Methylation Dependent Prote

Suggestions for Treatment of Chronic Fatigue Syndrome based on the Glutathione Depletion-Methylation Cycle Block Hypothesis: The Simple Approach

Methylation Dependent Prote
Methylation dependent protein

Richard A. Van Konynenburg, Ph.D.

I presented the Glutathione Depletion-Methylation Cycle Block Hypothesis for the pathogenesis of CFS in a poster paper at the 8th international conference of the International Association for Chronic Fatigue Syndrome in Ft. Lauderdale, Florida, on January 10-14, 2007. This poster paper is available here:

Since then I have received requests from some clinicians for a description of a treatment approach based on this hypothesis.

I am a researcher, not a clinician, and I am well aware that it is one thing to believe that one understands the pathogenesis of a disorder, but quite another to know how to treat patients who suffer from this disorder. Nevertheless, I will respond to these requests to the degree I am able. What I can say in this regard will be based on what I perceive are the most successful treatment approaches currently used in autism, which I believe shares the same basic pathogenetic mechanism with CFS, and also on limited experience in communicating by internet with the small number of CFS patients so far who have elected to try these approaches. Of course, I am counting on clinicians to apply their judgment to what I write here, based on their expertise and clinical experience, since responsibility for treatment falls to them.

I suspect that clinicians would like for me to supply a simple, straightforward approach that would be uniformly applicable to all CFS patients and thus readily useable in a typical busy practice in today’s medical climate, in which it is practicable to devote only a relatively short time to each individual patient. Believe me, I understand this, and I would very much like to be able to give such a response.

Now comes the “however.” At this point it appears that it will actually be necessary in most cases to devote considerable time to each patient, and to tailor the treatment program to the individual patient. In my opinion, the reasons for this do not appear now to be lack of understanding of the pathogenesis, but to be inherent in the genetic individuality of the patients as well as in the variety of their concomitant medical issues and, for many, in their general state of debility. I now see this need for individual treatment and significant time investment in each patient as the most significant problem in the practicable delivery of treatment to these patients. Hopefully this will become clearer as I explain further, and hopefully also, this problem can be ameliorated to some degree in the future as more experience is gained.

If you have read my pathogenesis paper, you know that I now believe that the fundamental biochemical issue in at least a large subset of the CFS patients is that the methylation cycle is blocked. Therefore, I think that the main goal of treatment must be to remove this block and to get the methylation cycle back into normal operation. I believe that it is also true that glutathione depletion is present in these patients and is directly responsible for many of the features of CFS, as I described in my recent poster paper, but I have found in interacting with clinicians as well as with many patients on the CFS internet lists, that it is usually not possible to normalize the glutathione levels on a permanent basis by direct approaches of glutathione augmentation.

Instead, it appears that the methylation cycle block must be corrected first, to break the vicious circle that is holding down the glutathione levels. In addition to this, some patients, because of particular genetic polymorphisms, cannot tolerate supplementation with glutathione or other substances intended to help them directly to build glutathione. One clinician estimated to me that this group amounts to about one-third of the patients.

The Simplified Approach – Based on what is being done in autism by the Defeat Autism Now! (DAN!) researchers and clinicians and independently by Dr. Amy Yasko, N.D., Ph.D., I am going to suggest two treatment approaches for CFS. The first is a simplified approach which may be applicable to patients who have not been ill for an extended period, and who are not very debilitated. Use of this simplified approach would be based on the hope that the patient does not have certain genetic polymorphisms, which would not be known in this simplified approach. If the patient does in fact have these polymorphisms, the simplified approach will not be successful, and then you will have to move on to the more complex treatment.

