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Methylation cycle hypothesis
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==Treatment== ===Yasko's Protocol=== The Yasko protocol looks at two different pathways of the methylation cycle, which she calls the '''long route''' and the '''short cut'''. The short cut utilizes [[betaine homocysteine methyltransferase|BHMT]], while the long route is via [[methionine synthase gene|MTR]]/MTRR and [[Cobalamin|Vitamin B12]] (Yasko, 2013).<ref name="Yasko_2013" /> Yaskoβs protocol has undergone a number of adaptations over the years. The information below refers to her 2013 Simplified Road Map to Health.<ref name="Yasko_2013" /> The Yasko protocol views methylation cycle support as a six-step process: #Regulate [[glutamate]] and [[GABA]] #*Since a high glutamate: [[GABA]] ratio can be hyperexcitatory, this is the number one priority in Yasko's version of the protocol. #Support the short cut pathway to help restore the methylation pathways without producing too many detoxification symptoms #Regulate [[lithium]] levels #*Since lithium is involved in B12 transport, lithium balance is important to the methylation cycle. Low levels of lithium in the blood or high amounts excreted the urine may require lithium supplementation. #Determine which kind of B12 is most absorbable based off of [[Catechol-O-methyltransferase|COMT]] and [[vitamin D receptor|VDR]] SNP status #Support the Long Route pathway utilizing folate or [[5-methyltetrahydrofolate|5-methyl-THF]] (5-MTHF), for [[methyltetrahydrofolate|MTHFR]] mutations #Customized support #*Yasko goes on to recommend a variety of different supplements depending on the patients' SNP status for COMT, VDR, MAO A, [[Acyl-coenzyme A cholesterol acyltransferase|ACAT]], MTHF, MTR, MTRR, BHMT, [[S-adenosylhomocysteine|AHCY]], CBS, [[Sulfite oxidase|SUOX]], [[Serine hydroxymethyltransferase|SHMT]], and [[Nitric oxide synthase|NOS]] genes.<ref name="Yasko_2013" /> ===Rich's protocol=== While Yasko pioneered the methylation protocol for autism, [[Rich Van Konynenburg]], trained as a physicist, was the first to apply the methylation protocol to CFS/ME and [[fibromyalgia]]. He wrote over a dozen papers that discussed the linkage between dysregulated methylation and fatiguing disorders, beginning in 2004.<ref name="Van_Konynenburg201103a">{{Cite web | last1 = Van Konynenburg | first1 = RA | authorlink1 = Rich Van Konynenburg | title = Glutathione and the Methylation Cycle| website = Phoenix Rising | date = Mar 6, 2011 | url = http://phoenixrising.me/treating-cfs-chronic-fatigue-syndrome-me/treating-chronic-fatigue-syndrome-mecfs-glutathione-and-the-methylation-cycle }}</ref><ref name="Van_Konynenburg201103b">{{Cite web | last1 = Van Konynenburg | first1 = RA | authorlink1 = Rich Van Konynenburg | title = Simplified Treatment Approach Based on the Glutathione Depletion- Methylation Cycle Block Pathogenesis Hypothesis for Chronic Fatigue Syndrome (CFS) | journal = Phoenix Rising| date = Mar 6, 2011| url = http://phoenixrising.me/treating-cfs-chronic-fatigue-syndrome-me/treating-chronic-fatigue-syndrome-mecfs-glutathione-and-the-methylation-cycle/simplified-treatment-approach-based-on-the-glutathione-depletion-methylation-cycle-block-pathogenesis-hypothesis-for-chronic-fatigue-syndrome-cfs-by-rich-van-konynenburg-ph-d}}</ref><ref name="Van_Konynenburg201203a">{{Cite web | last1 = Van Konynenburg | first1 = RA | authorlink1 = Rich Van Konynenburg| title = Glutathione Depletion-Methylation Cycle Block: A Hypothesis For the Pathogenesis of Chronic Fatigue Syndrome| journal = Phoenix Rising | date = Mar 4, 2012 | url = http://phoenixrising.me/research-2/glutathione-depletionmethylation-blockades-in-chronic-fatigue-syndrome/is-glutathione-depletion-an-important-part-of-the-pathogenesis-of-chronic-fatigue-syndrome-by-richard-van-konynenburg-independent-researcher }}</ref><ref name="Van_Konynenburg201203b">{{Cite web | last1 = Van Konynenburg | first1 = RA | authorlink1 = Rich Van Konynenburg | title = Glutathione Depletion Methyleation Cycle Block Hypothesis for the Pathogenesis of Chronic Fatigue Syndrome | journal = Phoenix Rising | date = Mar 4, 2012 | url = http://phoenixrising.me/research-2/glutathione-depletionmethylation-blockades-in-chronic-fatigue-syndrome/glutathione-depletion-methylation-cycle-block-a-hypothesis-for-the-pathogenesis-of-chronic-fatigue-syndrome-by-richard-a-van-konynenbury-ph-d }}</ref><ref name="Van_Konynenburg201204">{{Cite web | last1 = Van Konynenburg | first1 = RA | authorlink1 = Rich Van Konynenburg | title = Interpretation of the Methylation Pathways Panel (2011) | journal = Phoenix Rising | date = Apr 21, 2012 | url = http://phoenixrising.me/treating-cfs-chronic-fatigue-syndrome-me/treating-chronic-fatigue-syndrome-mecfs-glutathione-and-the-methylation-cycle/interpretation-of-results-of-the-methylation-pathways-panel-2011 }}</ref> Rich Van Konynenburg first postulated a depletion of [[glutathione]] was at the heart of many of the symptoms of CFS/ME, but quickly added information about methylation when he realized that the two were connected.