Glutathione Depletion—Methylation Cycle Block Hypothesis: The Customized Approach
developed by: Richard A. Van Konynenburg, Ph.D
Methylation Cycle – CustomRichard A. Van Konynenburg, Ph.D 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. Due to subsequent requests from clinicians for a description of a treatment approach based on this hypothesis, Van Konynenburg came up with a Simple Approach and a more Customized Approach, based on what he perceives to be the most successful treatment approaches currently used in autism, which he believes shares the same basic pathogenetic mechanism with CFS. In most cases, it will be necessary for the physician to use the Customized Approach and tailor the treatment program to the individual patient. Van Konynenburg has since updated his approach and added some cautions. Please note that some people who have tried this approach have had adverse effects, sometimes of a serious nature.
Van Konynenburg believes that the fundamental biochemical issue in a large subset of the CFS patients is that the methylation cycle is blocked. The main goal of this treatment approach is to remove this block and restore the methylation cycle. He also believes that glutathione depletion is directly responsible for many of the features of CFS, but that it is usually not possible to normalize the glutathione levels on a permanent basis by direct approaches of glutathione supplementation. Rather, the methylation cycle block must be corrected first, to break the vicious circle that is holding down the glutathione levels. In addition to this, about one-third of CFS patients, because of particular genetic polymorphisms, cannot tolerate supplementation with glutathione or other substances intended to help them directly to build glutathione.
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., he suggests two treatment approaches for CFS. The first is a Simple Approach better suited to patients who have been ill a relatively short time and are not disabled. 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 the customized program should be followed. 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 (Ref. 2 in his 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. Van Konynenburg believes that the second approach is the treatment that will be necessary for most CFS patients, especially those who are more debilitated/disabled, as well as those with certain genetic polymorphisms.
It is necessary to minimize the use of pharmaceuticals in treating CFS patients. Many CFS patients have polymorphisms in their detox enzymes, including CYP450 enzymes and Phase II detox enzymes. (See Detoxigenomic panel offered by http://www.genovations.com). Because of these polymorphisms, many patients are genetically unable to detox pharmaceuticals at normal rates, and cannot tolerate them. In addition, 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.
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 Van Konynenburg has presented for CFS will not fit all patients. For this reason, he recommends a relatively inexpensive glutathione measurement initially, such as the red blood cell total glutathione test offered by http://www.immuno-sci-lab.com (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 http://www.gdx.net/home/assessments/detox/reports/. If a below-normal value is found in either of these tests, there may be a good chance that this pathogenesis model fits the patient.
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 this 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 http://www.holisticheal.com. 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 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 http://www.autismanswer.com.
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.
As discussed in Van Konynenburg’s 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.
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.
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.
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.
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.
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.
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.
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.
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.
As you can see from the diagram in Van Konynenburg’s 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. Van Konynenburg thinks 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.
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.
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.
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.
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. Please see Dr. Yasko’s materials for the details.
This treatment approach is not simple, quick, easy or inexpensive, but Van Konynenburg thinks this rather complex process is what is required. He would very much appreciate it if you decide to try this treatment approach, that you will keep him informed of how it works out for your patients. He is happy to answer questions that come up as well.
A yahoogroup has been started for those wanting to explore Dr. Amy Yasko’s protocol and Rich Van Konynenburg’s treatment plans in depth: http://health.groups.yahoo.com/group/CFS_Yasko/. Please note, this is a treatment group and not a support group.