This simpler treatment approach is based partly on the treatment that was used by Dr. S. Jill James, Ph.D., et al. in the study that found the connection between the methylation cycle block and glutathione depletion in autism (This was Ref. 2 in my pathogenesis paper), but it makes use of supplements that are part of Dr. Amy Yasko’s treatment program. The second treatment approach is much more involved and is based on Dr. Yasko’s complete autism treatment. I currently believe that the second approach is the type of treatment that will be necessary also for most CFS patients, and certainly those of longer standing or greater debility, as well as those having certain genetic polymorphisms. However, I am including the simpler approach in an effort to match the practical demands of current medical practice, to the degree I understand them.

In the simplified treatment approach, potentially applicable to patients who have not been ill for an extended period, who are not very debilitated, and who will initially be assumed not to have certain genetic polymorphisms, one would proceed directly toward the goal of restarting the methylation cycle, together with some general nutritional support. If this treatment is tolerated and is efficacious in a particular case, I think it could actually be relatively straightforward. I think it should be borne in mind, though, that if the simplified approach is not effective for a particular patient, there is the risk that trying it could discourage the patient before she or he reaches the second option. So I think it would be proper and wise to discuss this issue with the patient up front, and to apply considerable clinical judgment as to whether the simplified approach should be tried on a particular patient.


The simplified approach would involve giving the following oral supplements daily, all of which are available from Dr. Yasko’s supplement website at

*¼ tablet (200 micrograms) Folapro (Folapro is 5-methyl tetrahydrofolate, an active form of folate, which is sold by Metagenics with a license from Merck, which holds the patent on synthesis).

* ¼ tablet Intrinsic B12/folate (This includes 200 micrograms of folate as a combination of folic acid, 5-methyl tetrahydrofolate, and 5-formyl tetrahydrofolate, aka folinic acid or leucovorin (another active form of folate), 125 micrograms of vitamin B12 as cyanocobalamin, 22.5 milligrams of calcium, 17.25 milligrams of phosphorus, and 5 milligrams of intrinsic factor)

* (up to) 2 tablets (It’s best to start with ¼ tablet and work up as tolerated) complete vitamin and ultra-antioxidant from Holistic Health Consultants (This is a multivitamin, multimineral supplement with some additional ingredients. It does not contain iron or copper, and it has a high ratio of magnesium to calcium. It contains antioxidants, some trimethylglycine, some nucleotides, and several supplements to support the sulfur metabolism.)

* 1 softgel capsule Phosphatidyl Serine Complex (This includes the phospholipids and some fatty acids)

* 1 sublingual lozenge Perque B12 (2,000 micrograms hydroxocobalamin with some mannitol, sucanat, magnesium and cherry extract)

* 1 capsule SAMe (200 mg S-adenosylmethionine)

* 1/3 dropper, 2X/day Methylation Support Nutriswitch Formula (This is an RNA mixture designed to help the methylation cycle. It is not essential, but is reported to be helpful.)

Note that I have specified hydroxocobalamin rather than methylcobalamin as the main supplemental form of vitamin B12. I’ve done this to accommodate patients who may have downregulating polymorphisms in their COMT (catechol-O-methyltransferase) enzyme, which many CFS patients seem to have. If they do not have these polymorphisms, methylcobalamin would be more effective, but in this simplified treatment, the patient’s polymorphisms will not be known. I am also including a small amount of SAMe, which is also a compromise, since the amount needed will again depend on COMT polymorphisms, which will not be known for this simplified treatment. The amount of B12 specified is also a compromise, since those with certain polymorphisms will benefit from a higher dosage than will those without them.

