activate” the folic acid (40% to 70% reduced function remember) and so we bypass that conversion step and just give the form he/she can use.  Now he/she can go on and methylate like non-mutants.

I’d like to summarize the key points.

  • MTHFR refers to a gene that has 4 mutations possible – 2 on the A, 2 on the C, or one of each.  It  is possible to have 3 or 4 mutations but from what I understand those folks are really sick and don’t live long.
  • Having one or more mutations affects folate metabolism, and downstream from that it affects methylation, one of the most common metabolic processes in the body.
  • Health conditions are numerous.
  • I didn’t say it yet but treating depression, cardiovascular disease, hormone imbalances, etc.  with drugs is just managing symptoms.  Identifying the root cause is my goal and its why I study functional medicine. Improve function.  Not manage symptoms.
  • Read Carrie’s testimonial here – we identified her MTHFR status and it has been life changing for her.  I think many of my patients have benefited from testing, but we often are improving many things at once.  In Carrie’s case, we identified her status, I made her a custom multi-vitamin and then life happened for a few months.  As an accident, it isolated the one intervention we did and so she knew the positive changes could only be from the “right” kind of vitamins.

Next week, I’ll talk specifically about MTHFR and Depression.  Stay tuned!

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 About Tracy Konoske, MS, RDN

meet_tracyFor the past 20 years, Tracy has served as a dietitian/nutritionist and educator to hundreds of patients throughout the US on their journeys to restoring health, and optimizing well being. 

Tracy has a passion for helping others heal, fueled by her own recovery from Chronic Neurological Lyme, Chronic Fatigue, Epstein Barr Virus, SIBO, and anxiety. 

Tracy says "I have the deepest respect and passion for the healing abilities of the human body.  Each day, I witness miracles when the body is provided optimal fuel:  a nutrient dense, whole, plant foods diet combined with any necessary lifestyle changes.  A talented teacher, known for explaining complex medical topics in plain English, Tracy will assist you in restoring your health and your freedom.  

Tracy helps people with chronic & mystery illness restore their health