Study: Unique Immune Dysfunction Useful in Understanding CFS

(12-07-04 http://www.cfidsreport.com) Science is a small step closer to understanding the underlying mechanisms behind CFS, according to a new study by immunologists at Temple University. Researchers there are examining the Rnase L pathway, an antiviral defense system that appears to function differently in people with CFS. According to the authors of the study in the October issue of Journal of Chronic Fatigue Syndrome, “the present study is the first to report a detailed examination of the relationship between the clinical and functional characteristics, immune abnormalities and the status of the RNase L pathway in CFS.”

A global network of researchers has studied the antiviral pathway since the discovery that Rnase L is unregulated in patients with CFS. In 1993, researchers also found that CFS patients have an atypical molecule of Rnase L. Normal Rnase L weighs 80 kDa. CFS patients have both this normal molecule and an abnormal molecule weighing 37 kDa, later dubbed “low molecular weight Rnase L”. Subsequent research has since established that higher amounts of low molecular weight Rnase L correlate to various levels of disability seen in CFS. Independent researchers have also found the molecule is useful in distinguishing CFS from depression and healthy controls.

The recent study found differences in the Rnase L pathway comparing CFS subjects, depression subjects, and healthy controls. The researchers found that depression controls “have an overall functional status much higher than CFS patients, which underscores the severity of functional impairment experienced by this cohort of CFS patients.” The CFS subjects also exhibited a host of immune abnormalities, such as low NK cell function and higher levels of circulating cytokines

The Temple team also found more subtle differences in those who had previous contact with CFS patients. According to the author, Rnase L activity was “more pronounced in the contact controls than in the non-contact controls”. Researchers feel this finding may someday help explain why CFS has occurred in clusters, spouses, and among families, although they do not feel CFS is a trasmissable illness. They add, “…the results of the present study are consistent with the immune activation model of CFS, but also add the possibility of additional biochemical changes not of obvious immune or cytokine-mediated origin… these abnormalities may be indicative of a persistent viral infection or a toxic state. ”

The current CDC definition encourages many differing fatiguing illnesses to be integrated within CFS research studies. Yet, many feel the definition is too broad to obtain reliable research results and can be easily manipulated. The authors caution that they restricted their CFS samples by using a “less heterogeneous” group of patients who were “significantly impaired by their illness”. The authors promise that further study will determine the “degree to which the clinical, functional and biochemical abnormalities observed in the CFS study group can be extrapolated to the larger group of patients who meet the criteria for CFS” They say their results highlight “the need to underscore the importance of documentation of clinical and functional parameters using standardized instruments alongside biochemical and immune parameters in research studies on CFS.”

#2  Article

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Source: HHV-6 Foundation

Chronic Fatigue Syndrome Linked to HHV-6 Virus

International Conference on Chronic Fatigue Points to Low-Grade Viral Infections in Brain

SANTA BARBARA, Calif., Feb. 18, 2005 (PRIMEZONE) -- The HHV-6 Foundation, an association formed to raise awareness, funding and further research for human herpesvirus 6 (HHV-6), has today announced that some cases of chronic fatigue syndrome (CFS) may be linked to human herpesvirus 6 A variant (HHV-6A). The announcement comes on the heels of the International Fatigue Conference on Fatigue Science that was held in Japan on February 9-11. The conference was attended by some 200 scientists from around the world.

Studies examining the role of the virus in CFS have had conflicting results over the years. The HHV-6 virus was discovered in the late 80s. Although the B variant is very common -- over 95% of the population has had it -- and causes roseola in infants, the A variant is less common. The A variant has been linked to CFS and multiple sclerosis (MS) and may hasten the progression of HIV. Dr. Ablashi reported that when the correct testing method is used, there is a strong association between HHV-6 and CFS.

Dr. Dharam Ablashi, co-discoverer of the virus and scientific director of the HHV-6 Foundation said, "There is good reason that it has taken a long time to build a case for this virus playing a role in chronic fatigue -- it's very difficult to find. The virus is 'neurotropic' meaning it prefers to live in the brain tissue. It is quite possible to find a significant infection in the brain tissue, but no virus in the serum by DNA testing."

Dr. Daniel Peterson, a leading CFS clinician from Sierra Internal Medicine in Nevada, supported this finding. He performed spinal taps on patients with abnormal MRI or severe problems with cognitive functioning and found active HHV-6A virus in the spinal fluid of 20% of those patients. Twenty nine percent of these patients were positive at least once in the serum, and he found many patients who were positive in the spinal fluid but not the blood. Warned Peterson, "Just because you can't find it in the blood doesn't mean it isn't there."

"Our primary objective at the moment is to get a test on the market that will be a sensitive indicator of active infection," said Kristin Loomis, executive director of HHV-6 Foundation. "The evidence presented at the conference will go a long way toward dispelling the notion, still held by some physicians, that CFS is purely psychiatric."

There was a great deal of evidence presented at the conference in support of an infectious cause of CFS. Dr. Takeshi Sairenji of Tottori University showed evidence that 60% of CFS patients vs. 11% of controls had evidence of chronic activated antiviral pathways. He suggested that chronic fatigue might be caused by interferon from viral infections such as HHV-6, Epstein Barr virus and Borna virus.

Dr. Peterson has been treating some of his most severe cases with intravenous antiviral therapy and the majority has responded. He does not tell them they have CFS; he tells them they have HHV-6A subacute encephalopathy. Others have begun calling it the Peterson Syndrome.

For additional information on research findings and where to get tested, go to www.hhv-6foundation.org.

About HHV-6 Foundation

The HHV-6 Foundation sponsors research on the role of HHV-6 in chronic fatigue syndrome, multiple sclerosis, HIV, epilepsy and other conditions. The Foundation has a Scientific Advisory Board that includes the world's top experts in HHV-6 and is funding basic research in this field. The Foundation is supported through private donations. For more information on the HHV-6 Foundation, visit www.hhv-6foundation.org or call 805-969-1174.

CONTACT:
Media Contact:
HHV-6 Foundation
Kristin Loomis
Executive Director
(805) 969-1174 kristin_loomis@...
HHV-6 Foundation & Department of Microbiology & Immunology
Dr. Dr. Dharam Ablashi
Scientific Director
Georgetown University School of Medicine
(302) 947-9634
k.ablashi@...

