Wow, thanks so much, Rich. I am going to look into the link you posted and read more about this. Your post is more info than I have found anywhere on low homocysteine. Is there anything I should take for any of these things? I know from a metametrix test that my methylation system (not sure what to call it?) is not quite right, but I don't know much about this stuff yet. I have tried Sam-e once, but it didn't seem to help.
In my opinion, the best test panel to run is the methylation pathways panel offered by the Health Diagnostics and Research Institute in New Jersey. This panel evaluates the status of the methylation cycle, the folate metabolism, and glutathione. In my opinion, this is the best diagnostic panel for CFS. If this panel indicates that these aspects are abnormal, the person has CFS, in my opinion. There is a relatively simple and inexpensive nonprescription treatment protocol, described at the website I cited in my earlier post that has helped many people with CFS. This protocol is designed to correct the root issue, which is a partial block in the enzyme methionine synthase, which utilizes vitamin B12 as a coenzyme, and which converts homocysteine to methionine. SAMe is one of the four metabolites in the methylation cycle, and adding it can be helpful for some people who have ME/CFS, but this does not correct the root issue, which this protocol is designed to do.
The contact information for the test panel is pasted below. I hope this is helpful.
Methylation Pathways Panel
This panel will indicate whether a person has a partial methylation cycle block and/or glutathione depletion. I recommend that this panel be run before deciding whether to consider treatment for lifting the methylation cycle block. I am not associated with the lab that offers this panel. The panel costs $300.
The panel requires an order from a physician or a chiropractor. The best way to order the panel is by fax, on a clinician’s letterhead.
Health Diagnostics and Research Institute
540 Bordentown Avenue, Suite 4930
South Amboy, NJ 08879
Phone: (732) 721-1234
Fax: (732) 525-3288
Lab Director: Elizabeth Valentine, M.D.
Dr. Tapan Audhya, Ph.D., is willing to help clinicians with interpretation of the panel by phone, or you can use the interpretive comments below:
Interpretation of the Health Diagnostics
Methylation Pathways Panel
Rich Van Konynenburg, Ph.D.
Several people have asked for help in interpreting the results of
their Health Diagnostics methylation pathway panels. Here are my
suggestions for doing so. They are based on my study of the
biochemistry involved, on my own experience with interpreting more
than 120 of these panel results to date, and on discussion of some of
the issues with Tapan Audhya, Ph.D.
The panel consists of measurement of two forms of glutathione
(reduced and oxidized), adenosine, S-adenosylmethionine (SAM) , S-
adenosylhomocysteine (SAH), and seven folic acid derivatives or
According to Dr. Audhya, the reference ranges for each of these
metabolites was derived from measurements on at least 120 healthy
male and female volunteer medical students from ages 20 to 40, non-
smoking, and with no known chronic diseases. The reference ranges
extend to plus and minus two standard deviations from the mean of
Glutathione: This is a measurement of the concentration of the
reduced (active) form of glutathione (abbreviated GSH) in the blood
plasma. From what I've seen, most people with chronic fatigue
syndrome (PWCs) have values below the reference range. This means
that they are suffering from glutathione depletion. As they undergo
the simplified treatment approach to lift the methylation cycle
block, this value usually rises into the normal range over a period
of months. I believe that this is very important, because if
glutathione is low, vitamin B12 is likely unprotected and reacts with toxins
that build up in the absence of sufficient glutathione to take them
out. Vitamin B12 is thus “hijacked,” and not enough of it is able to
convert to methylcobalamin, which is what the methylation cycle needs
in order to function normally. Also, many of the abnormalities and
symptoms in CFS can be traced to glutathione depletion.
Glutathione (oxidized): This is a measurement of the concentration
of the oxidized form of glutathione (abbreviated GSSG) in the blood
plasma. In many (but not all) PWCs, it is elevated above the normal
range, and this represents oxidative stress.
Adenosine: This is a measure of the concentration of adenosine in the
blood plasma. Adenosine is a product of the reaction that converts
SAH to homocysteine. In some PWCs it is high, in some it is low, and
in some it is in the reference range. I don't yet understand what
controls the adenosine level, and I suspect there is more than one
factor involved. In most PWCs who started with abnormal values, the
adenosine level appears to be moving into the reference range with
methylation cycle treatment, but more data are needed.
