subtr4ct

Update: We have had some nice progress. In a my last big post on Feb 22, I stated that I beleived the key to solving my wife's problems was determing why her adenosine is elevated (presumably -- although I am following up on the possibility of measuring it directly). Well, after seeing a DAN! (Defeat Autism Now!) doctor who ran a very large number of tests (finally! A doctor who does not take a painfully slow incrementalist approach) we have a couple of interesting new results. First, her urine metabolites of serotonin are unusually low. More importantly, I beleive, we have discoverd that she has seriously elevated antibodies to candida albicans. She has a concentration of IgG specific to candida albicans (in a 1:100 dilution of her blood) of about 55 ug/ml -- this number should be less than 1. Positive results are categorized by the lab (Commonwealth Medical Labs) as levels I,II,III, and IV, with any reading above 30 ug/ml falling into the IV category. So she is not only in the most serious category, she is there by a wide margin. This result, combined with her serious GI issues, suggests that a serious intestinal infection/over-growth of candida albicans could be the root problem. This is a somewhat controversial subject that many physicians do not presently accept. However, candidia albicans produces adenosine, at least in vitro [5]. So it doesn't seem like a stretch to believe that a serious candida albicans overgrowth could be causing the elevated adenosine, unusually low homocysteine, and methylation problems. Apparently, candida overgrowth can also cause increased intestinal permeability (again, a somewhat controverisal idea) as rhizoids from the fungus pucture the intestines. This leads to larger-than-desired molecules of partially digested food escaping the instestines (e.g. opioid peptides from gluten and casein), causing all kinds of problems, one of which is speculated to be brain inflamation. About a 1.5 months ago, she started on a gluten and casein-free diet, and started taking a high quality broad-spectrum digestive enzyme before each meal (Kirkman's EnZym Complete II with DPP-IV). This is intended to do a lot of digesting while the food is in the stomach, so fewer large food particles reach the intestines to begin with. These efforts have resulted in a tremendous improvement in her previously severe irritability and anxiety. Recently, we temporarily ran out of the enzymes, which quickly resulted in a return of the irritability and anxiety, and it just as quickly disappeared again upon resumption of the enzymes. We have also begun various anti-fungal measures, and it seems like we are just starting to see a slight improvement in her orhtostatic tachycardia (less beeping from the Polar watch, lower daily average heart rates). She is feeling better and having more energy. Hopefully I can report more improvement soon, and it will be very interesting to re-measure the homocysteine a couple of months down the road. best reagrds to all, subtr4ct new refernce: [5] http://www.ncbi.nlm.nih.gov/pubmed/1316920

I was jsut relaying the results reported by autism researchers in [3].

doctorguest: Thanks for the input! It is especially good to know that a hematologist is the appropriate variety of specialist for this type of issue. I agree that there clearly has not been a relationship between low homocysteine and POTS established. But there seems to be numerous anecdotes in this forum of POTS improving upon specialized B vitamin supplementation (e.g., the experience of "Old Lady Lighthead", who reports her condition improved when she brought her elevated homocysteine under control). Considering these anecdotes, and the results of Esler et al. regarding disturbed DNA methylation... Unfortunately people who are extremely ill and not realizing significant relief from symptom management strategies cannot wait for conclusive evidence. Can I safely infer from your post that you agree a plasma homocysteine of 3.3 umol/L should be considered a serious cause for concern? Perhaps we might agree on the appropriate short-run objectives of treatment in such a case, regardless of the strength of the evidence for a connection with POTS? Thanks again; I have learned a lot from your contributions to discussions in numerous threads here.

Lina: Thanks! See also my PM to you. Update: We added SAMe (400mg 1X/day) to the program, and took a new sample for plasma homocysteine about 9 days later (a total of almost two months after starting our overall efforts to improve her methylation status). Despite the fact that we have been shoveling methyl donors down her throat, her plasma homocysteine managed to go down slightly to 3.3 umol/L. Aaaarrrgghhh! I have become convinced that the same metabolic issues at work in the autistic children are at work here (reference [3] above). Specifically, high adenosine is impairing the SAH to homocysteine conversion. Adenosine is the other product of the SAH to homocysteine reaction, and elevated levels of either product (homocysteine or adenosine) are powerful inhibitors of this reaction. This eventually results in numerous problems due to impaired methylation capacity. This is somewhat speculative, however, as I don't know of an easy way to measure adenosine. Simplified problem overview: ??? --> elevated adenosine (presumed, based on available evidence and reference [3] above) --> impaired SAH to homocysteine conversion, low homocysteine --> low methionine, low SAM, impaired methylation capacity --> disturbed DNA methylation (presumed based on available evidence and [1]), extensive neurological problems (POTS, PMDD, IBS) What are the possible causes of elevated adenosine? What can be done to correct elevated adenosine? These are the issues I'm looking into now. Any ideas or comments greatly appreciated! subtr4ct