#3

New test identifies mysterious disorder
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Karen van Kampen, CanWest News Service
Published: Thursday, April 13, 2006 
CALGARY -- Before 1984, Marjorie van de Sande was an active Grade 1 teacher who coached rhythmic gymnastics and was learning to ski with her family.
Then, the Calgary woman had a string of bad luck. She was involved in a serious car accident in 1984. Two years later, she was diagnosed with cancer. In the winter of 1987, she was flattened by a sinus infection that lasted through the summer.
"I tried to rebuild myself," she said.
But when it was time to go back to school that fall, she was still wiped out. When her class would leave for the day, van de Sande would lie down beside her desk, too exhausted to make it to the staff room.
That was her last year of teaching.
And that was when van de Sande, now 65, realized something more than a sinus infection was wrong -- that's when she realized she was suffering from myalgic encephalomyelitis, more commonly known as chronic fatigue syndrome.
According to the Statistics Canada 2003 Canadian community health survey, some 341,126 Canadians have chronic fatigue syndrome, a debilitating disorder characterized by extreme, long-lasting exhaustion and flu-like symptoms.
Since it was identified in 1984 by Drs. Dan Peterson and Paul Cheney in Incline Village, Nev., the syndrome has been accompanied by confusion and controversy.
Many people -- including some health-care professionals -- don't believe it exists, attributing the symptoms to a variety of other causes, ranging from influenza to depression.
Learning of the mysterious illness, researchers from the Centres for Disease Control and Harvard University travelled to the Nevada ski village. They could identify symptoms, but not a cause.
To this day, treatment focuses on lifestyle management. Patients need lots of sleep, they must pace their activities and eat a diet high in protein.
Now, for the first time, chronic fatigue sufferers have some hope -- a diagnostic test that can show evidence of the disorder. It was developed by Dr. Kenny De Meirleir, an internal medicine specialist from Brussels.
In 1990, while he was doing a year of study in the United States, De Meirleir attended a seminar on the mysterious disorder. It made him think of two of his patients with similar symptoms.
In Brussels in the late '90s, De Meirleir developed a diagnostic test that shows evidence of the disorder. De Meirleir co-founded RED Labs, which offers the test. He is now a world leader in the field, assessing and treating more than 2,000 patients annually.
The test gauges the amount of an immune enzyme that protects the body against viruses. Those with chronic fatigue syndrome have an abnormal form of the enzyme that is more active, yet less effective than the healthy form of the agent.
This is exciting news for chronic fatigue syndrome sufferers who find it difficult to prove to family, friends and employers that something is clinically wrong with them. All they would need to do is take RED Labs' simple blood test, which would reveal whether they have a healthy amount of the enzyme.
Last fall, the test became available in North America for the first time, when the company opened a lab in Reno, Nev.
New test identifies mysterious disorder
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Karen van Kampen, CanWest News Service
Published: Thursday, April 13, 2006 
In November, Dr. Eleanor Stein, a Calgary psychiatrist and psychotherapist who works with chronic fatigue syndrome patients, started sending samples to the Reno lab for analysis.
Stein has sent samples for 15 patients. While cost of the $570 US test is covered by insurance in the United States, it is not covered in Canada.
Because Stein already has a two-year waiting list for new patients, she is hoping to get other physicians involved in treatment. But first, she wants to raise awareness of the disorder. To that end, De Meirleir went to Calgary to help spread the message.
De Meirleir led a workshop recently for medical practitioners to help them identify the disorder. He also held a separate lecture for patients.
Proceeds from the workshop will go toward raising awareness of the disorder among Alberta's medical community. Because so little funding is available for chronic fatigue syndrome, Stein and others active in the field have been unable to distribute a diagnosis sheet that was developed in 2003.
Having a test to identify chronic fatigue syndrome is a huge step forward for the field, Stein said.
Physicians can now point to clinical findings to show something is wrong with patients. These individuals can apply for disability with evidence to show their insurance companies they are unable to work.
The disorder afflicts more women than men, and is more common among those in their 40s, Stein said.
Stein knows how important this breakthrough is -- she has the disorder.
During her psychiatry residency, Stein was hit with abnormally severe exhaustion. She never felt rested, no matter how long she slept. She was told it could be depression, but Stein knew something else was wrong.
Living with chronic fatigue syndrome is draining, Stein said.
Imagine you have energy dollars, she suggests: "You wake up with 40 energy dollars, but you spend 50. You go into debt."
With the enzyme test, Stein and other patients can now show the world their suspicions were correct.
Van de Sande doesn't need to get the test to know her life has changed. Even all these years later, simple tasks such as shopping for groceries can be debilitating. Sometimes, she has to leave food in the car until the next day, when she has more energy.
Calgary Herald
 
#4 
It is with much sadness that the pioneering work by Dr Les Simpson and his assistant Dylan at the Red Blood Cell Research Limited in Dunedin, New Zealand, have ceased. After all avenues were explored this vital work received no further funding.  
This Red Blood Cell Research was set up in 1998 by Dr. Les Simpson so that he could continue his research into the the pathophysiology of chronic disorders. 
The majority of his work relates to ME and this began in 1983 in conjunction with Professor Campbell Murdoch who had recently arrived from Scotland to take up the position of Head of the Department of General Practice. At that time the technique of blood filtration was used to assess the stiffness of red cells and in 1986 it was reported that ME blood did not filter as well as the blood of blood donors.  
Because people with multiple sclerosis also complained of tiredness a similar study was carried out with multiple sclerosis blood and in 1987 it was reported that multiple sclerosis blood also filtered poorly. These findings stimulated the thought that scanning electron microscopy of red blood cells might provide some explanation for the poor filtrability of ME and MS blood. A technique was developed by modifying the standard procedure for the electron microscopy of samples obtained at operation.  
This involved the blood sample (5 drops of venous blood) being mixed as soon as possible with 5 ml of a special fluid - a fixative. Immediately-fixed blood samples did not show the sorts of red cell changes which Dr.Tapen Mukherjee reported as a letter to Lancet, and now, after more than 13,000 samples no such cells have been observed. The important difference was that Dr. Mukherjee washed and centrifuged his samples before fixation so the observed changes were a consequence of his preparatory technique.

Early observations showed very quickly that the medical textbook claim that all red cells have the same shape was not sustainable. In an article published in the British Journal of Haematology in 1989 it was shown that the red cells of healthy humans and animals could be classified into six different shape classes. Subsequently it has been found that chronic disorders in general share the common feature of altered red cell shape populations.  
Late in 1989 it was shown that blood samples from ME people in New Zealand had increased proportions of cup-transformed red cells. But by mid-1992 it was noted that only about 5% of ME people had cup-transformed red cells and the most common change was an increase in flat cells. It is not known what factor or factors was responsible for this change.

