CBS Upregulation, Myth or Reality?

Discussion in 'Fibromyalgia Main Forum' started by mrlondon, Jul 15, 2007.

  1. mrlondon

    mrlondon Member

    I've done a bit of reading about CBS upregulation in the medical literature (where it's known as CBS overexpression), and I'm posting my findings here. I've also posted it on the web, with links to the studies at this site:

    Here's the text, without the links:

    Upregulation of the CBS enzyme via two genetic polymorphisms has been theorized to possibly be detrimental to some people with CFS, based on the work by Dr. Amy Yasko in autism. These two polymorphisms were studied in 2000, and in that study, the Post Methionine Load (PML) test was used to determine the effects of the different polymorphism genotypes. That loading test can detect subtle defects in the transsulfuration pathway, which is affected by the CBS enzyme. The polymorphism with the greater effect was 699CàT (Y233Y). The study found that people with the TT (-/-) genotype of that polymorphism, and to a somewhat lesser degree CT, produce lower levels of homocysteine levels in response to the PML test, when compared with the CC genotype. Lower homocysteine levels from that test infers greater CBS activity. About 40% of the population has CC, 40% has CT, and 20% have TT. The other polymorphism, 1080CàT (A360A), was found to have less a significant effect, with the TT genotype only showing a significant decrease in homocysteine, if 2 other polymorphisms were excluded. Thus, 699TT seems to have the greatest affect on CBS activity.

    On the other hand, a similar study in 2003 on these polymoprhisms did not show a significant difference in homocysteine levels due to the different genotypes, in response to the PML test. One difference is that this new study was done on a different ethnic group, which is sometimes a factor in genetic studies. Also, while the mean age was the same in both studies, this new study had a much smaller range of ages, and did not include anyone younger than about 40 years old. This might be a factor, since CBS activity is known to decrease as a person gets older.

    Even more interestingly, is that a study on pregnant women in 2003 surprisingly showed an increase in basal homocysteine levels from the TT genotype, the same genotype that had the lowest homocysteine level in the 2000 study. This study did not give any possible reason for this result.

    In any event, even in positive studies, such as the one from 2000, and a recent one from 2007, only small changes in homocysteine levels have been observed. For example, in the latest study, basal homocysteine levels only differed by 2.7% between the CC and TT genotypes.

    This effect is in contrast to the effect seen in Down’s syndrome, where CBS upregulation is definitely known to occur. In one study on Down's syndrome children, basal homocysteine levels were reduced by 25%, and plasma levels of cystathionine, the product of transsulfuration, was increased by 3.8 fold.

    On the other hand, a later study on Down's syndrome adults did not show decreased homocysteine levels. This surprising result was theorized to be due to the fact that adults have a much lower requirement for folic acid. When folic acid was given to the Down's syndrome children, their homocysteine levels rose significantly.

    Thus, age may become a factor when considering the effects from CBS upregulation. The original claim that CBS upregulation might be a factor for some people with CFS, is based on work by Dr. Yasko , who claims that the CBS polymorphisms can have a significant effect for autistic children. Even if that claim is true, it's possible that it only has relevancy for children. Also, the claim may have no relevancy for CFS, due to other the fact that CFS doesn’t have many of the metabolic disturbances that exist in autism.

    It’s also been claimed that increased urinary taurine and ammonia can help diagnose CBS upregulation. While it's true that CBS upregulation can cause increased taurine and ammonia production, there's no evidence that measuring urinary levels is a proven way to test for this increased production.

    Urinary taurine is unreliable as a test for CBS upregulation, due to fact that urinary taurine is greatly dependent on other factors, such as dietary taurine intake. This likely explains why that even though a study on Down’s syndrome found a significant increase in plasma taurine, another study on Down’s syndrome found that urinary taurine levels were normal. Urinary inorganic sulfur was also not significantly different (which doesn’t confirm Dr. Yasko’s prediction of excess sulfur byproducts) . On the other hand, urinary thiosulfate was significantly increased. Thiosulfate is a metabolite of hydrogen sulfide, and CBS is one of only three enzymes known to be able to produce hydrogen sulfide, indicating that significant CBS upregulation was likely was occurring.

    Urinary ammonia is an even less reliable method for testing for CBS upregulation. This is because most of the ammonia in urine is produced by the kidneys for ph regulation. The ammonia that is produced in the body, is usually first converted to urea, before being excreted. This process mainly occurs in the liver, and it is quite capable of handling a large amount of ammonia. The liver has to have this ability, as it has to be able to detoxify the large amount of ammonia which is created in the body from the metabolization of amino acids. Excess ammonia, i.e., hyperammonia, only usually occurs either when liver functioning has been greatly reduced, or where a genetic defect in the urea cycle exists. Only by testing serum ammonia, can such a condition be diagnosed.

    In conclusion, the medical literature states that the CBS polymorphisms which supposedly cause CBS upregulation, have only very mild effects. There is no evidence that they can significantly cause any negative effects, such as overproduction of ammonia. And the medical literature doesn’t support the claim that elevated levels of urinary ammonia or taurine is indicative of CBS upregulation.