Greetings, I apologize in advance for the length of this post. In addition to wanting others' feedback/opinions/advice, I thought the info about this (atypical?) case might be helpful to someone else some day, just as I have found other posts here to be helpful. My wife has been diagnosed with POTS, with no neuropathy and onset in her fourth decade (i.e., she does not have the NET gene polymorphism). She has gone from basically normal to significantly disabled over the course of the last two years or so. She has most of the typical POTS symptoms, and a few others that I gather are not necessarily typical: A. marked irritability, with conditions of mild stress sometimes provoking episodes of rage, especially during the premenstrual period B. somewhat elevated iron status, despite not being a homozygote either of the two predominant hemochromatosis polymorphisms C. elevated IGF-1, with MRI being negative for pituitary adenoma D. adrenal fatigue E. mildly disturbed gonadotropin levels, estrogen dominance, polycystic ovaries (as revealed by laparoscopy) Given the results of Esler et al. [1], I believe that her case is likely due to epigenetic silencing of the NET gene. This inspired me to learn all I could about DNA methylation and the methionine cycle, with [2] being particularly informative. We were also compelled to measure her plasma homocysteine, which came out as 3.4 umol/L. I gather that plasma homocysteine should be about 7.5 umol/L, plus or minus 1 or 2 umol/L. The distribution is positively skewed, so readings 4 umol/L below 7.5 are less likely than reading 4 umol/L above 7.5. Apparently these measurements vary across labs, but from what I have read she may be below the 1st percentile of the distribution. Conditions of unusually low homocysteine seem to be barely on the radar of the medical profession. Exceptions are an extremely rare congenital condition that results in death in the first year of life (I forget the name), and autistic children, as described in [3]. The average plasma homocysteine for the children in that study was 5.8 umol/L, with the lowest among them being 4.0 umol/L. I am wondering if, like those autistic children, my wife has a decreased ability to cope with oxidative stress and impaired methylation capacity. More specifically, I wonder if there is a vicious cycle at work: orthostatic tachycardia --> chronically high aerobic energy production --> chronically high oxidative stress --> chronically high need for glutathione production and/or impaired adenosine to ATP conversion --> low homocysteine --> low SAM levels, impaired methylation capacity --> epigenetic silencing of the NET gene (altered expression of other genes as well?) --> orthostatic tachycardia --> ... A mysterious aspect of this is the cause of the low homocysteine. Is it low because so much of it is being transulfurated for cysteine (and eventually glutathione) production? Or is it low because high levels of adenosine, the other product of the SAH to homocysteine reaction, are suppressing homocysteine production? For the autistic children, [3] offers the latter explanation. But who knows for POTS? Our actions so far since discovering this about her homocysteine: I) bedrest -- this is to minimize tachycardia, aerobic energy production, and oxidative stress II) folinic acid, sub-lingual methyl-B12, and trimethylglyceine supplementation -- these are to encourage transmethylation of homocysteine and increase methionine levels III) n-acetyl-cysteine supplementation -- to increase glutathione levels and reduce the need for transsulfuration of homocysteine IV) weaning off of methyl predinsolone. Corticosteriods modulate the transulfuration of homocysteine [2]. With the exception of an initial boost, it wasn't really helping anyway. V) glutamine supplementation -- enhances gut production of glutathione VI) creatine supplementation -- this is intended to free up more SAM for methylation reactions other than creatine production. From [2]: "Creatine synthesis significantly influences the SAM/SAH ratio as it represents the bulk of SAM consumption... If a pathalogical condition is being worsened owing to competition of DNMTs with numerous other methyl transfer pathways as well as the inhibitory effects of SAH, lightening the burden of creatine synthesis may well have ameliorating effects." Also, this should help support intracellular energy levels and functioning if the adenosine to ATP pathway is impaired by oxidative stress [4]. After a month and a half on this program, her mood and energy levels have improved somewhat, although the potential for rage episodes persists especially during the premenstrual week. Heart rate increments are as bad as ever (she can sometimes run up to 150+ bpm after 15 or 20 minutes of standing). We have only just finally gotten completely off of the methyl prednisolone (which was very difficult). Hopefully more improvement is forthcoming. Questions for others here: Q1) Has anyone here been identified as having unusually low homocysteine? If so, what remedial action was taken? Q2) Any idea what type of specialist would recognize unusually low homocysteine as a problem? Better still, does anyone know of a doctor that would listen to me and seriously consider all of this (rather than just resigning us to symptom management)? We would happily travel. Thanks for reading, and thanks for any input or suggestions! References: [1] http://www.ncbi.nlm.nih.gov/sites/entrez?D...Search=16785272 [2] http://www.ncbi.nlm.nih.gov/sites/entrez?D...Search=15809266 [3] http://www.ncbi.nlm.nih.gov/sites/entrez?D...Search=15585776 [4] http://www.healingpediatrics.com/articles/...20oxidation.ppt