Editing Methylation cycle hypothesis

The '''methylation cycle hypothesis''' posits that a core component of the pathophysiology of [[chronic fatigue syndrome]] involves a partial block in the [[methylation cycle]]. Its application to CFS was developed chiefly by biochemist [[Rich Van Konynenburg]] based on [[Amy Yasko|Dr. Amy Yasko's]] protocol for [[Autism spectrum disorder|autism]], and is discussed heavily on [[Phoenix Rising|Phoenix Rising's]] forums.<ref name="Methylcyclehypothesis">{{Cite web | title = Status of methylation cycle model and treatment | date = Sep 19, 2009|last =Van Konynenburg|first = Rich  | authorlink = Rich Van Konynenburg| website = Phoenix Rising| url  =https://forums.phoenixrising.me/threads/status-of-methylation-cycle-model-and-treatment.406/|access-date=2022-05-19}}</ref><ref name="Phoenixmethylcycle">{{Cite web | title = Detox: Methylation; B12; Glutathione; Chelation| website = Phoenix Rising| url = http://forums.phoenixrising.me/index.php?forums/detox-methylation-b12-glutathione-chelation.6/|access-date=2022-05-19}}</ref>

==Theory==
[[File:One-carbon metabolism and the transsulfuration pathway.jpg|540px|right|frame|One-carbon metabolism and the transsulfuration pathway]]
A methyl group is a carbon atom that is bonded to three hydrogen atoms.  Therefore, the process of methylation is the addition of a CH3 group to a pre-existing chemical structure; and methyl donors are chemicals that can carry and then transfer methyl groups to other molecules.

Methylation is important because the presence of methyl groups on a molecule can block or encourage certain chemical reactions, functioning as a switch with the potential to turn a biological process on or off.  From a genetic standpoint, methylation can cause genes to either express, or become "silent".

The methylation cycle is a series of chemical changes that occur in the body, the primary purpose of which is to regulate neurotransmitters, regulate genetic repair and expression, and generate energy-rich molecules such as [[adenosine triphosphate|ATP]].  Many other important biological cyclical processes intersect with the methylation cycle.

The methylation cycle begins in the blood vessels with [[folate]] (B9) obtained from diet.  When [[methylenetetrahydrofolate reductase]] (MTHFR) acts on folate, it picks up a methyl group, transforming into [[methyltetrahydrofolate]] (MTHF).  MTHF is able to methylate homocysteine to methionine.

[[L-methionine|Methionine]] becomes [[SAM]], a second methyl donor.  SAM acts as a [[methyl donor]] for multiple chemicals in the body, including DNA and [[RNA]].  Therefore, methylation is crucial to the synthesis and repair of genetic material, as well as the epigenetic regulation of gene expression.

The donation of SAM's methyl group reduces it to [[SAM-e]] (S-adenosylmethionine), which reforms homocysteine, and the cycle begins again.<ref name="Bhargava">{{Cite journal | last1 = Bhargava | first1 = S  | authorlink1 = | last2 = Tyagi | first2 = SC | authorlink2 = | title = Nutriepigenetic regulation by folate–homocysteine–methionine axis: a review| journal = Mol Cell Biochem | volume = 387 | issue = 1 | pages = 55-6 | date = Feb 2014 | pmid = 24213682 | doi = 10.1007/s11010-013-1869-2}}</ref>

Various [[B vitamin]]s act as cofactors for methylation, including [[Riboflavin|B2]] and [[Cobalamin|B12]]. 

