Methylation and Glutathione, Keys to Chronic Fatigue Syndrome

1
Methylation and Glutathione, Keys to Chronic
Fatigue Syndrome

• Rich Van Konynenburg, Ph.D.
• Independent Researcher/Consultant
• richvank_at_aol.com
• Orthomolecular Health Medicine Society
• 14th Annual Scientific Meeting
• San Francisco
• February 29-March 2, 2008

2
The Bottom Line

• A comprehensive biochemical hypothesis has been
  developed to explain the etiology, pathogenesis,
  pathophysiology and symptomatology of chronic
  fatigue syndrome (CFS).
• The key biochemical features of this hypothesis
  are a chronic partial block of the methylation
  cycle at methionine synthase and a chronic
  depletion of glutathione.
• This hypothesis explains the observed genetic
  predisposition, observed biochemical
  abnormalities, and many seemingly disparate
  symptoms of CFS as reported in the peer-reviewed
  literature and as observed clinically.
• Lab testing is available to test this hypothesis
  and to determine whether it applies to a
  particular patient. So far it appears to apply
  to most CFS patients.
• This hypothesis is also being tested by using
  orthomolecular treatment including biochemically
  active forms of vitamin B12 and folate. It is
  currently being applied to at least several
  hundred patients by at least ten clinicians and
  is producing significant benefits in most
  patients. A preliminary clinical study of this
  treatment is planned.

3
Topics to be covered

• History of the Glutathione DepletionMethylation
  Cycle Block (GD-MCB) hypothesis
• Description of glutathione
• Description of the methylation cycle and
  associated biochemical pathways
• Etiology of CFS, according to this hypothesis
• Pathogenesis of CFS, according to this hypothesis
• The role of genetic polymorphisms in CFS
• Accounting for observed biochemical
  abnormalities, pathophysiology and symptoms of
  CFS with this hypothesis

4
Topics to be covered (continued)

• Why is CFS more prevalent in women?
• Lab testing to test this hypothesis and to
  determine whether it applies to a given case of
  CFS
• Hypothesis testing using a treatment based on
  this hypothesis
• Results of hypothesis testing to date
• Some questions that remain to be answered
• Planned clinical study
• References

5
History of GD-MCB Hypothesis

• The presence of numerous disparate symptoms in
  CFS suggested to the present author that there
  must be a fundamental biochemical anomaly
  affecting many cell types.
• Paul Cheney, M.D. reported almost universal
  glutathione depletion in CFS in 1999 1,2 Derek
  Enlander, M.D. 3 and Patricia Salvato, M.D. 4
  had been treating CFS patients with glutathione
  for some years.
• The present author reported in October, 2004,
  that many of the features of CFS can be accounted
  for directly by glutathione depletion, but that
  direct attempts to raise glutathione were
  transitory. Vicious circles were suspected 5.
• S. Jill James, Ph.D., et al. reported that in
  autism there is glutathione depletion combined
  with methylation cycle block. Lifting the
  methylation cycle block using methylcobalamin,
  folinic acid and betaine also restored normal
  levels of glutathione, suggesting that these two
  phenomena are linked (Dec. 2004) 6.

6
History of GD-MCB Hypothesis(continued)

• The present author noted similarities in
  biochemistry and some symptoms between autism and
  CFS, and suspected that the same mechanism was
  involved, so that similar treatments should be
  effective 7. A few people with CFS began
  trying Defeat Autism Now (DAN!) and Yasko
  treatments.
• The present author presented the GD-MCB
  hypothesis for CFS at the IACFS conference in
  January, 2007 8
• In late January, 2007, the present author
  suggested hypothesis testing using an
  orthomolecular simplified treatment approach for
  CFS (involving seven supplements) extracted from
  the complete treatment program of Amy Yasko,
  Ph.D., N.D., used primarily in autism 9.
• Starting on Feb. 19, 2007, some CFS patients
  began trying the simplified treatment approach.
  Number of supplements was decreased to five.
  Cost became less than 3.00 per day. Initial
  results were quite striking. Use spread via
  on-line support groups, and soon a few clinicians
  started using it in their practices, some in
  response to reports from their patients.
  Currently there are at least several hundred CFS
  patients being treated for methylation cycle
  block worldwide, and most are reporting
  continuing improvement. Structured clinical
  trials have not yet been performed.

