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The Methylation Cycle: Central to ME/CFS

Posted Apr 11 2014 10:41am
I sat down to write a post about vitamin B12 supplements for people with ME/CFS and how much they have helped my son and I. I soon realized, however, that I couldn’t explain the importance of B12 without first explaining what the methylation cycle is and why it is so critical to those of us with ME/CFS (and similar illnesses). I’m no expert, but here is what I have learned:

What Does Methylation Do?
I already knew in a vague way that methylation was an important process in the body, but now I understand it is absolutely critical to multiple bodily systems. Before delving into exactly what methylation is, let’s look at its role in the body. Here are some of the vital functions of the methylation process:
Critical to the manufacture of DNA and RNA, the body’s basic genetic material;Essential for several important neurological processes;Required for the manufacture of adrenal hormones, which affect all sorts of bodily functions, including sleep, energy, temperature regulation, and neurological functions;Responsible for several detoxification pathways, allowing your body to get rid of toxins, including excess medications, supplements, dead viruses or bacteria, as well as environmental toxins.

Almost everyone with ME/CFS (and many people with other similar illnesses) has a dysfunctional methylation process. It’s hard to tease out cause and effect because every one of our dysfunctional systems (immune, endocrine, nervous, etc.) causes further dysfunction in other systems. Put simply, ME/CFS is a very complex knot of vicious cycles where each problem worsens all the other problems. So, it is likely that the longer you have been sick, the worse off your methylation cycle is. In addition, the more health problems you have, the worse the methylation process gets (more vicious cycles), so someone like my son who has ME/CFS and also Lyme disease plus two other tick infections just keeps getting worse and worse – which is what we saw with him a few years ago and again this past year. Same goes for anyone with any kind of underlying infections behind their ME/CFS (which is probably most of us).

What Happens When Methylation Isn’t Working Properly?
So, if people with ME/CFS have messed up methylation cycles, what exactly does that mean? When the methylation process isn’t working properly, the following problems result:
Detoxification doesn’t work well (as explained above) so toxins build up in your body;Less serotonin, dopamine, and melatonin (all directly linked to sleep dysfunction as well as depression) are produced, as well as less of other neurotransmitters;Decreased production of adrenal hormones;Elevated levels of homocysteine, which can lead to cardiac problems;Decreased cellular energy production aka mitochondrial dysfunction, leading directly to fatigue and post-exertional malaise;Possibly also an underlying mechanism for depression (see note on serotonin and dopamine above).

Take a look at that list again – notice anything familiar? It’s pretty much a list of most of the symptoms and dysfunctions that define ME/CFS! So, now you begin to see how important methylation is to each and every ME/CFS patient.

Methylation’s Role in Infections

Detoxification, one of the processes affected by methylation, becomes supremely important if you have underlying infections (as the majority of ME/CFS patients do) and especially if you are treating those infections. In that case, you need an efficient detox process even more, in order to remove toxins like dead viruses and bacteria and excess medications and supplements from the body.

Those with Lyme or those being treated with antivirals are familiar with herx reactions, where symptoms worsen (often severely) with treatment because the body is being flooded with dead bugs and extra medication that it can not properly get rid of, causing the immune system to react against the increased presence of viruses or bacteria in the bloodstream. When methylation is not working well (as in most with ME/CFS) and therefore detoxification pathways aren’t working well, the herx reaction can get worse and worse, until the patient is stuck in crisis mode – totally incapacitated by herx symptoms, even when the medication (antibiotics or antivirals) are severely reduced. That’s where our son was twice – first, at the end of high school a few years ago and again, this past year (sophomore year of college).

What Exactly Is Methylation?
This is where it gets somewhat complicated, but even a basic understanding of the methylation process will help you understand what kinds of treatments might help. Methylation is a biochemical process in the body that uses certain raw materials (foods, vitamins, supplements) to convert molecules into other molecules. When the process is working well, all those things listed above happen as they should: DNA, RNA, and crucial neurological components are manufactured; critical hormones (for sleep, mood, healthy adrenal function, and more) are made; and the body detoxes effectively, getting rid of those things that might be harmful to you.