S-adenosymethionine (RBC) (SAM): This is a measure of the
concentration of SAM in the red blood cells. Most PWCs have values
below the reference range, and treatment raises the value. S-
adenosylmethionine is the main supplier of methyl groups in the body,
and many biochemical reactions depend on it for their methyl
groups. A low value for SAM represents low methylation capacity, and
in CFS, it appears to result from a partial block at the enzyme methionine
synthase. Many of the abnormalities in CFS can be tied to lack of
sufficient methyation capacity.
S-adenosylhomocysteine (RBC) (SAH): This is a measure of the
concentration of SAH in the red blood cells. In CFS, its value
ranges from below the reference range, to within the reference range,
to above the reference range. Values appear to be converging toward
the reference range with treatment. SAH is the product of reactions
in which SAM donates methyl groups to other molecules.
Sum of SAM and SAH: When the sum of SAM and SAH is below 268
micromoles per deciliter, it appears to suggest the presence of
upregulating polymorphisms in the cystathione beta synthase (CBS)
enzyme, though this may not be true in every case.
Ratio of SAM to SAH: A ratio less than about 4.5 also represents low
methylation capacity. Both the concentration of SAM and the ratio of
concentrations of SAM to SAH are important in determining the
5-CH3-THF: This is a measure of the concentration of 5-methyl
tetrahydrofolate in the blood plasma. It is normally the most
abundant form of folate in the blood plasma. It is the form that
serves as a reactant for the enzyme methionine synthase, and is thus
the most important form for the methylation cycle. Many PWCs have a
low value, consistent with a partial block in the methylation cycle.
The simplified treatment approach includes FolaPro, which is
commercially produced 5-CH3-THF, so that when this treatment is used,
this value rises in nearly every PWC. If the concentration of 5-CH3-
THF is within the reference range, but either SAM or the ratio of SAM
to SAH is below the reference values, it suggests that there is a
partial methylation cycle block and that it is caused by
unavailability of sufficient bioactive B12, rather than
unavailability of sufficient folate. I have seen this frequently,
and I think it demonstrates that the “hijacking” of B12 is the root
cause of most cases of partial methylation cycle block. Usually
glutathione is low in these cases, which is consistent with lack of
protection for B12, as well as with toxin buildup.
10-Formyl-THF: This is a measure of the concentration of 10-formyl
tetrahydrofolate in the blood plasma. It is usually on the low side in PWCs.
This form of folate is involved in reactions to form purines, which
form part of RNA and DNA as well as ATP.
5-Formyl-THF: This is a measure of the concentration of 5-formyl
tetrahydrofolate (also called folinic acid) in the blood plasma.
Most but not all PWCs have a value on the low side. This form is not used
directly as a substrate in one-carbon transfer reactions, but it can
be converted into other forms of folate. It is one of the
supplements in the simplified treatment approach, which helps to
build up various other forms of folate.
THF: This is a measure of the concentration of tetrahydrofolate in
the blood plasma. In PWCs it is lower than the mean normal value of 3.7
nanomoles per liter in most but not all PWCs. This is the
fundamental chemically reduced form of folate from which several
other reduced folate forms are made. The supplement folic acid is
converted into THF by two sequential reactions catalyzed by
dihydrofolate reductase (DHFR). THF is also a product of the
reaction of the methionine synthase enzyme, and it is a reactant in
the reaction that converts formiminoglutamate (figlu) into
glutamate. If figlu is high in the Genova Diagnostics Metabolic
Analysis Profile, it indicates that THF is low.
Folic acid: This is a measure of the concentration of folic acid in
the blood plasma. Low values suggest folic acid deficiency in the
current diet. High values are sometimes associated with inability to
convert folic acid into other forms of folate, such as because of
polymorphisms in the DHFR enzyme. They may also be due to high
supplementation of folic acid.
Folinic acid (WB): This is a measure of the concentration of folinic
acid in the whole blood. See comments on 5-formyl-THF above. It
usually tracks with the plasma 5-formyl-THF concentration.
Folic acid (RBC): This is a measure of the concentration of folic
acid in the red blood cells. The red blood cells import folic acid
when they are initially being formed, but during most of their
approximately four-month life, they do not normally import, export, or use
it. They simply serve as reservoirs for it, giving it up when they
are broken down. Many PWCs have low values. This can be
caused by a low folic acid status in the diet over the previous few
months, since the population of RBCs at any time has ages ranging
from zero to about four months. However, in CFS it can also be
caused by damage to the cell membranes, which allows folic acid to
leak out of the cells. Dr. Audhya reports that treatment with omega-
3 fatty acids can raise this value over time.