7
GlutathioneWhat is it and what does it do?
(10-14)

• A tripeptide, composed of glutamate, cysteine and
  glycine
• Found in all cells, blood, bile and epithelial
  lining fluid of the lung
• Synthesized by cells, particularly in the liver
• The most abundant thiol-containing substance in
  cells
• Has reduced and oxidized forms, GSH and GSSG
• Ratio of GSH to GSSG controls the redox potential
  in cells
• Serves as basis for the antioxidant system,
  quenching reactive oxygen species
• Conjugates several classes of toxins for removal
  from the body in Phase II detox, and quenches
  free radicals generated in Phase I detox in
  general
• Supports immune system, especially cell-mediated
  immunity
• Plays important role in synthesis of proteins
  that contain cysteine
• Participates in bile production
• Has many other roles

8
Methylation cycle and associated biochemical
pathways (15-20)
dietary protein

• Folate cycle
  Methylation cycle
• Transsulfuration
• pathway
• Sulfoxidation and synthesis
• of taurine and sulfate

methionine
methionine synthase
homocysteine
cysteine
glutathione (GSH)
9
What does the methylation cycle do? (21)

• Supplies methyl (CH3) groups for a large number
  of biochemical reactions in the body.
• Controls the overall sulfur metabolism, balancing
  the needs for methyl groups, for GSH to control
  oxidative stress, and for other sulfur
  metabolites, including cysteine, taurine and
  sulfate.
• Coordinates the production of new DNA with the
  supply of methyl groups, which are used to
  methylate DNA, among many other roles.

10
(basic) Methylation cycle (15-20)
methionine
MAT
S-adenosyl- Methionine (SAMe)
MTs
MTR, MTRR
S-adenosyl- Homocysteine (SAH)
homocysteine
ACHY
11
(basic) Methylation cycle with BHMT pathway added
(15-20)

• Note that BHMT is found only in liver and kidney
  cells(22).

methionine
MAT
S-adenosyl- methionine
DMG
MTs
MTR, MTRR
BHMT
S-adenosyl- homocysteine
TMG (betaine)
homocysteine
AHCY
12
(complete) Methylation cycle (15-20)
dietary protein
ATP
methionine
MAT
S-adenosyl- methionine
PPi Pi
DMG
NADPH
methyl acceptor
MTs
MTR, MTRR
BHMT
S-adenosyl- homocysteine
B12
methylated product
TMG (betaine)
homocysteine
H2O
AHCY
adenosine
13
(basic) Folate cycle (15-20)
THF
TS
SHMT
MTR MTRR
Me- B12
5,10- methylene THF
5-Methyl THF
MTHFR
14
(more complete) Folate cycle (15-20)
thymidine synthesis (for DNA)
dUMP
THF
TS
serine
SHMT
MTR MTRR
P5P (B6)
Me- B12
glycine
5,10- methylene THF
5-Methyl THF
MTHFR
purine synthesis (for DNA/RNA)
15
(combined) Methylation and Folate cycles (15-20)

• Note that the methylation cycle and the folate
  cycle are present in all cells of the body (22).

dietary protein
ATP
thymidine synthesis (for DNA)
dUMP
methionine
MAT
THF
S-adenosyl- methionine
PPi Pi
DMG
TS
NADPH
serine
MTs
methyl acceptor
SHMT
MTR MTRR
BHMT
S-adenosyl- homocysteine
P5P (B6)
B12
glycine
TMG (betaine)
methylated product
5,10- methylene THF
5-Methyl THF
homocysteine
H2O
AHCY
MTHFR
purine synthesis (for DNA/RNA)
adenosine
16
(combined) Methylation and Folate cycles (showing
link to transsulfuration pathway via CBS) (15-20)
dietary protein
ATP
thymidine synthesis (for DNA)
dUMP
methionine
MAT
THF
S-adenosyl- methionine
PPi Pi
DMG
TS
NADPH
serine
MTs
methyl acceptor
SHMT
MTR MTRR
BHMT
S-adenosyl- homocysteine
P5P (B6)
B12
glycine
TMG (betaine)
methylated product
5,10- methylene THF
5-Methyl THF
homocysteine
H2O
AHCY
MTHFR
purine synthesis (for DNA/RNA)
adenosine
P5P (B6)
CBS
17
Transsulfuration pathway (15-20)

• Note that a complete transsulfuration pathway is
  found only in cells of the liver, kidneys,
  pancreas, intestine, lens of the eye, and (at
  much lower capacity) the brain (22-24).