In the 1990's Dr. Simpson visited ME support groups in Australia, South Africa, the United Kingdom and Canada. The blood samples obtained after those visits totalled more than 2100 and the most common change was an increase in flat cells. However, 11% who were well at the time of sample collection had normal results. This demonstrates very clearly the relationship between wellbeing and red cell shape changes. As a result, patients are advised not to have a blood sample taken when they are feeling well - because the result will be normal.

It seems not to matter exactly what type of red cell shape change is involved as the outcome is the same; the cells reduce the rate of blood flow in capillaries. So it has been proposed - first at the Cambridge Symposium on ME in 1990 and in another article in 1998, that ME is a dysfunctional state resulting from reduced rates of capillary blood flow due to the presence of shape-changed, poorly-deformable red cells.  
Any impairment of capillary blood flow will mean that tissues will not receive the oxygen and nutrient substrates needed at a rate sufficient to sustain normal tissue function. Obviously, the effects of this would be most serious in those tissues which normally have a high rate of utilisation of oxygen and nutrient substrates. As such tissues include the brain and nervous tissue, muscles and secreting glands it is not surprising that dysfunction of such tissues is indicated by the development of symptoms.

This demonstration of an abnormality in blood which has been declared to be normal on the basis of the usual laboratory tests, is important as it could provide a basis for treatment. Given that the change in red cell shape is accompanied by red cell stiffening with reduced deformability it has been proposed that treatment should be aimed at improving red cell deformability and thus increasing the rate of capillary blood flow. In 1974 it was reported that prostaglandin E! reduced the viscosity of the lipid bilayer of the red cell membrane and in the following year another group reported that prostaglandin E1 improved blood filtrability.  
The blood levels of prostaglandin E1 can be increased by dietary supplementation with 4000mg daily of evening primrose oil. For reasons not yet explained, not all ME people respond to primrose oil, so it should be noted that the omega-3 fatty acids in fish oil have been shown to have the same effect on the red cell membrane as prostaglandin E1. There are other agents which also have a beneficial effect on red cell stiffness.
It should be noted that there are many studies which have used SPECT scans or other techniques to show that in various chronic disorders there are reduced rates of cerebral blood flow. While the cause of the reduced rates of cerebral blood flow are never explained, it is an expected effect of poorly deformable red cells - and such cells have been shown to exist in conditions with reduced rates of cerebral blood flow.

Altered red cell shape populations have been found in ME, CFS, Down Syndrome, CFIDS, cerebral palsy, multiple chemical sensitivity, manic depression, multiple sclerosis, Gulf War Syndrome, Fibromyalgia, arachnoiditis and aging. This implies that all of these conditions might benefit from improved red cell deformability. However it should be noted that although Fibromyalgia has flat cells like those of ME, Fibromyalgia pain remains unexplained. Nor has an opportunity presented itself to explore how many of these chronic states would respond in placebo-controlled trials of agents which improved red cell flexibility.
 
http://www.nrg.com.au/~nrmecfs/research.htm
 
ARTICLE #5
 
 
GLUTATHIONE DEPLETION—METHYLATION CYCLE BLOCK:

A HYPOTHESIS FOR THE PATHOGENESIS OF CHRONIC FATIGUE SYNDROME


by

Richard A Van Konynenburg, Ph.D.
(Independent Researcher and Consultant)

richvank@...



8th International IACFS Conference on
Chronic Fatigue Syndrome, Fibromyalgia
and other Related Illnesses

Ft. Lauderdale, Florida, U.S.A.
January 10-14, 2007
INTRODUCTION AND HYPOTHESIS


At the Seventh International Conference of the AACFS in 2004, the author 
proposed and defended the hypothesis that glutathione depletion is an 
important part of the pathogenesis of CFS (1).

In the conclusions of that paper it was noted that it seemed likely that 
there are vicious circle mechanisms involved in CFS that prevent 
glutathione repletion from being the complete answer for treating this 
disorder.

Recent autism research (2,3) suggests that in that disorder a vicious 
circle involving the methylation cycle apparently chronically holds down 
the level of glutathione.

The present author has recently proposed (4) that this same mechanism is 
active in many cases of CFS. This model for CFS will be referred to as 
the Glutathione Depletion—Methylation Cycle Block (GD-MCB) Hypothesis.

This mechanism appears to be capable of explaining and drawing together 
numerous features of CFS that have been reported in the peer-reviewed 
literature.



What is the methylation cycle,
and what does it do?
(See diagram http://www.co-cure.org/scan0003.bmp )

The methylation cycle (also called the methionine cycle) (5) is a major 
part of the biochemistry of sulfur and of methyl (CH3) groups in the 
body. It is also tightly linked to folate metabolism and is one of the 
two biochemical processes in the human body that require vitamin B12 
(the other being the methylmalonate pathway, which enables use of 
certain amino acids to provide energy to the cells).

This cycle supplies methyl groups for a large number of methylation 
reactions, including those that methylate (and thus silence) DNA (6), 
and those involved in the synthesis of a wide variety of substances, 
including creatine (7), choline (7), carnitine (8), coenzyme Q-10 (9), 
melatonin (10), and myelin basic protein (11). Methylation is also used 
to metabolize the catecholamines dopamine, norepinephrine and 
epinephrine (12), to inactivate histamine (13), and to methylate 
phospholipids (14), promoting transmission of signals through membranes.

The role of the methylation cycle in the sulfur metabolism is to supply 
sulfur-containing metabolites to form a variety of important substances, 
including cysteine, glutathione, taurine and sulfate, via its connection 
with the transsulfuration pathway (5).

This cycle balances the demands for methylation and for control of 
oxidative stress (15)
How is the methylation cycle dysfunctional in autism, and how is this 
related to
glutathione depletion?


In autism the methylation cycle was found by James et al. (2,3) to be 
blocked at methionine synthase, which is the step involving methylation 
of homocysteine to form methionine (see diagram).

Two effects of this block that they measured are a significant decrease 
in the level of plasma methionine and lowering of the ratio of 
S-adenosylmethionine to S-adenosylhomocysteine. The latter causes a 
decreased capacity for promoting methylation reactions (16).