<ref name="Van_Konynenburg201203b" /> By 2006, Konynenburg had developed and presented what is now known as Rich's Protocol; in 2011, he presented the final, simplified version of the protocol. #One-quarter tablet (200 micrograms) [[Actifolate]] #One-quarter tablet Intrinsic B12/folate (200 mcg of folate as folic acid, [[Methyltetrahydrofolate|5-methyl tetrahydrofolate]], and 5-formyl tetrahydrofolate (folinic acid or [[leucovorin]]), 125 mcg of vitamin B12 as [[cyanocobalamin]], 22.5 mg of [[calcium]], 17.25 mg of [[phosphorus]], and 5 mg of [[intrinsic factor]]). #Up to two tablets General Vitamin Neurological Health Formula from Holistic Health Consultants (a multivitamin, multimineral with some [[TMG]] and supplements that help support [[sulfur metabolism]]). #One softgel capsule phosphatidyl serine Complex for [[phospholipid]]s and [[essential fatty acid]]s #Activated B12 Guard (Perque) (2,000 mcg [[hydroxocobalamin]] with some [[mannitol, sucanat]], [[magnesium]] and [[cherry extract]]) Van Konynenburg emphasized the adage ''start low, and go slow'' with these supplements, due to the potential for detoxification symptoms. Methylation support formula and SAM-e were previously included in the protocol, but are now omitted.<ref name="Van_Konynenburg201103b" /> Additionally, Rich suggested avoiding choline or TMG supplementation, as it could ''push'' the [[BHMT]] pathway at the expense of the methionine pathway, and to avoid over-supplementing with different forms of folate that would compete for absorption. Finally, Rich stated that some ME/CFSers may benefit from the addition of glutathione or molybdenum. Van Konynenburg's protocol does not rely on information about patient's SNP data, but is a more ''one size fits all'' approach. ===Freddd's Protocol=== Freddd is a member of the online ME/CFS community [[Phoenix Rising]]. He developed his own version of the [[Methylation cycle|methylation]] protocol working with Dr Rich Van Konynenberg, and began posting articles descriptions of his experiences in 2011. In Freddd's protocol, supplements are started at very low doses and titrated, or increased until no effect is noted. The recommendations end with supplements at suprapharmacological levels. #Stop taking any supplements that contain hydroxycobalamin, cyanocobalamin, folic acid, glutathione, and [[glutathione#precursors|glutathione precursors]] (e.g. [[N-acetylcysteine|NAC]], [[glutamine]], and undenatured [[Whey products|whey]]). #Supplement with basic cofactors for a week. :Basic cofactors consist of: #*[[Vitamin A|Vitamins A]] and [[Vitamin D]] (11,000 IU and 3000 β 5000 IU respectively) #*[[Vitamin C]] at 4000+ mg per day #*[[Vitamin E]] #*[[B vitamin#vitamin B complex|B vitamin complex]] with [[Pyridoxal-5'-phosphate|P5P]], [[biotin]] and [[Pantothenic Acid|pantethine]] (without including cyano [[B12]] or [[Folate|folic acid]]) #*A 1:1 [[magnesium]]:[[calcium]] supplement #*[[Zinc]], 50 mg per day #*[[Omega 3 fatty acid]]s, 2-6 caps per day #*Optional Basic Cofactors include: #**[[Glycophospholipid]]s #**Additional [[Pantothenic Acid|pantethine]] #**[[Multimineral]] supplements ([[choline]], [[selenium]]) #**[[Alpha lipoic acid]] #**[[D-Ribose]] #**[[Coenzyme Q10|CoQ-10]] #Titrate B12s while adjusting methylfolate and [[potassium]] #*[[Methylcobalamin]] (MeB12) should start at 15-20 mg per day #*[[Cobalamin|Adenosylcobalamin]] (AdoB12) should start at 10 mg per ''week'' #Titrate [[methylfolate]] to sufficiency, starting at 1 mg #*Continue adjusting [[potassium]] as needed #*If unable to relieve symptoms of folate or potassium deficiency, lower vitamin B1, [[Vitamin B2|B2]] and [[Niacin|B3]] intake as needed. #*After a week on MeB12, replace MeB12 with AdoB12 for one day. #Titrate [[L-carnitine#fumarate|L-carnitine fumarate]] (LCF) to effectiveness, starting at 125 mg per day and aiming for 500-1000 mg per day, stopping when an increase of 250 mg makes no difference. #Titrate [[SAM-e]], starting with 100 mg and increasing to 200-600 mg per day. #Titrate [[Trimethylglycine|TMG]], starting with 250 mg or less. If it does nothing, discontinue. #Titrate [[biotin]] #CNS Penetration Test β the penetration test is to determine whether the B12s are entering the cerebrospinal fluid. #*[[MeB12]] β use 2 tablets, adding one each half hour to total. #*[[AdoB12]] β wait a few days after previous test; then, try 50 mg AdoB12 (2 tablets), adding one each half hour to total.
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