If you have tried Rich's Simplified Methylation Protocol please take the poll
(This poll was created by Caledonia. after a glitch in the first poll showed up, we shut that down and recreated it here - sorry about the problems.).
The Methylation cycle , a reiteration and update of ME CFS research by Rich van Konynenburg, PhD.
The methylation cycle
Derek Enlander MD, Mount Sinai School of Medicine, New York
denlander@aol.com
I worked with Rich van Konynenburg for several years since 2007. Unfortunately he died shortly after I invited him to present his research at a 2013 national meeting at our ME CFS center, Mount Sinai School of Medicine in New York, unfortunately he died shortly after the meeting . In his classic research he stated that a fundamental ME CFS biochemical issue may be a blockage of the methylation cycle. The main goal of ME CFS treatment should remove this block. We worked on this theory together. This blockade causes amino acid and glutathione depletion. This causes various symptoms seen in ME CFS. Simple therapy is difficult due to poor glutathione absorption, indeed if it were possible, it does not provide permanent relief. The methylation cycle block should be corrected to improve the glutathione levels. 30% of ME CFS patients possibly suffer from genetic polymorphisms which decreases the effects of glutathione supplementation or indeed supplementation of other amino acids.
This paper is a reiteration of his work and is published in his memory.
Dr. Amy Yasko,the nutritionist,,has performed important research in the the methylation cycle in Autism. It should be stated that Autism is not related to ME CFS. but we can learn from her work on the methylation cycle. She suggested various non prescription substances may supplement and possible correct the methylation cycle specifically when there is no genetic polymorphisms . Dr. S. Jill James, Ph.D., et al. in the study that found the connection between the methylation cycle block and glutathione depletion.
In the simplified treatment approach, 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.
Protocol
GearUp Multi Methylation capsules one in the morning
Catapult for brain fog contains Phosphatidyl serine
GearUp Hydroxy B12
SAMe
We believe that in Vitamin B12 treatment, Methylcobalamin is more effective than other forms of cobalamin. But Rich van Konynenburg specified hydroxocobalamin rather than methylcobalamin as the main supplemental form of vitamin B12 to accommodate patients who may have a polymorphism in their COMT (catechol-O-methyltransferase) enzyme. If patients do not have this polymorphisms, methylcobalamin is more effective. SAMe is added in an initially small dose 200mg daily, dependent on COMT polymorphism. The amount of B12 can be increased, dependent on the reaction to the initial dose, a higher B12 dose will be more effective in a large number of patients.
Treatment Course
The treatment of the immune system in ME CFS has two aspects. Rectifying a problem in the methylation cycle and the second supplementing the production and function of the natural killer cells.
Initially the patient may feel worse, the protocol should initiate detoxification and commence the removal of the bye products of pathogens and viruses. In some patients it is possible that treatment causes a reaction due to polymorphism in the CBS (cystathionine beta synthase) enzyme. in such cases treatment will be more complicated .
In the initial effects of detox the toxic heavy metals are liberated from various sites in the body and the heavy metal lab tests may be transiently elevated. If taurine and ammonia are elevated in a urine amino acids test after four weeks of treatment, this may suggest a CBS upregulation polymorphisms, requiring a more complicated treatment approach.... Plan B below.
The taurine and ammonia urine tests should precede the initial treatment The Initial treatment should continue for approx four weeks before doing the second urine tests . The results will not be apparent before then . It is possible that the increased symptoms are intolerable and the test then has to be performed earlier and PLAN B instituted.
TREATMENT ISSUESThere is a detox problem in ME CFS, treatment should minimize the use of drugs and pharmaceuticals. The action of pharmaceuticals is based on their therapeutic moment and subsequently their ease of elimination. Drugs are eliminated at various rates by enzymes in the body’s detox system, usually in the liver, kidneys, lungs and intestines. CFS patients may have polymorphisms in these detox systems and enzymes, including CYP450 enzymes . Genovation labs have a clinical lab test (
http://www.genovations.com). Because of these polymorphisms, many patients are genetically unable to remove and detox drugs at a normal rate, many patients do not tolerate drugs. Patients with a glutathione depletion and methylation cycle block can suffer from biochemical inhibition and polymorphism in their detox systems. Both factors cause ME CFS patients to increasingly suffer from the toxic effects of various drugs and even non pharmaceutical herbal products and supplements.