    Dr. Yasko claims that CBS upregulation can lead to “a lack of glutathione.” However, while glutathione is reduced in Down's syndrome, medical researchers do not believe that this is due to the CBS upregulation. Instead, they believe it is due to the overexpression of the superoxide dismutase (SOD) gene, which also occurs in Down's syndrome: “The reduced plasma glutathione observed in the children with DS most likely reflects an adaptive antioxidant response to chronic oxidative stress, resulting from SOD overexpression.” This conclusion is possibly confirmed by a lab study on CBS overexpression in mice, where even though homocysteine levels were significantly reduced by the CBS upregulation, gluathione levels were unchanged.

    Thus, while some of the aspects of Dr. Yasko’s treatment plan may have usefulness, we do not see support for her theories on CBS upregulation.
  2. SnooZQ

    SnooZQ New Member

    Thank you for this interesting & thought-provoking post. I found and read the your web posting of this article. I found your presentation to be reasonable & well-documented, professional in tone, without needing to resort to personal attack.

    Thank you for going to the trouble to make your scientific analysis comprehensible to the lay reader. I very much appreciated those functioning links embedded within the webtext, that bring up the research abstracts relevant to the points you are making.

    Yasko does make some mention of SOD & other oxidative stress issues, in her DVDs (recorded talks) at least. The ox stress issues are mentioned, if memory serves, linking in to her overall hypothesis in a peripheral fashion.

    I do not have enough scientific background to fully evaluate the merits of Yasko's hypothesis. As you have said, there are questions about extrapolating findings in autism to findings in CFS. I would guess those same questions might be asked in regard to research on the Down's population, extrapolated to CFS.

    Whether or not Amy Yasko is completely correct in each point of her theory, I think her biggest contribution has been one of education & marketing. If nothing else, lay readers are rocked by the complexity of what she tries to get across ... and she is just skimming the surface.

    I think it is also productive to get hypotheses out there for discussion, with potential for validation. Is this not part of the nature of scientific & medical progress?

    Best wishes. [This Message was Edited on 07/17/2007]
  3. Diva55

    Diva55 New Member

    Perhaps you can update your profile with your background so we can see what interest you have in this site.

    I've noticed your postings on other FM sites and it would appear that you like to act as a "myth buster" for many treatments.

    However, I'm not saying that the information on this thread is a "myth" as I find any information on the full protocol interesting.

    I don't see that you have posted this infomation on CFS_Yasko group where most people are doing the full protocol? I may have missed it.
  4. SnooZQ

    SnooZQ New Member

    a scientific hypothesis is questioned, does not mean it is entirely devoid of credibility. The fact that Mrlondon went to the trouble to rebut, in professional fashion, one point of the Yasko Hypothesis, is a sort of backward compliment to Yasko.

    A theory can fail in one point, yet still be an important contribution to the body of knowledge. The history of scientific progress is riddled with serendipitous discoveries that occur while pursuing some line of reasoning later found to have been erroneous (which I'm not saying the YH is, as a whole).

    Sometimes a treatment works, and it isn't really understood why. Or there is an explanation that is supplanted later on by a better explanation.

    I didn't take Mr London's post as a reason to throw the baby out with the bathwater.

    Ya never know when you're gonna trip over black gold while huntin' 'possum in the back 40. (ref. Beverly Hillbillies)
  5. woofmom

    woofmom New Member

    And some believed that cigarettes, asbestos, ddt, viox, etc. weren't harmful. Just because the FDA said so.
  6. mrlondon

    mrlondon Member

    Hi - I updated my profile, as someone suggested.

    Dr. Yasko's research has many aspects to it, so it's not surprising that some mistakes were made along the way. Most treatments have some flaw or another, that are eventually corrected. I believe that her using the urinary ammonia test like she is doing, is one such flaw. I'm not the only person who thinks this way. See the post by rlneub on this page:

    I think it's important to either prove or disprove the ammonia and CBS upregulation theories, because people whose autistic children have this problem, are told that they need to use the Ammonia Support supplement, which is extremely expensive, and I've found some parents complaining about the cost. This is what really led me to post my message. - Mark
  7. deliarose

    deliarose New Member

    I welcome your work Mark.

    Every CFS treatment is experimental at this stage, and I think we have to keep open minds.

    And frankly I would be happy to hear that ammonia is not an issue for adults on this protocol, because I'm on the protocol, I have the CBS upregulation, (dunno if I am producing too much ammonia) but I sure as hell don't want to have to deal with this problem!

  8. aaron_c

    aaron_c Member


    I realize this is quite old, but... I recently read the well-researched bit that you posted above, and as someone with ME who is homozygous for the CBS C699T snp, I am quite interested what you had to say. Has there been any further discussion between yourself and Amy Yasko? It seems more like the beginning of a conversation than an ending (I hope!).

    I am particularly interested in the light of Rich Van Konynenburg's findings that seemed to support Yasko's assertion for people with ME. (I believe he mentions this in the second of his "Sweden" videos, but unfortunately I cannot find the paper that he published with Dr. Neil Nathan.)

    I would greatly appreciate any light you might be willing to shed on this issue.

    Thank you so much,

    Aaron C