homocysteine
serine
H2O
NH3
CBS
P5P (B6)
cystathionine
alpha- ketobutyrate
dietary protein
P5P (B6)
glycine
glutamate
CTH
cysteine
protein synthesis
gamma- glutamyl- cysteine
glutathione (GSH)
GCL
GS
ATP
ATP
CDO
18
Sulfoxidation and synthesis of sulfate and
taurine (15-20)
cysteine
alpha- ketoglutarate
O2
CDO
CO2
cysteine- sulfinic acid
CSAD
GOT2
glutamate
hypotaurine
beta sulfinyl- pyruvate
O2, H2O
H, H2O2
½ O2
Mo
spontaneous decomposition
peroxynitrite?
bisulfite
taurine
pyruvate
sulfate
SUOX
19
Etiology of CFS, according to this hypothesis

• Genetic predisposition (25)
• and
• 1. Some combination of a variety of physical,
  chemical, biological and or psychological/emotiona
  l stressors, the particular combination differing
  from one case to another, which initially raises
  cortisol and epinephrine and depletes
  intracellular reduced glutathione (GSH)
  (1,2,26-30)
• or
• 2. Stressors combined with genetic polymorphisms
  in enzymes that use glutathione (GSH) (31)

20
Most common pathogenesis of CFS, according to
this hypothesis

• 1. Stressors lower glutathione (GSH) (1,2,26-30),
  which produces oxidative stress (27, 28,30,
  33-44), allows toxins to accumulate (45-48), and
  removes protection from B12 (49).
• 2. Oxidative stress partially blocks methionine
  synthase (MTR) (50) and shifts cysteine toward
  cystine.
• 3. Accumulated toxins (probably especially
  mercury) react with much of the B12 (49, 51,52).
• 4. Partial block of methionine synthase (MTR)
  becomes chronic.
• 5. Cystathionine-gamma-lyase (CTH) converts
  cystine to hydrogen sulfide, which is then
  converted to thiosulfate (53).
• 6. Sulfur metabolites drain down to form
  thiosulfate, which is excreted, lowering
  methionine.
• 7. Intracellular cysteine levels become too low
  to restore glutathione levels to normal.
• 8. Resulting vicious circle becomes chronic.

21
Cystathionine gamma lyase (CTH) pathway (53, 54)
diverts cysteine to thiosulfate under oxidative
stress conditions (hypothesis)
pyruvate
cysteine
oxidative stress
cysteine
thiocysteine
cystine
hydrogen sulfide
CTH
non-enzymatic decomposition
NH4
thiosulfate
bisulfite
sulfate
?
thiosulfate reductase?
SUOX
Mo
oxygen
H2O
GSSG
hydrogen sulfide
GSH
22
A less common pathogenesis, according to this
hypothesis

• 1.There are genetic polymorphisms in glutathione
  peroxidases (GPx) and/or glutathione transferases
  (GSTs), so that glutathione is not effectively
  used (31).
• 2. Stressors lead to same effects as above, even
  though glutathione levels do not drop, and may
  even be elevated (27).
• 3. Oxidative stress leads to partial block of
  methionine synthase (MTR) (50) and toxins build
  up (45-48), reacting with B12 (49, 51, 52).
• 4. Partial block becomes chronic.

23
Why do these pathogenetic processes take place in
the people who develop CFS, but not in other
people?

• A major factor is likely to be differences in the
  combinations of inherited genetic polymorphisms.
• There has not yet been a complete genome study of
  the polymorphisms that are more frequent in CFS
  than in the general population.
• There is evidence from family and twin studies as
  well as limited polymorphism studies that there
  is a genetic component in the development of CFS
  (25).

24
Genetic polymorphisms (SNPs) associated with CFS

• So far, SNPs in genes for the following proteins
  have been found to be present at higher frequency
  in CFS in general or in a subset, either alone or
  in combination
• Immune system
• Tumor necrosis factor (TNF) (55)
• Interferon gamma (IFN-gamma) (55)
• Neurotransmitter systems
• Tryptophan hydroxylase 2 (TPH2) (56,57)
• Serotonin transporter (5-HTT) gene promoter (58)
• Serotonin receptor subtype HTR2A (25)
• Monoamine oxidase A (MAO A) (56)
• Monoamine oxidase B (MAO B) (56)
• Catechol-O-methyltransferase (COMT) (57)
• HPA Axis
• Angiotensin converting enzyme (ACE) (59)

25
Accounting for observed biochemical
abnormalities, pathophysiology and symptoms with
this hypothesis

• Gedanken experiment approach examine the
  normal functions of glutathione and methylation,
  and consider what might be expected to occur if
  these functions were not carried out.
• It is found that this gedanken experiment
  approach reproduces many observed features of CFS
  in detail.
• Features that were not discovered and explained
  by this approach can be traced back to these same
  causes by starting with the features and
  considering what might cause them, i.e. reasoning
  in the opposite direction.
• The result of this bidirectional thought process
  is that essentially all the observed features of
  CFS can be specifically accounted for by this
  hypothesis.

