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Methylation pathways panel

Discussion in 'Diagnostic Guidelines and Laboratory Testing' started by richvank, Jun 21, 2010.

  1. richvank

    richvank Senior Member

    Hi, all.

    So far, I think that nearly everyone with ME/CFS who has taken the methylation pathways panel offered by Health Diagnostics and Research Institute (formerly Vitamin Diagnostics, Inc.) in New Jersey has been found to have abnormalities on this panel. The Glutathione Depletion--Methylation Cycle Block hypothesis for the pathogenesis of ME/CFS predicts that this would be the case. This hypothesis would be consistent with XMRV involvement, either in contributing to causation of at least some cases of ME/CFS or as an acquired passenger, benefiting from immune dysfunction resulting from glutathione depletion as a result of other initial causes.

    I think there is a good chance that this panel could serve as the biomarker panel for diagnosis of ME/CFS, as well as the gauge of progress in treatment. A clinical treatment study that I think supports this possibility can be found at

    I have no financial interest in this lab or this panel.

    For others who might be interested in getting this panel, here's the contact information:

    Methylation Pathways Panel

    This panel will indicate whether a person has a partial methylation cycle block, draining of folate metabolites from the cells, and/or glutathione depletion. I recommend that this panel be run before deciding whether to consider treatment for lifting the methylation cycle block.

    The panel requires an order from a physician or a chiropractor. It costs $300 plus the cost of shipping the blood samples to the lab. The best way to order the panel is by fax, on a clinicians letterhead.

    Available from:

    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., at the lab is willing to help clinicians with interpretation of the panel by phone, or you can use the interpretive comments below:

    Interpretation of the Vitamin Diagnostics
    Methylation Pathways Panel

    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. of 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

    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.

    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
    methylation capacity.

    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.

    Best regards

  2. wciarci

    wciarci Wenderella

    Hi Rich, I am about to go onto the simplified methylation protocol, as you know I have been taking many supplements over the last few years but not the exact supplements in the exact amounts of your protocol. Should I take the test and if so, should I stop all supplements and for how long? Thanks

  3. richvank

    richvank Senior Member

    Hi, Wendy.

    I do recommend taking this panel, because it will tell you your current status with regard to the partial methylation cycle block and glutathione.

    In the clinical study we ran, the patients continued to take the supplements as we repeated this panel at 3, 6, and 9 months, and we saw very systematic (but relatively slow) changes in the results, so based on that experience, my opinion is that it is O.K. to continue taking the supplements, because the partial methylation cycle block and glutathione depletion are rather "stubborn" abnormalities. If they are present, they will show up whether or not supplementation is continued.

    I hope this testing and treatment pay off for you.

    Best regards,

  4. wciarci

    wciarci Wenderella

    Thanks Rich, I will order the test and the supplements. I will continue with the B12 shots but ask my doctor to change to a better form. I did sublingual for a while but still needed the shots for the B12 to be 'normal'.

  5. Wayne

    Wayne Senior Member

    Ashland, Oregon
    Thanks much Rich for your succinct post. A lot of good actionable information.

    I, like I assume most others on this board, anticipate getting tested for XMRV in the coming months. I was wondering f you had any thoughts on whether it would be desirable to do either the XMRV testing or the methylation panel first.


  6. bigdreams87


    I really want to get this test done. Is there a way to get it done with out a doctor? I will see if the new Osteopath I am seeing July 1st will let me order through her.
  7. richvank

    richvank Senior Member

    Hi, Wayne.

    XMRV is becoming more interesting, but it may be a while before it is really settled what its role is in CFS, and also before a treatment is available that has had some testing. In view of that, I would suggest doing the methylation pathways panel first, because there is treatment available now for partial methylation cycle block and glutathione depletion.

    Best regards,

  8. richvank

    richvank Senior Member

    Hi, bigdreams.

    This panel requires an order signed by a physician or a chiropracter. Hopefully your new osteopath will be receptive.

    Best regards,

  9. Sparrowhawk

    Sparrowhawk Senior Member

    West Coast USA
    If someone could point me to where on PR there may be results from people who took this test and used it to guide their methylation protocol, I would be most grateful, thanks.

    I gather most folks just do the 23andMe test, run it through genetic genie, and supplement accordingly on a hit or miss basis? I'd prefer to be a bit more guided if my results merit such an approach.
  10. Valentijn

    Valentijn Senior Member

    I've been working on a list of methylation-related SNPs taken from 23andMe results, which is quite a bit larger than the Yasko list and supported by actual research. So far it's just individual lists in entitled "Interesting (gene) Variations", where (gene) is VDR, MTHFR, etc.

    Currently you'd have to search your results manually to find the SNPs, but we should be getting a program online somewhere soon to do it automatically.
    Sparrowhawk likes this.
  11. Helen

    Helen Senior Member

    I am glad to see that you lift this topic that I think is most important when looking for the cause of ME/CFS - and as a guide for treatment.

    Rich told me that he had got more than 200 test reports, Methylation Pathways Panels, from PWME´s, and all but a few showed a blocked methylation. I wish there would be a study with this Methylation Pathways Panel, correlated with SNP´s, preferable MTHFR and MTRR/MTR as they affect the methylation most. Maybe you have seen the seminar that Rich had in Sweden? About 44:42 in the first video part of it he says "that´s the key to the whole thing"

    In this link there are two test reports from globalpilot . I haven´t found more.

    I have done the same testing, but unfortunately I am not able to scan the results and show them in an input. A friend of mine had them done too. We found the testresults very useful as a base for a methylation protocol as our gene tests don´t tell what´s really going on in the body.

    If anyone, who has been diagnosed with ME, that has had a Methylation Pathways Panel done, would post it I think that would be most interesting for a ME researcher interested in methylation. Even more interesting together with SNP`s.

    Maybe someone reading this would start a new thread on this topic? As English isn´t my native language I think someone else would do it much better than me.
    Sparrowhawk likes this.
  12. Sparrowhawk

    Sparrowhawk Senior Member

    West Coast USA
    Wow Helen you are quite fluent if English is not your native language.

    I intend to wait to see what the 23and Me results show, and if I do have those issues then check on current methylation.

    I did watch the entire Sweden lecture last weekend, it was really enlightening. Rich seems to have had a great talent for breaking things down into understandable chunks. Super clarity.
  13. Sparrowhawk

    Sparrowhawk Senior Member

    West Coast USA
    . I look forward to reviewing the thread and to the eventual resource you described that will assist folks to compare their results with your list. What a great resource to provide, well done.
    Valentijn likes this.
  14. pemone

    pemone Senior Member

    Can someone tell me is the Health Diagnostics Methylation pathways panel still considered to be the best test for expression of methylation issues?

    What is cost of this test?

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