Treatment Course

After this treatment is begun, you can expect the patient to feel worse initially, and I think it would be proper and wise to make the patient aware of this before the treatment is begun. It is necessary to determine whether this feeling is occurring because the treatment is working and the patient’s body is beginning to detox and kill viruses, or whether it is occurring because the patient does in fact have upregulation polymorphisms in their CBS (cystathionine beta synthase) enzyme, in which case you will have to move on to the more complicated complete treatment regimen. Which of these is the case can be determined by taking spot urine samples for a urine toxic metals test and a urine amino acids test from Doctor’s Data Laboratories. These can be ordered through Dr. Yasko if you would like to receive her interpretation of the results, or they can be ordered directly from Doctor’s Data Laboratories (

If the toxic metals are elevated on the urine toxic metals test, this will indicate that the patient has begun to detox, which is desirable. If taurine and ammonia are elevated on the urine amino acids test, this will suggest that the patient does have CBS upregulation polymorphisms, in which case you will have to stop this treatment and move to the more complicated approach described below. It would be best to do this treatment for a week or two before doing the urine tests, so that meaningful results can be obtained on these tests, unless the patient cannot tolerate it. If the latter is the case, then you will have to go on to the more complicated treatment approach described below.

As I have emphasized, the simplified treatment approach may or may not be tolerated by a particular patient, and I will explain why it might not be tolerated later in this discussion.

Now I will move on to the more complicated treatment approach that I currently believe will be necessary for most of the patients. I will not supply all the details of this treatment approach in this letter, but will try to give you an overall picture of the sequence of steps involved. I recommend reading Dr. Yasko’s book “The Puzzle of Autism,” and consulting her other materials as well. These are available from by searching on “Amy Yasko.”

Before getting into this treatment approach, I first want to discuss some important issues, and then I will discuss the treatment, step by step:


1. It is necessary to minimize the use of pharmaceuticals in treating CFS patients. There are at least two reasons for this. As you know, the use of pharmaceuticals is based on their being eliminated at certain rates by the body’s detox system, found primarily in the liver, kidneys and intestines. However, many CFS patients have polymorphisms in their detox enzymes, including CYP450 enzymes and Phase II detox enzymes. (If desired, these can be characterized by the Detoxigenomic panel offered by Because of these polymorphisms, many patients are genetically unable to detox pharmaceuticals at normal rates, and cannot tolerate them. In addition to this, all patients who have the glutathione depletion and methylation cycle block suffer from biochemical inhibition of their detox systems, whether they have these polymorphisms or not. Because of these two factors, CFS patients suffer from the toxic effects of pharmaceuticals. Treatment using nutritional supplements is necessary, and some herbals can be tolerated as well.

2. Because of the broad nature of the current case definition for CFS, the population defined by it is very heterogeneous. It is likely that the pathogenesis model I have presented for CFS will not fit all patients. For this reason, I recommend a relatively inexpensive glutathione measurement initially, such as the red blood cell total glutathione test offered by (phone them for details) or by Mayo Laboratories. Perhaps a better test is the serum reduced glutathione test offered as part of the Comprehensive Detox Panel at If a below-normal value is found in either of these tests, I think that there is a good chance that this pathogenesis model fits the patient.

3. Different patients have different genetic polymorphisms in the enzymes and other proteins that impact the methylation cycle and the associated biochemical cycles and pathways. Some of these polymorphisms will have important impacts on the choice of specific parts of the treatment program. In using the more complicated treatment approach, it will be necessary to characterize the polymorphisms before it will be possible to make some of the decisions about selection of particular treatment aspects.

The most comprehensive panel for this is Dr. Yasko’s Comprehensive Basic SNP (single nucleotide polymorphism) Panel I, available from Dr. Yasko has selected the polymorphisms on this panel by correlating their presence with severity of autism symptoms and with the results of biochemical testing (mainly spot urine tests for organic acids, amino acids, and essential and toxic metals). This is a somewhat unorthodox method that jumps over the usual intermediate steps involved in studying polymorphisms, and there is not universal agreement about her results in the research community, but I think Dr. Yasko’s treatment outcomes are speaking for themselves, as can be seen from the voluntary testimonials of parents of autistic children on the parents discussion group at

As a researcher, of course, I look forward to the day when these polymorphisms will be thoroughly researched and characterized, and have encouraged those involved in such work to forge ahead. The results from this genetic panel require interpretation. One can either study Dr. Yasko’s materials to gain her insights on interpreting the results in general, or order her interpretation of the particular results, which is called a Genetic Analysis Report or GAR. The GAR is a computer-generated report with some general material that applies to all the cases, and specific sections that are chosen in response to the particular genetic polymorphisms found in the individual patient. As such, the continuity of the discussion in the GAR is not what would be found in a report written from scratch for each particular patient, and it may have to be read more than once to make all the connections in one’s mind, but the material contained is specific to the particular genetic panel results, and Dr. Yasko updates the material used in generating the GARs as more is learned.