If methylation is not working properly due to various [[B vitamin]] deficiencies, disease states, or genetic mishap, higher levels of homocysteine may result.  [[Homocysteine]] is an inflammatory marker that may increase risk of [[thrombosis]] and [[endothelial dysfunction]], cause errors in vascular smooth muscle proliferation<ref name="Tanaka" /> and skeletal muscle metabolism <ref name="Bhargava" />, and contribute to heart disease.<ref name="Tanaka">{{Cite journal | last1 = Tanaka | first1 = T  | authorlink1 = Toshiko Tanaka | last2 = Scheet | first2 = P  | authorlink2 = Paul Scheet | last3 = Giusti | first3 = B  | authorlink3 = Betti Giusti | last4 = Bandinelli | first4 = S  | authorlink4 = Stefania Bandinelli | last5 = Piras | first5 = MG | authorlink5 = Maria Grazia Piras | last6 = Usala | first6 = G  | authorlink6 = Gianluca Usala | last7 =Lai | first7 = S  | authorlink7 = Sandra Lai | last8 =Mulas | first8 = A  | authorlink8 = Antonella Mulas | last9 =Corsi | first9 = AM | authorlink9 = Anna Maria Corsi | last10 = Vestrini | first10 = A  | authorlink10 = Anna Vestrini | last11 = Sofi | first11 =  F  | authorlink11 = Francesco Sofi | last12 = Gori | first12 = AM | authorlink12 = Anna Maria Gori | last13 = Abbate | first13 =  R  | authorlink13 = Rosanna Abbate | last14 = Guralnik | first14 =  J  | authorlink14 = Jack Guralnik | last15 = Singleton | first15 =  A  | authorlink15 = Andrew Singleton | last16 = Abecasis | first16 =  GR | authorlink16 = Goncalo Abecasis | last17 = Schlessinger | first17 =  D  | authorlink17 = David Schlessinger | last18 = Uda | first18 =  M  | authorlink18 = Manuela Uda | last19 = Ferrucci | first19 = L  | authorlink19 = Luigi Ferrucci | title = Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations| journal = Am J Hum Genet | volume = 84 | issue = 5 | pages = 712 | date = May 2009 | pmid = 19303062 | doi = 10.1016/j.ajhg.2009.02.011 }}</ref>  

Poor methylation can negatively impact the body's ability to produce and regulate glutathione, produce high-energy molecules, regulate [[Neurotransmitter]]s, repair DNA, and convert [[serotonin]] to [[melatonin]].<ref name="Nathan2011">{{Cite web | last1 = Nathan | first1 = N  | authorlink1 = Neil Nathan| title = A Simplified Methylation Protocol is Effective for the Treatment of Chronic Fatigue Syndrome and Fibromyalgia
| website = ProHealth | date = May 11, 2011| url = http://www.prohealth.com/library/print.cfm?libid=16138 }}</ref>

The methylation cycle hypothesis states that many if not all of the symptoms of CFS are caused by errors in the genes that regulate or have a strong impact on one-carbon metabolism, such as [[MTHFR]], [[Cystathionine beta synthase|CBS]], [[Dihydropteridine reductase|DHPR]], [[methionine synthase reductase|MTRR]], or [[monoamine_oxidase#MAO-A|MAO-A]].  Through knowledge obtained by their genetic [[SNP]]s, patients can address inconsistencies in their one-carbon metabolism by supplementing nutrients in which they are deficient, or that encourage bypassing problematic aspects of the cycle, such as folinic acid, in order to optimize the efficiency of the methylation and related cycles.<ref name="Yasko_2013">{{Citation | last1 = Yasko | first1 = Amy | authorlink1 = Amy Yasko | title = Your SIMPLIFIED Road Map to Health | journal = Neurological Research Institute | date = 2013 | url = https://www.knowyourgenetics.com/media/pdf/Simplified%20Protocol.pdf }}</ref>

==Evidence==

There is little direct evidence to support the popular methylation protocols. However, numerous patients have reported benefit while others have reported no benefit.