- There are various case definitions for ME CFS. Therefore the population defined by these definitions is very heterogeneous. Thus the treatment of various patients may differ. Definite specific blood tests do not exist. We may use various test results and symptoms to piece together the diagnosis. Post Exertional Malaise as defined in the Canadian Consensus Criteria is an important symptoms relatively unique. Expense is a problem insurance companies do not cover some of the more complexbolld tests. Inquire whether the insurance company will pay for the tests before the test is performed. An initial glutathione measurement should be performed. initially, the red blood cell total glutathione test is offered by http://www.immuno-sci-lab.com or by Mayo Laboratories. An alternative serum reduced glutathione test offered as part of the Comprehensive Detox Panel at http://www.gdx.net/home/assessments/detox/reports/.
- Genetic enzyme polymorphisms and protein abnormalities impact the methylation cycle and associated biochemical cycles and pathways. Some of these polymorphisms have important impacts on the choice of treatment program.
- Single nucleotide polymorphism Panel I, available fromhttp://www.testing4health.com. usually not reimbursed by insurance companies. Patients who have been ill for an extended period of time , can accumulate toxins from various sources and infections causing a burden on the immune response. Their detox system may has been dysfunctional for many years. Hopefully reinitiating the methylation cycle restarts both the immune and detox systems. Pathogens and infected cells may die off at higher rates, toxins will be mobilized. The resulting detoxification may be unpleasant, and may even be intolerable. In may seem that the treatment is not effective. The patient must be informed of transient ill effects, otherwise they may stop treatment in exasperation.
- GI problems are frequent in ME CFS. The “bowel biome” has been exposed by researchers Dr John Chia has written about the problem. Various constipation and diarrhoea problems have been explored . 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.
- A gentle laxative Go! has been effective in regulating constipation, a frequent symptom in ME CFS.
- Dr Mayhill in the UK has shown mitochondrial defect in ME CFS . It has been suggested that depletion of magnesium , taurine and glutathione can lead to mitochondrial dysfunction, elevation of excitatory neurotransmitters and depletion of inhibitory neurotransmitters. This in turn can create an intolerable anxiety which will affect treatment. 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 and will cause anxiety in the seeming absence of positive treatment effects.
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. It is mandatory that a complete medical history and comprehensive blood testing be performed. If certain organ systems are abnormal, the symptom set may be other than ME CFS
9. It has been suggested that serum aluminum can cause immune disturbance (Yasco), this finding has not been replicated by other researchers.
10. A number of doctors have used chelation as a means of reducing heavy metal toxicity. We are not convinced that this widespread use is helpful. EDTA chelation should only be used when serum tests for heavy metals are elevated.
11. The CBS polymorphism (cystathionine beta synthase enzyme) is located at the entrance to the transsulfuration pathway and converts homocysteine to cystathionine. The result is that there is an increased flow though the transsulfuration pathway lowering the production of glutathione, as well as elevated production of ammonia, sulfite and hydrogen sulfide which are toxic. If a patient has CBS polymorphisms, it is necessary to deal with this aspect before restarting the methylation cycle. production of these toxins may explain why some patients cannot tolerate direct efforts to build glutathione using sulfur-containing substances, while others improve.
12. After 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. 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.The late Dr Lerner used a mega doses of valtrex for 2-3 months, several patients benefitted from the therapy. 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. The metabolic pathway is slowed using dimethylglycine, a product of the BHMT reaction. This shunts the flow through the parallel methionine synthase pathway. This has the effect of an adjunct effect on the folate cycle, consecutively affecting the biopterin cycle, linked to the folate cycle. The folate cycle is active in cell production and repair, making new RNA and DNA in T cells in cell-mediated immunity and of courd=se in other cell proliferation. 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, in very small amounts.
17. Remyelination is dysfunctional during the blockage of the methylation cycle. Myeline is the protein sheath which surrounds the neurone. Methylation is necessary to synthesize myelin's basic protein, demyelination should improve transmission of impulses in the nervous system.