4. As I have discussed in my paper, people who have been ill for an extended period of time (many months to many years) will have accumulated significant infections and significant body burdens of toxins, because both their cell-mediated immune response and their detox system will have been dysfunctional during this time. When the methylation cycle is then restarted, both the immune system and the detox system will begin to function better. When they do, pathogens and infected cells will begin to die off at higher rates, and toxins will be mobilized. The resulting detoxification will be unpleasant, and may even be intolerable. If the patient has not been prepared in certain ways, discussed below, she or he may not be willing to continue this and may drop out of the treatment program.

5. One of the most important preparatory activities is to make sure the gastrointestinal system is operating well enough to be able to absorb nutrients, including both food and the oral supplements used in the treatment, and also well enough to be able to dispose of toxins into the stools on a regular basis. If this is not done, it is likely that the treatment will not be successful. Treatments for the G.I. system, as well as for other aspects described below, are discussed in Dr. Amy Yasko’s book. Some CFS patients have reported benefit from Xifaxan to treat deleterious bacteria in the gut. This antibiotic is not absorbed from the G.I. tract, so it does not present problems for the detox system.

6. Another very important aspect of the preparation is to deal with the overstimulation or overexcitation of the nervous system that is present in CFS. This probably results from several causes, including depletion of magnesium and in some cases depletion of taurine, low blood flow to the brain because of low cardiac output, glutathione depletion in the brain producing mitochondrial dysfunction, and dietary and other factors causing elevation of excitatory neurotransmitters and depletion of inhibitory neurotransmitters. It is important that this be dealt with because if it is not, the patient will be less able to tolerate the detox inherent in the treatment.

7. Another important step is to ensure that the patient’s nutritional status is supported. Many CFS patients are in a rather debilitated state, partly because of deficiencies of essential nutrients. They are also in a state of oxidative stress. Appropriate nutritional supplements can correct these problems at least to some degree and get the overall metabolism of the patient into a better state, so that they can better tolerate the detox part of the treatment.

8. Particular organs or systems may not be functioning well and may need extra nutritional or herbal support. Which ones will vary from one patient to another, so this part of the treatment must be tailored to the individual patient.

9. Chronic bacterial infections should be addressed. According to Dr. Yasko, females in particular appear to be prone to streptococcal infections. She also finds that aluminum appears to be associated with the bacteria, so that when the bacteria die off, aluminum is excreted. While antibiotics can be used, there are downsides to this, both in terms of difficulty in detoxing some of the antibiotics and in terms of killing beneficial intestinal flora and encouraging deleterious ones, such as Clostridia dificile. In addition, some CFS patients have experienced tendon problems from the fluoroquinolone antibiotics. Dr. Yasko prefers natural antimicrobial treatments.

10. When the methylation cycle is restored, the normal detox system is able to deal with more of the toxins. Dr. Yasko also uses low doses of oral EDTA, but not the sulfur-containing chelators (DMSA and DMPS), to help remove aluminum as well as other metals, including mercury. DMSA and DMPS are not used because they can also bind glutathione, so that if a patient who is low in glutathione receives these chelators, their glutathione status can be worsened. Also, DMSA and DMPS are rich in sulfur, and CFS patients with certain polymorphisms cannot tolerate them. She also uses some natural RNA formulas for detoxing, as well as for a number of other purposes during the treatment. These are somewhat costly, and are not required as part of the treatment, but are reported to be helpful.