In addition, they found (2,3) that the flow through the transsulfuration 
pathway (see diagram) was also decreased, resulting in lower plasma 
levels of cysteine and glutathione and a lowered ratio of reduced to 
oxidized glutathione, all of which they measured. This lowered ratio 
reflects a state of oxidative stress (17).

The block in the methylation cycle and the glutathione problem were 
found to be linked, since supplements used to restore the methylation 
cycle to normal operation (methylcobalamin, folinic acid and 
trimethylglycine) also restored the levels of reduced and oxidized 
glutathione (2).

Do genetic factors contribute to producing this methylation cycle 
dysfunction in autism?

It is known from studies of twins that genetics plays an important 
predisposing role in autism (18). The fact that the rate of incidence of 
autism has increased dramatically in recent years is evidence that there 
is also an important environmental component in the development of cases 
of autism (3), since the population’s genetic inheritance is relatively 
constant over much longer periods.

James et al. (3) found that there are measurable genetic differences 
between children with autism and healthy controls. The differences they 
measured are associated with genes that encode enzymes and other 
proteins impacting the methylation cycle, the folate metabolism and the 
glutathione system.

In particular they found differences in allele frequency and/or 
significant gene-gene interactions for genes encoding the reduced folate 
carrier (RFC), transcobalamin II (TCN2), catechol-O-methyltransferase 
(COMT), methylenetetrahydrofolate reductase (MTHFR), and one of the 
glutathione transferases (GST M1).

These genetic results, combined with the biochemical observations of 
dysfunction in the methylation cycle, strongly suggest that variations 
in genes associated with this cycle and its related biochemistry are 
involved in the genetic predisposition to developing autism.


What evidence suggests that this same dysfunction and similar genetic 
factors are also present in chronic fatigue syndrome?

1. Methionine concentrations are reported to be below normal in both 
plasma (19) and urine (20) in CFS patients. Low methionine can be caused 
by a methylation cycle block.


2. Four magnetic resonance spectroscopy studies in CFS (21-24) have 
found elevated choline-to-creatine ratios in various parts of the brain. 
Both choline and creatine arise partly from the diet and partly from 
synthesis in the body. Since the syntheses of these two substances are 
the main users of methylation (7), a methylation deficit would be 
expected to decrease the rate of synthesis of both of them, and hence to 
decrease their levels in the cells. When this occurred, it would be 
unlikely that their ratio would remain the same, since the fractions of 
each supplied by synthesis would not likely be the same, nor would the 
decrease in rates of synthesis of these two substances likely to be 
proportional to their levels in the cells. Since creatine synthesis is 
the greater user of methylation (7), it might be expected that the 
choline-to-creatine ratio would increase, as is observed. It therefore 
appears that a methylation cycle block could explain this 
well-replicated observation in CFS.

3. Some substances that require methylation for their biosynthesis have 
been found to be at below-normal levels in CFS patients, and/or patients 
have been found to benefit by supplementing them. This has been reported 
in eleven of the studies in CFS of carnitine, beginning with the work of 
Kuratsune et al. (25-34), both the studies of coenzyme Q10 (35, 36), a 
study that included choline as phosphatidylcholine in a combination 
supplement (37), and one recent study of melatonin (38) (though it 
should be mentioned that earlier studies of melatonin in CFS found 
normal or elevated levels, and/or did not find benefit from 
supplementation (see review in ref. 39), suggesting that other issues in 
addition to the methylation deficit might be involved in the case of 
melatonin. See “Magnesium depletion” later in this paper).

4. Vitamin B12, which plays a key role in the methylation cycle and was 
one of the supplements used to restore this
cycle in the autism work (2), has a long history (39,40) as one of the 
most helpful of the essential nutrients in CFS when given in high-dosage 
injections. Lapp and Cheney (41, 42) found that in urine organic acids 
testing of 100 CFS patients, 33% had elevated homocysteine, 38% had 
elevated methylmalonate, and 13% had both (29,30). The elevated 
homocysteine implicates the methylation cycle,
What evidence suggests that this same dysfunction is also present in 
chronic fatigue syndrome? (continued)

while the elevated methylmalonate indicates that the other pathway that 
requires vitamin B12 showed deficiency as well. Lapp and Cheney (42) 
found that 50 to 80% of over 2,000 patients reported benefit from 
high-dose vitamin B12 injections. Evengard et al. (43) reported that 
vitamin B12 levels in the cerebrospinal fluid of 10 of 16 CFS patients 
were below their detection limit of 3.7 pmol/L. Regland et al. (44) 
found both low vitamin B12 (in 10 out of 12 patients) and high 
homocysteine (in all 12 patients studied) in the cerebrospinal fluid of 
CFS patients. There were significant correlations between these 
parameters and symptoms.

Regland et al. (45) performed an open trial in which they gave 1,000 
microgram weekly injections of hydroxocobalamin for at least 3 months to 
the 10 female patients from this study who had both low B12 and elevated 
homocysteine. They found that the treatment was significantly more 
beneficial if the patient did not have the thermolabile allele of the 
polymorphic gene for MTHFR. They concluded that vitamin B12 deficiency 
was probably contributing to the increased homocysteine levels. They 
also found that the effect of vitamin B12 supplementation was dependent 
on whether the available methyl groups were further deprived by the 
existence of thermolabile MTHFR. This work implicated the methylation 
cycle in
What evidence suggests that this same dysfunction is also present in 
chronic fatigue syndrome? (continued)

the pathogenesis of CFS, and it also pointed to the importance of a 
genetic component, involving one of the same genes that have been 
implicated in autism (3).

5. Folinic acid was recently found to produce subjective improvement in 
symptoms in 81% of 58 CFS patients tested (46). This was also one of the 
supplements used to restore the methylation cycle in the autism research 
(2).

6. Many studies have reported evidence for oxidative stress in CFS (47-61).

7. There have been several reports of depletion of reduced glutathione 
in at least a substantial subset of CFS patients (49-51, 53,54,59,62). 
Reduced glutathione augmentation is now widely used by CFS clinicians, 
who have found that augmenting glutathione by various means has been 
helpful to many of their patients (49,50,63-65).

8. Polymorphisms in the gene coding for the COMT enzyme were found by 
Goertzel et al. (66) to be some of the most important of those examined 
for distinguishing CFS cases from controls. As noted earlier, COMT is a 
methyltransferase, associated with the methylation cycle. In autism, the 
COMT 472G>A polymorphism showed significant difference between cases and 
controls (3).
If this same dysfunction is present in both autism and CFS, how can the 
obvious differences between these two disorders be explained?