18 The Natural Killer (NK ) cells.
Did research on hey I minute substance call macrophage activating factor (MAF). His work went into decline because of inappropriate claims to curing cancer. However it was fun is that M AF did have an effect on a natural killer cells. Prof. Kenny to me earlier and Belgium call me Andrew my attention to and I have an we jointly decided to look into the possibility of using MAF in ME CFS. MAF it Is obtainable and let hey enter muscular injection and also as a byproduct of certain strains of probiotic bacteria. When the strains replicate they produce minute quantities of MAF which show positive results in the treatment of ME CFS
We find is that patients can have good results when they take 75 ML of the probiotic bacteria and culture medium which can be either yogurt or agar solution daily. In cases of lactose intolerance agar solution is preferable.
Genetic abnormalities.
The methylation cycle is complex. It is subject to many enzymes and enzymatic production mutations, we list the common Genetic abnormalities.
Mutations in the enzymes listed occur at multiple points in their amino acid sequences. Abnormal (mutation) genes (+) or normal genes (-) are obtained in most cases from our parents (+/+, +/-, or - -) .
If mutation is homozygous(+/+), it can have greater effect than a heterozygous (+/-) or no abnomality. (-/-).
We summarize the different mutation categories:
Homozygous Mutation +/+ both genes affected.
Heterozygous Mutation +/- one gene affected.
No mutation - /- normal
Mutations and Enzyme markers do not always or specifically indicate abnormal function, the results unfortunately are not absolute. The mutations can indicate a potential problem. The immune system when confronted by stress, a virus, trauma, pathogens of various types or toxic exposure may cause the mutated gene to react. These factors including Mercury or other heavy metals will impact the methylation and folic acid cycles, shutting down immune system reactions.
Some patients order genetic testing to determine gene mutations, it is expensive and not mandatory.
Here is a list of various enzymes and possible gene mutations and their reactions
CBS (Cystathione-Beta-Synthase) C699T – helps to convert homocysteine into glutathione (major antioxidant in the body). If a defect exists it will affect ammonia detoxification because excess sulfur in the body (endogenous or exogenous sources, ie. supplements like MSM, Epsom Salt or medications such as DMPS) can be converted to ammonia. Also, this defect can affect an enzyme called G6PDH which has negative effects on blood sugar metabolism and red blood cell formation and blood vessel stability (easy bruising, bleeding, broken blood vessels).
heterozygous defect. Partial defect. Higher risk for ammonia detoxification issues.
homozygous defect. Both genes affected. Significant propensity for ammonia detoxification issue. Will need to be careful with sulfur containing supplements, ie. MSM and medications, ie. DMPS.
COMT (Catechol-O-Methyltransferase) V158M – helps to methylate dopamine, serotonin, norepinephrine. Essentially slows down or regulates production of these neurochemicals. no mutation may indicate that the enzyme works too efficiently and will use up resources of methyl groups (CH3),
heterozygous mutation Partial defect in system = partial ability to use up CH3 groups. Will be able to handle some methylating supplements, ie. Methyl-12, SAMe, Theanine, DMG.
homozygous mutation. Both genes are affected. Significant defect in system. This indicates that the enzyme works sluggishly. Essentially slows down methylation of above listed brain chemicals. In some situations is a better scenario for an autistic child because they will tend not to use up excess methyl groups (chemical currency). Will need to be careful with too many methylating supplements, ie, Methyl-B12, SAMe, Theanine, DMG/TMG. The overuse of these supplements could cause over stimulating leading to hyperactivity, irritability, erratic behavior, etc.
MTHFr C667T (Methylene Tetrahydrofolate Reductase) – helps to convert homocysteine to methionine in the methylation pathway. This enzyme pathway has global effects for immune function, muscle metabolism, neurochemical production and regulation, and detoxification.
heterozygous mutation. Partial defect in methylation, one gene is affected usually not a significant methylation supplement problem
homozygous mutation. Both genes affected. The enzyme systems works very sluggishly which significantly impairs the process of methylation.
MTHFr A1298C (Methylene Tetrahydrofolate Reductase) – helps to convert BH2 to BH4 for serotonin and dopamine production. effect on ammonia detoxification, and protects against too much histamine (stimulates allergic reactions, over- production of stomach acid).
heterozygous mutation. Partial defect system. This translates into a partial problem with A1298C’s function – particularly important when considering the balance of dopamine and serotonin which can increase the propensity for mood swings and non-yeast, non-clostridia (intestinal bacteria) abnormal behavior from too much ammonia.
homozygous mutation. Both genes affected. The enzymes system works very sluggishly which significantly impairs the conversion of BH2 to BH4 and it related effects.
