@Lisa: What I find problematic about the methylation protocol is that there is no clear test where Rich or Freddd would say that it excludes a methylation problem. Rich recommends a lot of tests but none to exclude a methylation problem. I haven't heard about any specific laboratory parameter where both would say that B12 and Metafolin are not part of the problem.
My understanding is that Rich would say that if people are okay on this Health Diagnostics test, they don't have a methylation problem. I've yet to see anybody with ME/CFS come up normal on it, or get back to normal on it through any sort of treatment, either. I wonder how Freddd would do on it, at this point.
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Methylation Pathways Panel
Written by Rich van K (with Lisas results from Fall 2010 noted):
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 requires an order from a physician or a chiropractor. The best way to order the panel is by fax, on a clinician's letterhead.
Available from:
Health Diagnostics and Research Institute
540 Bordentown Avenue, Suite 4930
South Amboy, NJ 08879
USA
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.
Interpretation of the Health Diagnostics and Research Institute
Methylation Pathways Panel
by Rich Van Konynenburg, Ph.D.
Several people have asked for help in interpreting the results of their Health Diagnostics and Research Institute 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., at the Health Diagnostics and Research Institute.
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 vitamers.
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 these measurements.
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.
3.4 LOW (Ref range 3.8-5.5)
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.
.58 HIGH (Ref range 0.16-0.50)
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.
16.2 LOW (Ref range 16.8-21.4)
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.
226 (Ref range 221-256)
FWIW, supplementing SAM-e always has made me quite sick.
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.
57 HIGH (Ref range 38-49)
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.
283
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 methylation capacity.
3.9 LOW
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.
11.9 (Ref range 8.4-72.6)
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.
1.9 (Ref range 1.5-8.2)
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.
2.7 (Ref range 1.2-11.7)
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.
0.97 (Ref range 0.6-6.8)
In Fall 2007, my FIGLU on MetaMetrixs IONS test was very high.
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.
12.5 (Ref range 8.9-24.6)
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.
16 (Ref range 9-35.5)
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.
412 (Ref range 400-1500)