Major differences are seen in the gender ratio and in the symptoms of 
these two disorders.
Autism is found primarily in boys, at a ratio of about 4 to1 (boys to 
girls) (67), while CFS occurs mainly in adult women at a ratio measured 
at 1.8 to 1 (women to men) by Jason et al. (68) in one large 
epidemiological study and 4.5 to 1 (women to men) by Reyes et al. (69) 
in another.
The most striking symptoms in autism involve the brain and are very 
characteristic of this disorder. They are described as follows by the 
Diagnostic and Statistical Manual of Mental Disorders (70):
1. Qualitative impairment in social interaction, as manifested by at 
least two of the following:
a. Marked impairment in the use of multiple nonverbal behaviors such as 
eye-to-eye gaze, facial expression, body postures, and gestures to 
regulate social interaction.
b. Failure to develop peer relationships appropriate to developmental 
level.
c. A lack of spontaneous seeking to share enjoyment, interests, or 
achievements with other people (e.g., by a lack of showing, bringing, or 
pointing out objects of interest).
d. Lack of social or emotional reciprocity.

2. Qualitative impairments in communication as manifested by at least 
one of the following:
a. Delay in, or total lack of, the development of spoken language (not 
accompanied by an attempt to compensate through alternative modes of 
communication such as gestures or mime).
b. In individuals with adequate speech, marked impairments in the 
ability to initiate or sustain a conversation with others.
c. Stereotyped and repetitive use of language or idiosyncratic language.
d. Lack of varied, spontaneous make-believe play or social imitative 
play appropriate to developmental level.

3. Restricted repetitive and stereotyped patterns of behavior, 
interests, and activities, as manifested by at least one of the following:
a. Encompassing preoccupation with one or more stereotypic and 
restricted patterns of interest that is abnormal either in intensity or 
focus.
b. Apparently inflexible adherence to specific, nonfunctional routines 
or rituals.
c. Stereotypic and repetitive motor mannerisms (e.g., hand or finger 
flapping or twisting, or complex whole-body movements).
d. Persistent preoccupation with parts of objects.
CFS involves a large variety of symptoms (71,72), the chief ones being 
extreme fatigue, post-exertional malaise and/or fatigue, sleep 
dysfunction, muscle pain, and symptoms involving the brain that are 
significant but less profound than in autism (e.g. cognitive and memory 
difficulties).

The author proposes that these differences result at least in part from 
the different ages at onset. Autism develops early in life, before the 
brain is completely developed and before puberty, while the onset of CFS 
occurs after brain development is completed and (for the most part) 
after puberty.

Pangborn (73) has discussed five hypotheses that have been suggested to 
explain the higher prevalence of autism in boys. Of these, the one that 
appears to be most consistent with the present author’s hypothesis of a 
common pathogenesis between CFS and autism is the one put forward by 
Geier and Geier (74). Their hypothesis proposes
If this same dysfunction is present in both autism and CFS, how can the 
obvious differences between these two disorders be explained? (continued)

that the higher prevalence of autism in boys results from the 
potentiation of mercury toxicity by testosterone, while estrogen is 
protective. There is increasing evidence that mercury was a significant 
factor in the etiology of many cases of autism, because 
mercury-containing thimerosol was used as a preservative in vaccines 
given to them. Since thimerosol was removed from childhood vaccines, the 
number of new cases of neurodevelopmental disorders, including autism, 
has been found to be dropping (75).

The present author has proposed a hypothesis (76) to explain the higher 
prevalence of CFS in women, involving an additional bias toward 
oxidative stress due to redox cycling in the metabolism of estradiol 
when certain polymorphisms are present.

With regard to symptoms, it seems likely that the role of methylation in 
the formation of myelin basic protein (77) is at least part of the 
explanation for the major problems in brain development in autism and 
the symptoms that result from them.

Fatigue is not recognized to be a major feature of autism. However, it 
should be noted that the evaluation of fatigue is usually based on 
self-report, which is not possible in children who are unable to speak. 
Also, it seems possible that fatigue may be manifested differently in 
very young children as compared with adults. Features such as 
hyperactivity and irritability may reflect fatigue in these patients.

Chronic pain may also be difficult to identify and characterize in 
children who do not have speech. A recent paper suggests that chronic 
pain may be the initial presenting symptom in cases of undiagnosed 
autism (78).

Many of the other phenomena found in CFS are also found in autism, but 
historically they have not received as much attention in autism as the 
brain-related symptoms, perhaps because the latter are so striking and 
profound. Some of the other phenomena that autism has in common with CFS 
in addition to those already mentioned are elevated proinflammatory 
cytokines (79), Th2 shift in the immune response (80), low natural 
killer cell activity (81), mitochondrial dysfunction (82, 83), carnitine 
deficiency (83), hypothalamus-pituitary-adrenal (HPA) axis dysfunction 
(84), gut problems (85), and sleep problems (86).



How does the Glutathione Depletion—Methylation Cycle Block (GD-MCB) 
Hypothesis explain other aspects of chronic fatigue syndrome?

Etiology: According to the GD-MCB Hypothesis, CFS is caused by a 
combination of two factors:
(1) a genetic predisposition (87), which is currently only partly known, 
and
(2) some combination of a variety of physical, chemical, biological 
and/or psychological/emotional stressors, the particular combination 
differing from one case to another (See Ref. 1 for a review.).

So far, polymorphisms in genes coding for the following proteins have 
been found to be associated with CFS in general or with a subset:

(1) Serotonin transporter (5-HTT) gene promoter (88)
(2) Corticosteroid binding globulin (CBG) (89)
(3) Tumor necrosis factor (TNF) (90)
(4) Interferon gamma (IFN-gamma) (90)
(4) Proopiomelanocortin (POMC) (91)
(5) Nuclear receptor subfamily 3, group C, member 1, glucocorticoid 
receptor (66,91)
(6) Monoamine oxidase A (MAO A) (91)
(7) Monoamine oxidase B (MAO B) (91)
(8) Tryptophan hydroxylase 2 (TPH2) (66,91)
(9) Catechol-O-methyltransferase (COMT) (66)
How does the GD-MCB Hypothesis explain other aspects of chronic fatigue 
syndrome?
(continued)

In addition, a COMT polymorphism has reported to be associated with 
fibromyalgia (92, 93), and polymorphisms in the genes for the 
detoxication enzymes CYP2D6 (cytochrome P450 2D6) and NAT2 (N-acetyl 
transferase 2) have been found to be associated with multiple chemical 
sensitivities (94). These may be relevant to CFS because of its high 
comorbidities with these two disorders.