I find the best way to understand the methylation process is to look at it visually:



(NOTE: Diagram is from an excellent article on B12 at ProHealth . Click on diagram to enlarge)
You may not recognize or understand all of the components, but this diagram shows how each step leads to another step and how interrelated the 3 different cycles shown here are to create the full methylation process. You can also see some of the important inputs to the process: proteins, amino acids, vitamin B12, folate & folic acid. And I think it is quite clear that if any one part of this process breaks down – for instance, there isn’t enough B12 or folate – then the entire process will fail, leading to the kinds of problems listed above.

What Can You Do?
Several methylation experts have emerged who understand the critical importance of the methylation cycle in people with ME/CFS and related illnesses and have made it their life’s work to try to help. Each of the experts has his or her own protocol, so there are some choices; however, they all rely on the critical components of the methylation cycle: vitamin B12 and folate (in various forms).

Dr. Amy Yasko is perhaps best known for pioneering a methylation protocol, designed to help repair dysfunctional methylation processes (and thereby improve the patient’s symptoms in a number of different areas). Interestingly, the focus of her work is in autism in children but it is equally applicable to ME/CFS (not the first time links between ME/CFS and autism have shown up). She has her own explanation of the methylation cycle , if you want to learn more, along with additional diagrams (more complicated than what I included here). Dr. Yasko advocates first getting some genetic testing done and then customizing the methylation protocol based on your results (more on that below).

With our son, we started with Dr. Rich van Konyenburg’ssimplified methylation protocol , which I have written about here before. My son was in such terrible shape to start with that we had some difficulties, so I e-mailed Rich directly, and he was kind of enough to respond personally and help us through some of those challenges. Unfortunately, Rich died unexpectedly last year, leaving a big gap in our small world of expert ME/CFS resources. The last version of his simplified methylation protocol is available here , with an excellent Q&A on methylation written by one of Rich's colleagues here.

Typically, any methylation protocol begins with a good quality multi-vitamin, vitamin B12 (more on that in the next post!), and 5-MTHF, a form of folate. However – and this is critically important – anyone with ME/CFS should start very slowly with tiny doses and only gradually increase, as tolerated. Any of these supplements can cause their own sort of “herx” reaction, as they get the methylation process working again, suddenly getting detoxification working again and flooding the bloodstream with toxins. As with most things in ME/CFS, low and slow is the rule. For instance, our son started with just a quarter of a 5-MTHF tablet every other day, very slowly working up to his current dose of 400mcg per day.

Our son improved a bit on Rich’s protocol, but he was scheduled to start college in a month or so and was still too sick to manage it (as I mentioned earlier, his case is even more complex than most because of the 3 tick infections he is fighting along with his ME/CFS). Our Lyme doctor recommended a consultant who is a registered dietician and has an MS in biochemistry. She is brilliant and not only understands this complicated methylation process but also how that fits in with all the other complicated biochemical processes that are dysfunctional in ME/CFS and Lyme patients.

In the methylation arena, she ran a methylation panel for our son and made recommendations specifically based on his results. She also recommended dietary changes, in part because gluten, casein (the protein found in milk), and gliadin (a protein in oats) can all block part of the methylation process. Also foods high in oxalates aren't good for people with ME/CFS (I don't fully understand why yet - still working on that one!).

With her help (and some other changes as well), our son recovered enough to start his freshman year of college alongside his peers, living on campus and taking 3 classes with enough energy left over for a social life. It felt like an absolute miracle to us, and treating the methylation problems was definitely a big part of that.