MTR (Methionine Synthase – MS) – enzyme is necessary to produce methionine from homocysteine. It requires Methyl-B12 , a mutation defect may cause reduced enzyme activity and methylation depletion (CH3) as in COMT (-/-)
heterozygous mutation. Partial defect in system.
homozygous mutation. Both genes affected. This defect causes an INCREASE in enzyme function which increases the risk of methylation depletion. methylating supplements Methyl-B12, DMG, Theanine, SAMe, etc. may help
MTRR (Methionine Synthase Reductase – MSR) – is necessary to regenerate Methyl-B12 so a constant supply of homocysteine can be converted to methionine. Defect decreases enzyme activity add Methyl B12 to supplement
heterozygous mutation. Partial defect in system – will need to be cautious with too many methylating substances. – Alec shows homozygous (both genes affected) mutation in this enzyme complex. This translates into decreased ability to regenerate Methyl-B12.
homozygous mutation. Both genes are affected. This mutation DECREASES function of enzyme. Definitely need Methyl-B12 – even if COMT ++ (which usually indicates a possible intolerance to methylating supplements).
VDR Bsm/Taq (Vitamin D Receptor) – helps support COMT in the regulation of dopamine levels – think behavior issues! It uses methyl groups to do this.
VDR Bsm/Taq (+/+) = homozygous mutation. Both genes affected. If mutation is present will be more sensitive to methyl donor supplements, ie. Methyl-B12, SAMe, DMAE, Theanine, DMG, TMG. Also, will need to watch for behavior issues related to fluctuations in dopamine production – mood swings!
NOS (Nitric Oxide Synthase) – helps in the formation of nitric oxide which has a role in oxidative stress and chemical production. If NOS mutation is present it can affect the urea cycle with respects to ammonia detoxification (hand-flapping, over-stimulatory behavior).
homozygous mutation with both genes affected. effects related to ammonia detoxification issues in association with CBS mutation.
ACE Deletion (Angiotensin Converting Enzyme) – This enzymes leads to high levels of angiotensin II which causes an increase in aldosterone. High aldosterone leads to increase potassium loss in the urine and increased sodium retention. Animal studies show a correlation between high angiotensin II with increased anxiety and decreased learning and memory. Decreased potassium can lead to fatigue and decreased energy production as cellular membrane activation, particularly for the brain and peripheral nervous system is dependent upon sodium
otassium balance. ACE deletion are more completed correlated to a marker called AHCY enzyme.
*Mood Swings: CBS, COMT (+/-, +/+) VDR mutations can cause mood swings.
• Patients with Mutations may need to decrease or discontinue methylating supplements such theanine, MSM, methyl-B12, SAMe, melatonin, curcumin.
Heavy Metal Testing: The idea that viral unloading takes place before heavy metal excretion can occur is based . It has been suggested that viruses can cause metal trapping in the body. Clinical lab tests can show heavy metal elevation in the blood or in the urine. Mercury, lead, cadmium aluminum and arsenic are known to blunt or stop the immune response
• Viruses create an inability to detoxify heavy metals adequately.
- Patients who are good methylators will have less viral and heavy metal toxins in their body, in contrast to poor methylators who will have more viral load and heavy metal toxins.
- Patients who do not carry mutations in the MTHFr, CBS, MTR, and MTRR enzyme pathways may be more capable of excreting heavy metals. COMT is one of those curious mutations were the mutation actually slows down the enzyme function potentially offering some protection against methyl group depletion (which is a favorable thing for a person on the autistic- spectrum). However, the bottom side is that the COMT enzyme complex is sluggish which compromises other functions such as neurotransmitter (brain chemical) deactivation.
Ammonia toxicity
The liver and kidneys are important in the elimination of ammonia and its byeproducts. A successful Ammonia Detoxification Protocol is
- Milk Thistle two capsules daily
- Activated Charcoal – 1⁄2 to 2 capsules at bedtime.
• Magnesium Citrate – 250 to 500mg in aqueous solution (magnesium flush) 3 hours following the activated charcoal this will produce bowel movements and fecal elination.
- Yucca (herbal remedy) – 1⁄2 to 1 capsule per day.
- Hepapressin improves the immune and hepatic systems.