All these proteins touch on the pathogenesis mechanism described in this 
paper, which is what would be expected if this Hypothesis is valid.

With regard to the stressors found to precede onset of CFS, they are 
known to raise cortisol secretion (prior to onset and early in the 
course of the illness), to raise epinephrine secretion and to place 
demands on glutathione, leading to oxidative stress (1).

According to this Hypothesis, when reduced glutathione is sufficiently 
depleted and the oxidative stress therefore becomes sufficiently severe 
in a person having the appropriate genetic predisposition, a block is 
established at methionine synthase in the methylation cycle (95,2,3). 
Because the methylation cycle is located upstream of cysteine and 
glutathione in the sulfur metabolism, these are further depleted, and a 
vicious circle is formed.

Note that infectious pathogens are included among the possible 
biological stressors that can contribute to the onset of CFS. In 
particular, Borrelia burgdorferi, the bacterium responsible for Lyme 
disease, has been found to deplete glutathione in its host (96). This 
may explain the very similar pathophysiologies of chronic Lyme disease 
and CFS. This may also explain the epidemic clusters of CFS, which seem 
to have been produced by a virulent infectious pathogen (or pathogens). 
Perhaps the genetic factors are less important in producing the onset if 
a very virulent pathogen is present.

Epidemiology: According to the GD-MCB Hypothesis, the prevalence of CFS 
is determined by the frequency in the population of the combined 
presence of certain genetic polymorphisms (yet to be completely 
identified) and of the above described stressors occurring 
coincidentally in those having the polymorphisms. As noted earlier, the 
author has proposed that the higher prevalence in women is a result of 
increased bias toward oxidative stress, resulting from redox cycling in 
the metabolism of estradiol when certain polymorphisms in detoxication 
enzymes are present (76).

Suppression of parts of the immune response: Elevation of cortisol due 
to long-term stressors causes a suppression of the cell-mediated immune 
response and a shift to Th2 (97).

Depletion of reduced glutathione likewise causes a shift to Th2 (98, 99).

The elevation of cortisol prior to onset and in the early course of the 
illness also (temporarily) suppresses inflammation (100).


The cytotoxicity of natural killer (NK) cells and CD8 T cells in CFS has 
been found to be low, and Maher et al. found this to be associated with 
a deficiency of perforin secretion (101). According to the GD-MCB 
Hypothesis, in CFS perforin secretion is inhibited by depletion of 
reduced glutathione because glutathione is needed to form the disulfide 
bonds in their proper configurations in secretory proteins (102). 
Depletion of glutathione therefore causes misfolding and recycle of 
perforin molecules, which have twenty cysteine residues and thus ten 
disulfide bonds (103). This misfolding mechanism would affect other 
secretory proteins in CFS that are synthesized in cells having 
glutathione depletion as well, which may account for the observation of 
misfolded proteins in the spinal fluid of CFS patients by Baraniuk et 
al. (104).

Proliferation of T lymphocytes is inhibited by the block in the folate 
cycle, which inhibits production of new RNA and DNA (105).

Viral and intracellular bacterial reactivation: According to the GD-MCB 
Hypothesis, depletion of reduced glutathione is the trigger for the 
reactivation of latent viral and intracellular bacteria in CFS. The 
infections found initially in a case of CFS are usually due to those 
pathogens that are capable of residing in the body in the latent state, 
suggesting that these infections arise by reactivation (106). In 
general, intracellular glutathione depletion is associated with the 
activation of several types of viruses (1, 107-111) as well as Chlamydia 
(112), and it may account for reactivation of other latent intracellular 
bacteria as well. In herpes simplex type 1 viral infection, raising the 
glutathione concentration inhibits viral replication by blocking the 
formation of disulfide bonds in glycoprotein B (111). Since glycoprotein 
B appears to be present in all herpes virus types (113), it is likely 
that glutathione depletion is responsible for reactivation of 
Epstein-Barr virus, cytomegalovirus and HHV-6 in CFS.

The Coxsackie B3 virus genome is known to code for glutathione 
peroxidase, a selenium-containing enzyme (114). Taylor has suggested 
(115) that such viruses suppress the immune system of the host by 
depleting its selenium, thus inhibiting the host’s use of glutathione 
peroxidase. Since glutathione peroxidase makes use of glutathione, 
depletion of reduced glutathione itself would therefore assist this 
virus in its mechanism of infection.

Populations more deficient in selenium would be expected to be more 
vulnerable to Coxsackie B3 infection. It is interesting to note that 
nearly all the studies of Coxsackie virus in CFS have come from the UK. 
The population there has become more deficient in selenium since the 
1970s, when major sources of grain in the diet were changed to areas 
with selenium-deficient soils (116).

Immune activation: This occurs when the immune system detects the 
reactivation of pathogens (117).

Activation of 2-5A, RNase-L pathway (118): This pathway is activated by 
interferon and double stranded RNA as part of the cellular response to 
viral reactivation. According to the GD-MCB Hypothesis, RNase-L remains 
activated in CFS because of the suppression of the cell-mediated immune 
response and the consequent failure to defeat the viral infection (See 
“Suppression of parts of the immune response,” above.)

Mitochondrial dysfunction and the onset of physical fatigue: As 
hypothesized by Bounous and Molson (119), competition between the 
oxidative skeletal muscle cells and the immune system for the decreased 
supply of glutathione and cysteine causes depletion of reduced 
glutathione in the skeletal muscles. According to the GD-MCB Hypothesis, 
this inhibits the glutathione peroxidase reaction and allows hydrogen 
peroxide to build up. This in turn probably exerts product inhibition on 
the superoxide dismutase reaction, which allows superoxide, produced as 
part of normal oxidative metabolism, to rise in the mitochondria of the 
oxidative skeletal muscle cells. Superoxide reacts with nitric oxide to 
produce peroxynitrite, as Pall (120) has pointed out. Superoxide also 
interacts with aconitase in the Krebs cycle to inhibit it (121), and 
peroxynitrite can cause partial blockades in the Krebs cycle and also 
the respiratory chain (120, 122). These reactions lower the rate of 
production of ATP, and this constitutes mitochondrial dysfunction. Since 
ATP is needed to power muscle contraction, lack of it produces physical 
fatigue.