We discovered, however, that you have to be diligent to stay ahead of all the complex problems in ME/CFS and Lyme. After two months, our son gave up on the restricted diet (he was feeling pretty good by then). He kept up the folate and B12 supplements, and continued with his Lyme treatment and all of the treatments for ME/CFS. Eventually, he began gradually declining again, until he was back in crisis mode and completely incapacitated during this winter break (note: this was more than methylation problems but we could tell that was part of the picture). We got back in touch with our consultant, got him back on an even stricter diet (he was so sick, he was willing to try anything). He is again recovering, back in school living on campus, and able to enjoy a social life with his friends, too. Part of his recovery is due to treating yeast overgrowth caused by his Lyme treatment, and part of it is due to getting back on track with the methylation process.

To help with methylation and associated processes, he (and I) take the following supplements (links below), remembering that we added these very gradually and slowly:
  • 400 mcg 5-MethylTetraHydroFolate (5-MTHF) (we use Doctor's best brand - but we followed Rich's recommendations at first until he got up to this dose and could take these capsules)
  • Xymogen ActivNutrients multivitamin with no Iron or Copper (rec by our biochemist - we buy it at cost through her office but here are online sources - apparently, it is important to leave our Iron & Copper when you have infections)
  • Xymogen ALAMax and Resveratin to assist in mitochondrial energy support (I take a different brand of alpha lipoic acid and Jamie is currently off ALA temporarily while we get his yeast problems under control).
  • Calcium D-glucarate for detox support
  • S-Acetyl Glutathione for detox support and energy (studies have shown people with ME/CFS to have low glutathione levels)
  • N-Acetyl Cysteine (NAC) - Jamie is off this temporarily until his yeast problems are gone, but I increased my dose after reading that 1200 mg per day can help with weight loss (it did!) plus it is critical to detox and liver support in ME/CFS.
  • Milk Thistle - brand varies, taken at end of day and helps with detox - critical for liver support.
  • Vitamin B12 - Hydroxycobalamin injections 1000 mcg twice a week (Jamie); daily combination B12 product for me (more on B12 in the next post)

More recently, my son and I both had genetic testing done through 23andme (maybe I need another post on that!) and ran our results through Genetic Genie to find out what genetic defects we each have relative to methylation. A couple of problem areas showed up for each of us, so our next step is to work with our biochemist consultant to understand what the genetic results mean and how to adjust the methylation protocol accordingly (as Yasko recommends, too).

This post turned out much longer than I had planned, but it is a complicated and important subject. Next up is a post on the use of B12, including importance, uses, dosing, types, etc. From what I’ve read, it seems that everyone with ME/CFS can benefit from vitamin B12 supplementation, but it has to be done right in order to be effective. That one is already half-written, so I hope to post it here within the next week. Please share your own experiences with treating methylation and/or questions in the comments area. I am still learning about this critical part of ME/CFS, and I’m sure others would benefit from comments and questions also.

NOTE: Someone reminded me that I didn't mention SAMe in this summary. if you look at the diagram above, you can see that SAMe is a part of the methylation cycle; however, it is not recommended that all people with ME/CFS supplement with SAMe. My son tried it and got worse. Here's the way that Rich Van Lonyenburg explained it to me
"This was initially included in the protocol I proposed, but so many people could not tolerate it that I took it out.  SAMe will come up automatically if the partial block of methionine synthase is lifted by the methylation protocol.  I think that some people have difficulty dealing with all the sulfur if given NAC and SAMe.  The sulfur must all pass through the sulfite oxidase reaction, and if it can't handle it, sulfite builds up and gives headaches, difficulty in breathing, and/or rashes.  It also further lowers glutathione."

One of the common genetic defects related to methylation causes an inability to metabolize sulfur compounds, and this is relatively common in people with ME/CFS (both my son and I both have this defect and have reacted badly to sulfa antibiotics), so perhaps this is part of the reason why supplementing with SAMe sometimes makes ME/CFS patients worse. So if you do try it in spite of Rich's warning, watch for negative reactions which may worsen over time.
               
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