11. As mentioned in item 3 above, it is important to characterize relevant polymorphisms prior to bringing up the methylation cycle operation. One of the most important aspects of this is to evaluate polymorphisms in the CBS (cystathionine beta synthase) enzyme, which is located at the entrance to the transsulfuration pathway and converts homocysteine to cystathionine. Although this is somewhat controversial within the research community, Dr. Yasko finds that certain polymorphisms cause an increase in the activity of this enzyme. The result is that there is too large a flow down the transsulfuration pathway, and somewhat counter intuitively this results in lowered production of glutathione, as well as elevated production of taurine, ammonia, sulfite and hydrogen sulfide. The last three of these substances are toxins. If a patient has CBS polymorphisms, it is necessary to deal with this aspect before restarting the methylation cycle. If this is not done, efforts to start this cycle will result in increased production of these toxins. This may explain why some patients cannot tolerate direct efforts to build glutathione using sulfur-containing substances, while others derive some benefit from this. Dealing with this CBS up regulation situation can take a month or longer.

12. Only after all these issues have been addressed is the patient ready to start supplementing with larger amounts of the folates and cobalamins to begin major restoration of operation of the methylation cycle.

13. As you can see from the diagram in my pathogenesis paper, there are two possible pathways from homocysteine to methionine. One involves the enzyme methionine synthase, which requires methylcobalamin and is linked to the folate cycle as well, and the other involves the enzyme betaine homocysteine methionine transferase (BHMT), and requires trimethylglycine or one of the phospholipids (phosphatidyl-serine, -choline, or -ethanolamine). Ultimately, it is important to get the methionine synthase pathway back into operation, but in Dr. Yasko’s practice it has been found that it is easier to start up the BHMT pathway first. I think the reason is that S-adenosylmethionine (SAMe) interacts with methionine synthase, and by first starting up the BHMT pathway, one ensures that there is enough SAMe to start up the methionine synthase pathway.

14. As these steps are taken, the immune system and the detox system will start to function at higher levels, and die-off and detox will begin. These processes are monitored using periodic spot urine testing, and decisions about when to proceed to the next step in the treatment program are based on this urine testing.

15. Viral infections are dealt with naturally as the immune system recovers, though Valtrex is used in some cases. As the viruses die off, it is observed that heavy metal excretion increases. Heavy metal excretion is tracked using periodic spot urine tests and is plotted as a function of time to determine the progress.

16. When appropriate indications are seen in the urine testing, the BHMT pathway is slowed using dimethylglycine, which is a product of the BHMT reaction, and thus exerts product inhibition on it. This shunts the flow through the parallel methionine synthase pathway. This has the effect of bringing up the folate cycle, which is linked to it, and also bringing up the biopterin cycle, which is linked to the folate cycle. The folate cycle is needed to make new RNA and DNA to proliferate new cells, such as T cells in cell-mediated immunity. The biopterin cycle is necessary for the synthesis of serotonin and dopamine as well as for the operation of the nitric oxide synthases. Some patients benefit from direct supplementation of tetrahydrobiopterin, often in very small amounts.

17. The treatments up to this point should resolve most of the symptoms of CFS. The last step is to support remyelination, which has been dysfunctional during the time when the methylation cycle was blocked, because methylation is necessary to synthesize myelin basic protein. This should improve the operation of the nervous system.

That is a rough outline of the treatment process, and again, I refer you to Dr. Yasko’s materials for the details.

I’m sorry that this treatment approach is not simple, quick, easy and inexpensive, but unfortunately, I think this rather complex process is what is required, for the reasons I’ve given. I hope this is helpful, and I would very much appreciate it if you decide to try this treatment approach, that you will keep me informed of how it works out for your patients. If I can answer questions that come up, please let me know.

Rich Van Konynenburg (January 25, 2007)



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