RNase-L cleavage, leading to formation of the low molecular weight 
version (123): Depletion of reduced glutathione removes inhibition of 
the activity of calpain (124), which is located in the cytosol with 
RNase-L, and calpain cleaves RNase-L (125). (Elastase, the other enzyme 
found by Englebienne et al. (125) to be able to cleave RNase-L in the 
laboratory, is confined to granules and vesicles inside living cells 
(126), and thus is not in contact with RNase-L.)

Failure to defeat viral and intracellular bacterial infections and 
continuing immune activation: According to the GD-MCB Hypothesis, these 
occur because of depletion of reduced glutathione (127) and also because 
the folate metabolism block prevents production of new DNA and RNA for 
proliferation of T lymphocytes (105).

Depletion of magnesium: There is a long history showing depletion of 
magnesium in CFS and benefits of supplementation, both orally and by 
injection (See review in Ref. 39). Magnesium depletion may be 
responsible for a variety of symptoms that are found in CFS (128), 
including mitochondrial dysfunction, muscle twitching, muscle pain, 
sleep problems and cardiac arrhythmia. In connection with sleep 
problems, Durlach et al. have found that magnesium depletion is 
associated with abnormalities in the level of melatonin and 
dysregulation of biorhythms (129). Manuel y Keenoy et al. (54) found 
that the subset of CFS patients that was resistant to repletion of 
magnesium in their clinical study also showed glutathione depletion. It 
has also been found that glutathione depletion causes magnesium 
depletion in red blood cells (130). According to the GD-MCB Hypothesis, 
the depletion of intracellular magnesium in CFS is another result of 
depletion of reduced glutathione.

Buildup of toxins: Glutathione depletion allows toxins, including heavy 
metals, to build up, because there is not enough glutathione to 
conjugate these toxins as rapidly as they enter the body. Mercury is of 
particular concern, because the population in general has considerable 
exposure to it from dental amalgams, fish consumption, and environmental 
sources such as nearby coal-fired power plants. There is considerable 
clinical experience of mercury buildup in CFS patients (1). Immune 
testing has also shown evidence that the immune system has responded to 
elevated mercury in CFS patients (131-133).

Solidification of the vicious circle: After the vicious circle has 
developed involving the methylation cycle block and the depletion of 
glutathione, another factor must come into play to lock in this 
situation chronically. It seems likely that buildup of toxins is the 
factor responsible for this, by blocking the formation of 
methylcobalamin and thus the activity of methionine synthase. It has 
been shown that one of the important roles of glutathione normally is to 
protect the very much smaller (by six orders of magnitude) 
concentrations of cobalamins from reaction with toxins by forming 
glutathionylcobalamin (134). Without this protection, cobalamins are 
vulnerable to reaction with a variety of toxins. An example is mercury. 
It has been found that very small concentrations of mercury are required 
to block the methionine synthase reaction (135). Because of this 
additional factor, attempts simply to correct the glutathione depletion 
and the oxidative stress after the cobalamins have reacted with toxins 
in most cases will not restore normal function of the methylation cycle (1).

Neurotransmitter dysfunction: The production of melatonin from serotonin 
as well as the metabolism of the catecholamines require methylation, as 
noted earlier, and according to the GD-MCB Hypothesis, they are 
inhibited because of the decreased methylation capacity. Also, genetic 
polymorphisms involving enzymes in the neurotransmitter system have been 
found to be more frequent in at least some subsets of CFS patients, as 
noted earlier. These factors cause dysfunction of the neurotransmitters.

Further development of mitochondrial dysfunction: As the course of the 
illness progresses, it is likely that other factors that result from 
glutathione depletion and the methylation cycle block come into play and 
further suppress the operation of the mitochondria. These include the 
buildup of toxins and infections, depletion of magnesium, and damage to 
the phospholipid membranes of the mitochondria by oxidizing free 
radicals (136). Because the essential fatty acids in these membranes are 
polyunsaturated, they are the most vulnerable to oxidation (137), and 
they become depleted, at least in some CFS patients (See review in Ref. 39).


HPA axis blunting (138): According to this Hypothesis, glutathione 
depletion in the pituitary gland inhibits production of 
proopiomelanocortin (POMC) (which has two disulfide bonds in its 
N-terminal fragment (139)), and hence secretion of ACTH (which is part 
of POMC), by the same mechanism as inhibition of perforin synthesis 
(102) (See “Suppression of parts of the immune response,” above.). This 
results in the lowering of cortisol secretion by the adrenal glands, 
which is a late finding in the course of the illness (140). As noted 
earlier, genetic polymorphisms in POMC may also be involved in a subset 
of CFS patients (91).

Diabetes insipidus (excessive urination, thirst, decrease in blood 
volume): According to this Hypothesis, glutathione depletion inhibits 
production of arginine vasopressin (141), which has one disulfide bond 
(142), by the same biochemical mechanism by which it inhibits perforin 
and ACTH synthesis (102). It is likely that the secretion of oxytocin, 
which also has one disulfide bond and is also synthesized in the 
hypothalamus, is also inhibited. Measurements of oxytocin in CFS have 
not been reported, but there is evidence that it is low in some 
fibromyalgia patients (143), which may be relevant because of the high 
comorbidity of CFS and fibromyalgia. A clinician has reported benefit 
from oxytocin injections in fibromyalgia patients (144).
How does the GD-MCB Hypothesis explain other aspects of chronic fatigue 
syndrome? (continued)


Low cardiac output (145): According to this Hypothesis, this occurs 
because depletion of reduced glutathione in the heart muscle cells 
lowers the rate of production of ATP, as in the skeletal muscle cells. 
This produces diastolic dysfunction as observed by Cheney (146, 147). 
Both low blood volume (see Diabetes insipidus, above), which produces 
low venous return, and diastolic dysfunction, which decreases filling of 
the left ventricle, produce low cardiac output. In addition, in some 
cases, as observed by Lerner et al., viral infections produce 
cardiomyopathy (148). According to the GD-MCB Hypothesis, this is a 
result of depletion of reduced glutathione and suppression of 
cell-mediated immunity. This is another factor that can decrease cardiac 
output in CFS.

Orthostatic hypotension and orthostatic tachycardia (149): According to 
this Hypothesis, these occur because of low blood volume, low cardiac 
output and HPA axis blunting (See Diabetes insipidus, Low cardiac 
output, and HPA axis blunting, above.).