26
What are some things that might be expected if
glutathione were depleted, and are they observed
in CFS?

• Oxidative stressobserved (27,28,30,33-44).
• Mitochondrial dysfunction and low ATP output,
  leading, for examples, to physical fatigue in
  skeletal musclesobserved and diastolic
  dysfunction in the heart, leading to low cardiac
  outputobserved (62)
• Buildup of toxins, including heavy
  metalsobserved (5, 45, 46).
• Immune response shift to Th2observed (63).
• Inability of T cells to proliferate in response
  to mitogensobserved (64).
• Reactivation of herpes family viral
  infectionsobserved (65).
• Thyroid problemsobserved (66).
• Low secretion and dysregulation of certain
  cysteine-containing secretory proteins, including
  ACTH, antidiuretic hormone, and perforin (67).
• Low ACTH leads to blunting of the HPA
  axisobserved (68), low antidiuretic hormone
  leads to high daily urine volumes and constant
  thirstobserved (69), and low perforin leads to
  low cytotoxic activity of the natural killer
  cells and the CD8 (killer) T cellsobserved
  (70).

27
What are some things that might be expected if
the methylation capacity were diminished, and are
they observed in CFS?

• Overexpression of many genes because of lack of
  gene silencing by methylationobserved (71).
• Lowered synthesis of choline and
  creatineabnormal ratio of choline to creatine
  observed in brain (72-75).
• Lowered synthesis of carnitinedeficit observed
  (76).
• Lowered synthesis of coenzyme Q-10supplementation
  observed to be beneficial (77).
• Lowered synthesis of myelin basic proteinslow
  brain processing speed observed (78).

28
How does this hypothesis account for the higher
prevalence of CFS in women than in men?

• During their potentially reproductive years,
  estrogens are produced in larger amounts in
  women, and must be metabolized.
• Some people (both men and women) inherit
  polymorphisms in the genes that code for some of
  the detox enzymes involved in the metabolism of
  the estrogens (CYP1B1, COMT and GST enzymes).
• In women, these polymorphisms can lead to redox
  cycling when metabolizing estrogens. This adds
  an additional bias toward depletion of
  glutathione and development of oxidative stress.
• Oxidative stress initiates the pathogenesis of
  CFS.
• (For more details, see 2007 IACFS poster paper
  http//phoenix-cfs.org/GenderCFSKonynenburg.htm )

29
Lab testing

• The methylation panel (offered by Vitamin
  Diagnostics, Inc., and the European Laboratory of
  Nutrients) is the most definitive for detecting
  methylation cycle block and glutathione
  depletion.
• Urine testing for methylmalonic acid and
  formiminoglutamic acid (figlu) are also very
  helpful. When these are elevated, they indicate
  low adenosylcobalamin and low tetrahydrofolate,
  respectively. When both methylamalonic acid and
  figlu are elevated, it is very likely that
  methionine synthase is partially blocked.

30
Methylation panel (Vitamin Diagnostics,Inc. and
European Laboratory of Nutrients)

• Metabolites measured
• S-adenosylmethionine (red blood cells)
• S-adenosylhomocysteine (red blood cells)
• Adenosine
• 5-methyl tetrahydrofolate (serum)
• 10-formyl tetrahydrofolate (serum)
• 5-formyl tetrahydrofolate (folinic acid) (serum)
• Tetrahydrofolate (serum)
• Folic acid (serum)
• Folinic acid (whole blood)
• Folic acid (red blood cells)
• Glutathione (GSH) (serum)
• Oxidized glutathione (GSSG) (serum)
• So far, the present author has seen seven
  results of this panel run on CFS patients. Six
  have shown a methylation cycle partial block and
  depletion of reduced glutathione relative to
  oxidized glutathione. The seventh had a
  methylation cycle block but normal glutathione
  levels. Data from more patients are needed.