Indirect evidence supporting a possible benefit of methylation cycle supplements include findings of increased [[homocysteine]] in the [[cerebrospinal fluid]] of CFS and [[fibromyalgia]] patients.<ref name="Regland1997">{{Cite journal | last1 = Regland | first1 = B  | authorlink1 = B Regland | last2 = Andersson | first2 = M  | authorlink2 = M Andersson | last3 = Abrahamsson | first3 = L  | authorlink3 = L Abrahamsson | last4 = Bagby | first4 = J  | authorlink4 = J Bagby | last5 =Dyrehag | first5 = LE | authorlink5 = LE Dyrehag | last6 = Gottfries | first6 = CG | authorlink6 = Carl-Gerhard Gottfries | title = Increased Concentrations of Homocysteine in the Cerebrospinal Fluid in Patients with Fibromyalgia and Chronic Fatigue Syndrome | journal = Scandinavian Journal of Rheumatology | volume = 26 | issue = 4 | pages = 301-307 | date = 1997 | pmid = 9310111  | doi = 10.3109/03009749709105320 | url = http://www.tandfonline.com/doi/abs/10.3109/03009749709105320#.Vlc19N-rTMU }}</ref>

There is compelling evidence that some  ME/CFS patients are low in [[methylation cycle]] metabolites, and there are some studies that provide direct evidence of methylation cycle dysregulation in ME/CFS.  However, it is important to note that there are limited studies on either protocol’s effect on methylation, and no studies on Yasko’s utilization of SNP data to drive decision-making about supplements.    

There is a great deal of anecdotal evidence to support these therapies.  However, the longer a therapy continues, the higher and higher the likelihood of improvement regardless of circumstance, especially in an illness with as much natural variability as ME/CFS.

===Evidence===
Evidence that CFS/ME patients are low in methylation cycle metabolites:

===B vitamin evidence===
{{Main article|B vitamin}}
*In a small study of 58 chronic fatigue syndrome patients with a history of Epstein-Barr infection and [[B cell|B-cell]] immunodeficiency, 81% responded to folinic acid. <ref name="Lundell">{{Cite journal | last1 = Lundell | first1 = K  | authorlink1 = Kathleen Lundell | last2 = Qazi | first2 = S  | authorlink2 = Sanjive Qazi | last3 = Eddy | first3 = L  | authorlink3 = Linda Eddy | last4 = Uckun | first4 = FM | authorlink4 = Fatih Uckun | title = Clinical activity of folinic acid in patients with chronic fatigue syndrome | journal = Arzneimittel-Forschung | volume = 56 | issue = 6 | pages = 399-404 | date = 2006 | pmid = 16889122 | doi = 10.1055/s-0031-1296741}}</ref>
*Folate was found to be clinically low in approximately 50% of people with CFS in a study by Jacobson et al. 1993.<ref name="Jacobson">{{Cite journal | last1 = Jacobson | first1 = W  | authorlink1 = W Jacobson | last2 = Saich | first2 = T  | authorlink2 = T Saich | last3 = Borysiewicz | first3 = LK | authorlink3 = LK Borysiewicz | last4 = Behan | first4 = WMH | authorlink4 = Wilhelmina Behan | last5 =Behan | first5 = PO | authorlink5 = Peter Behan | last6 = Wreghitt | first6 = TG | authorlink6 = TG Wreghitt | title = Serum folate and chronic fatigue syndrome | journal = Neurology | volume = 43 | issue = 12 | pages = 2645 | date = Dec 1993| pmid = 8255470       | doi = 10.1212/WNL.43.12.2645}}</ref>

===SAM-e evidence===
{{Main article|SAM-e}}

===Glutathione depletion===
{{Main article|Glutathione}}

==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" /> Yasko’s 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 – 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 – the penetration test is to determine whether the B12s are entering the cerebrospinal fluid.  
#*[[MeB12]] – use 2 tablets, adding one each half hour to total.
#*[[AdoB12]] – wait a few days after previous test; then, try 50 mg AdoB12 (2 tablets), adding one each half hour to total.

==See also==
*[[Methylation cycle]]
*[[MTHFR]]
*[[23andMe]]
*[[:Category:Supplements|Supplements]]

==References==
{{Reflist}}

[[Category:Medical hypotheses]] 
[[Category:Methylation]] 
[[Category:Protocols]]