Loss of temperature regulation: As pointed out by Cheney (146), this 
occurs because of low cardiac output (see Low cardiac output, above), 
which causes the autonomic nervous system to decrease blood flow to the 
skin. This removes the ability to regulate the rate of heat loss from 
the skin.
How does the GD-MCB Hypothesis explain other aspects of chronic fatigue 
syndrome?
(continued)


Hashimoto’s thyroiditis (150) and elevated incidence of thyroid cancer 
(151): According to this Hypothesis, Hashimoto’s thyroiditis occurs in 
CFS because depletion of reduced glutathione in the thyroid gland allows 
damage to thyroglobulin by hydrogen peroxide, as proposed by Duthoit et 
al. (152). In addition, hydrogen peroxide damage to DNA in the thyroid 
gland may be responsible for the elevated incidence of cancer there. 
Hydrogen peroxide is produced normally by the thyroid to oxidize iodide 
in the process of making thyroid hormones (153).

Increasing variety of infections (154) and inflammation (155): According 
to this Hypothesis, viral, intracellular bacterial and fungal infections 
accumulate over time because the cell-mediated immune response is 
dysfunctional (See “Suppression of parts of the immune response,” 
above.). Inflammation becomes more severe because of the decreased 
secretion of cortisol later in the course of the illness (See “HPA axis 
blunting,” above), and because of the rise in histamine as a result of 
lack of sufficient methylation capacity to deactivate it (156).

Slow gastric emptying (157) and gastroesophageal reflux: According to 
this Hypothesis, in CFS these result from mitochondrial dysfunction in 
the parietal cells of the stomach, due to depletion of reduced 
glutathione, which results in low production of stomach acid. 
(Anecdotally, many CFS patients have reported absence of eructation 
after ingestion of sodium bicarbonate solution on an empty stomach, 
suggesting low stomach acid status.) A slower rate of gastric emptying 
was found to be associated with higher pH, i.e. lower acid status (158).

Gut problems: According to this Hypothesis, several of the above factors 
converge to produce problems in the gut in CFS, often referred to as 
irritable bowel syndrome (IBS). These factors include glutathione 
depletion, low cardiac output, immune suppression, low stomach acid 
production, neurotransmitter dysfunction (note that serotonin plays a 
major role in gut motility), and increasing variety of infections and 
inflammation.

The degree of abnormality of a lactulose breath test (indicating small 
intestinal bacterial overgrowth) in fibromyalgia patients was found by 
Pimentel et al. to be greater than in IBS patients without fibromyalgia 
(159). In addition, they found that the abnormality was correlated with 
somatic pain (159). (This may be relevant because of the high 
comorbidity of CFS with fibromyalgia.)

Brain-related problems: According to this Hypothesis, several of the 
above factors also converge to produce problems in the brain. These 
include glutathione (and cysteine) depletion, low cardiac output, 
failure to defeat infections and continued immune activation, 
neurotransmitter dysfunction, decreased methylation capacity to maintain 
myelin, and increasing variety of infections and inflammation.

Relapsing (Crashing) (160): Many CFS patients have chronically low 
glutathione levels. According to this Hypothesis, when the level of 
stressors is temporarily increased, the levels of reduced glutathione 
become more severely depleted, and this produces the so-called crashing 
phenomenon. After a period of rest, reduced glutathione levels are 
increased to the chronically low levels that existed prior to the 
increased stressors.

Alcohol intolerance (161): According to this Hypothesis, because of 
mitochondrial dysfunction, the skeletal muscles of CFS patients depend 
more than normal on glycolysis for ATP production. Increased use of 
glycolysis requires increased use of gluconeogenesis by the liver to 
convert lactate and pyruvate back to glucose (Cori cycle). In CFS, this 
is hampered by low cortisol levels. The metabolism of ethanol by the 
liver further inhibits gluconeogenesis,
producing hypoglycemia and lactic acidosis. This accounts for the 
alcohol intolerance reported by many CFS patients.

Weight gain: According to this Hypothesis, the weight gain often seen in 
CFS results from the inability to metabolize
carbohydrates and fats at normal rates, because of partial blockades in 
the Krebs cycle produced by depletion of reduced glutathione. Excess 
carbohydrates are cycled back to glucose by gluconeogenesis, and 
ultimately are converted to stored fat.

Low serum amino acid levels (19): According to this Hypothesis, these 
result from the burning of amino acids as fuel at higher rates than 
normal. Amino acids are able to enter the Krebs cycle by anaplerosis, 
downstream of the partial blockades, so they can be used as fuel in 
place of carbohydrates and fats.

The pathogenesis of CFS becomes increasingly complex as it proceeds, 
because of the interactions and feedback loops that develop. For this 
reason, determining the cause-effect relationships for all the aspects 
of the resulting pathophysiology is a problem that is exceedingly 
difficult. Nevertheless, understanding the etiology and early 
pathogenesis provides a basis for developing a more effective treatment 
approach.


CONCLUSIONS

There is abundant and compelling evidence that the glutathione 
depletion—methylation cycle block mechanism is an important part of the 
pathogenesis for at least a substantial subset of chronic fatigue 
syndrome patients.

A pathogenesis hypothesis based on this mechanism is capable of 
explaining and unifying many of the published observations regarding 
chronic fatigue syndrome, and it provides a basis for developing a more 
effective treatment approach.



KEY TO DIAGRAM (See http://www.co-cure.org/scan0003.bmp )


The diagram shows the methylation cycle at the top right, the folate 
cycle at the top left, and the transsulfuration pathway at the bottom right.

The enzymes that catalyze the reactions are shown in boxes:

BHMT Betaine homocysteine methyltransferase
CBS Cystathionine beta synthase
CDO Cysteine dioxygenase
CGL Cystathionine gamma lyase
GCL Glutamate cysteine ligase
GS Glutathione synthase
MAT Methionine adenosyltransferase
MS Methionine synthase
MSR Methionine synthase reductase
MTase Methyltransferase (a class of enzymes)
MTHFR Methylene tetrahydrofolate reductase
SHT Serine hydroxymethyltransferase
TS Thymidylate synthase

Most of the metabolites are spelled out. The ones that are abbreviated 
are as follows:

DMG Dimethylglycine
SAH S-Adenosylhomocysteine
SAM S-Adenosylmethionine
THF Tetrahydrofolate
TMG Trimethylglycine (betaine)

The cofactor and coenzyme are as follows:

P5P Pyridoxal phosphate, the active form of
Vitamin B6
B12 Methylcobalamin, one of the active forms of
Vitamin B12
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