31
Testing the GD-MCB hypothesis by using treatment
based on it

• The main goal of such treatment would be to raise
  the activity of methionine synthase.
• This appears to be best done by the simultaneous
  application of bioactive forms of vitamin B12 and
  bioactive forms of folate, since both are
  required by methionine synthase (MTR), and often
  both are deficient.
• Some support for the BHMT pathway would likely
  also be helpful, since this promotes synthesis of
  SAMe, which supports methionine synthase
  reductase (MTRR).
• General nutritional support would likely be
  helpful as well, since many CFS patients have
  nutritional deficiencies.

32
Simplified Treatment Approach

• Derived from part of step 2 of the full
  methylation cycle block treatment program
  developed by Amy Yasko, Ph.D., N.D. and used
  primarily in autism (9).
• Consists of five nutritional supplements, taken
  daily
• 1. Hydroxocobalamin (2,000 micrograms,
  sublingual)
• 2. 5-Methyl tetrahydrofolate (200mcg)  3.
  Combination of folic acid, 5-methyl
  tetrahydrofolate, and folinic acid (200 mcg),
  cyanocobalamin (125 mcg), calcium (22.5 mg),
  phosphorus (17.25 mg), and intrinsic factor (5
  mg)  4. A multivitamin, multimineral supplement
  including antioxidants, trimethylglycine,
  nucleotides, supplements to support the sulfur
  metabolism, a high ratio of magnesium to calcium,
  and no iron or copper (up to two tablets)  5.
  Phosphatidyl serine complex (one softgel)
• Note Even though this treatment consists only
  of nutritional supplements, patients who are on
  it need to be under the care of a physician, in
  order that any individual health issues that may
  arise may be properly dealt with.

33
Composition of multi-vitamin, multi-mineral
supplement used in simplified treatment
approach

• Serving Size 6 Tablets (note that up to 2
  tablets per day are used in the treatment)
• Amount per serving Vitamin A (as palmitate)5000
  IU,Vitamin C (ascorbic acid)500 mg,Vitamin D (as
  cholecaliciferol)400 IU,Vitamin E (as d-alpha
  tocopheryl succinate)400 IU,Vitamin K (as
  phytonadione)40 mcg,Vitamin B-1 (as
  benfotiamine)25 mg,Vitamin B-2 (as
  riboflavin)12.5 mg,Niacin (as niacinamide)37.5
  mg,Vitamin B-6 (as pyridoxal-5-phosphate)12.5
  mg,Folic Acid100 mcg,Vitamin B-12 (cyanocobalamin
  B12)250 mcg,Biotin150 mcg,Pantothenic Acid (as
  d-calcium pantothenate)50 mg,Calcium (as calcium
  d-glucarate)25 mg,Magnesium (as citrate,
  oxide)100 mg,Zinc (as monomethionine)5
  mg,Selenium (as L-selenomethionine)100
  mcg,Manganese (as arginate)1 mg,Chromium (as
  polynicotinate)100 mcg,Molybdenum (as amino acid
  chelate)75 mcg,Potassium (as citrate)5
  mg,Broccoli florets powder160 mg,Citrus
  bioflavonoids50 mg,Choline (as bitartrate)25
  mg,Inositol25 mg,PABA (para-amino benzoic acid)5
  mg,Garlic (Allium sativum) bulb powder200
  mg,L-methionine150 mg,Milk thistle (Silybum
  marianum) seed extract100 mg,N-acetyl-cysteine75
  mg,Pine (Pinus maritimus) bark extract25
  mg,Taurine250 mg,Turmeric (Curcuma longa) root
  extract50 mg,Intrinsic Factor5 mg,Trimethylglycine
  (TMG)50 mg, Free Form Nucleotide Complex100
  mg,Boron1 mg,L-Carnitine (Tartrate)100 mg.
• (Ref. http//www.holisticheal.com)

34
Results of treatment

• Informal reports from clinicians
• Informal reports from patients
• Beneficial changes
• Detox and die-off symptoms
• Serious adverse effects reported by a few
  patients.

35
Informal reports from clinicians (conveyed with
their permission)

• David Bell, M.D. (Lyndonville, NY) I have a
  good treatment response in roughly 50 of my
  long-term patients who have not responded
  particularly well to standard symptom-based
  therapies. I am very encouraged
• Karen Vrchota, M.D. (Winona, MN) 78 out of 109
  patients 72 have marked improvement.
  Patients are slowly improving week to week and
  month to month. Those started in July 2007 have
  not peaked yet that is, they are still
  improving.
• Neil Nathan, M.D. (Springfield, MO) Ive got
  about 75 patients on the protocol now, and have
  results from about 60. Roughly, 70 report
  noticeable improvement, and 15 to 20 report
  marked improvement. 30 to 40 report reactions
  in one form or another. Most of these are very
  mild. It's clear that it does work. We now have
  to define how to use it optimally.

36
Informal reports from clinicians (conveyed with
their permission) (continued)

• Derek Enlander, M.D. (NYC) Using his own
  protocol, which includes methylation cycle
  treatment (but does not include 5-methyl THF),
  Dr. E. reports that he has 112 patients under
  treatment, and that 65 to 70 of them show
  improvement.
• Sarah Myhill, MB BS (Wales) Dr. M. has 10-12
  CFS patients on her methylation supplement
  package, but does not yet have feedback from all
  of them. However, she reports that There is no
  doubt that for some this is a very worthwhile
  intervention.
• Jacob Teitelbaum, M.D. (Hawaii) Some doctors
  in the Fibromyalgia and Fatigue Centers of
  America have started using the protocol. I am
  excited about its potential and am awaiting
  feedback.

37
Beneficial changes reported by various patients

• Improvement in sleep (though a few have reported
  increased difficulty in sleeping initially).
• Ending of the need for and intolerance of
  continued thyroid hormone supplementation.
• Termination of excessive urination and night-time
  urination.
• Restoration of normal body temperature from lower
  values.
• Restoration of normal blood pressure from lower
  values.
• Initiation of attack by immune system on
  longstanding infections.
• Increased energy and ability to carry on higher
  levels of activity without post-exertional
  fatigue or malaise. Termination of crashing.
• Lifting of brain fog, increase in cognitive
  ability, return of memory.
• Relief from hypoglycemia symptoms.
• Improvement in alcohol tolerance.
• Decrease in pain (though some have experienced
  increases in pain temporarily, as well as
  increased headaches, presumably as a result of
  detoxing).

38
Beneficial changes reported by various patients
(continued)

• Notice of and remarking by friends and therapists
  on improvements in the patients condition.
• Necessity to adjust relationship with spouse,
  because not as much caregiving is needed. Need
  to work out more balanced responsibilities in
  relationship in view of improved health and
  improved desire and ability to be assertive.
• Return of ability to read and retain what has
  been read.
• Return of ability to take showers standing up.
• Return of ability to sit up for long times.
• Return of ability to drive for long distances.
• Improved tolerance for heat.
• Feeling unusually calm.
• Feeling "more normal and part of the world."
• Ability to stop steroid hormone support without
  experiencing problems from doing it.
• Lowered sensation of being under stress.
• Loss of excess weight.

39
Detox and die-off related symptoms reported by
various patients

• Headaches, heavy head, heavy-feeling
  headaches.
• Alternated periods of mental fuzziness and
  greater mental clarity.
• Feeling muggy-headed or blah or sick in the
  morning.
• Transient malaise, flu-like symptoms.
• Transiently increased fatigue, waxing and waning
  fatigue, feeling more tired and sluggish,
  weakness.
• Dizziness.
• Irritability.
• Sensation of brain firing bing, bong, bing,
  bong, brain moving very fast.
• Depression, feeling overwhelmed, strong emotions.
• Greater need for healing naps.
• Swollen or painful lymph nodes.
• Mild fevers.
• Runny nose, low grade sniffles, sneezing,
  coughing.

40
Detox and die-off related symptoms reported by
various patients (continued)

• Sore throat.
• Rashes.
• Itching.
• Increased perspiration, unusual smelling
  perspiration.
• Metallic taste in mouth.
• Transient nausea, sick to stomach.
• Abdominal cramping/pain.
• Increased bowel movements.
• Diarrhea, loose stools, urgency.
• Unusual color of stools, e.g. green.
• Temporarily increased urination.
• Transiently increased thirst.
• Clear urine.

41
Serious adverse effects reported by a few patients

• Exacerbation of comorbid autoimmune disease.
• Exacerbation of comorbid autonomous multinodular
  goiter.
• Cessation of peristalsis for two weeks.
• Persisting low fever of unknown origin.
• Flare-up of Lyme disease that had been controlled
  with antibiotics.
• Conclusion from this experience Even though
  this treatment consists only of food supplements,
  structured clinical trials are needed to
  determine the efficacy of this treatment
  quantitatively and to learn how it may be safely
  applied.

42
Some questions that remain to be answered

• 1. For which PWCs would this be an appropriate
  treatment approach?
• 2. For what fraction of the entire PWC population
  will this treatment approach be beneficial?
• 3. How can PWCs who are likely to experience
  adverse effects from this treatment approach be
  identified beforehand, so that these effects can
  be avoided?
• 4. Are there PWCs who are too debilitated to be
  able to tolerate the detoxing and die-off
  processes that result from this treatment
  approach, and if so, would the full Yasko
  treatment approach be suitable for them?
• 5. Will the simplified treatment approach produce
  continued improvement over time for those who are
  finding it beneficial, and will they be cured?
• 6. Will the simplified treatment approach be
  effective in cases of "pure fibromyalgia" as it
  appears to be in many cases of CFS?
• 7. How can this treatment approach be further
  improved?

43
Planned clinical study

• Objective Determine effectiveness of a
  treatment to lift the methylation cycle block
• 100 patients, satisfying diagnostic criteria for
  both CFS and fibromyalgia, in one practice (Neil
  Nathan, M.D., Springfield, MO)
• Informed consent
• Lab testing (2X) Methylation panel,
  characterization of certain polymorphisms,
  thyroid panel including autoantibodies
• Questionnaires to collect pertinent data and
  evaluate symptoms (3X)
• Treatmentsimplified treatment approach (five
  supplements daily)
• Patient logs
• Treatment durationsix months
• This study will not be randomized, doubly
  blinded, or placebo controlled, but hopefully it
  will demonstrate that the treatment is worthy of
  a more controlled study.

44
The Bottom Line

• A comprehensive biochemical hypothesis has been
  developed to explain the etiology, pathogenesis,
  pathophysiology and symptomatology of chronic
  fatigue syndrome (CFS).
• The key biochemical features of this hypothesis
  are a chronic partial block of the methylation
  cycle at methionine synthase and a chronic
  depletion of glutathione.
• This hypothesis explains the observed genetic
  predisposition, observed biochemical
  abnormalities, and many seemingly disparate
  symptoms of CFS as reported in the peer-reviewed
  literature and as observed clinically.
• Lab testing is available to test this hypothesis
  and to determine whether it applies to a
  particular patient. So far it appears to apply
  to most CFS patients.
• This hypothesis is also being tested by using
  orthomolecular treatment including biochemically
  active forms of vitamin B12 and folate. It is
  currently being applied to at least several
  hundred patients by at least ten clinicians and
  is producing significant benefits in most
  patients. A preliminary clinical study of this
  treatment is planned.

45
Additional reading

• Van Konynenburg, R.A., Is Glutathione Depletion
  an Important Part of the Pathogenesis of Chronic
  Fatigue Syndrome? poster paper, AACFS 7th Intl.
  Conf., Madison, WI, October 8-10, 2004
• http//phoenix-cfs.org/GluAACFS04.htm
• Van Konynenburg, R.A., Glutathione
  DepletionMethylation Cycle Block, A Hypothesis
  for the Pathogenesis of Chronic Fatigue
  Syndrome, poster paper, 8th Intl. IACFS Conf. on
  CFS, Fibromyalgia, and Other Related Illnesses,
  Fort Lauderdale, FL, January 10-14, 2007
• http//phoenix-cfs.org/GSHMethylationVanKonynenbu
  rg.htm
• Van Konynenburg, R.A., Why is the Prevalence of
  Chronic Fatigue Syndrome Higher in Women than in
  Men? poster paper, 8th Intl. IACFS Conf. on CFS,
  Fibromyalgia, and Other Related Illnesses, Fort
  Lauderdale, FL, January 10-14, 2007
• http//www.phoenix-cfs.org/ResGenderCFSKonynenbur
  g.htm
• Van Konynenburg, R.A., Simplified Treatment
  Approach Based on the Glutathione
  Depletion-Methylation Cycle Block Pathogenesis
  Hypothesis for Chronic Fatigue Syndrome (CFS),
  article, July 18, 2007
• http//phoenix-cfs.org/GSHMethylDeplTheoryJuly07.
  htm
• and
• http//phoenix-cfs.org/GSHMethylTrtPlanJuly07.htm

46
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56
Folate metabolism