Russell Irvin Johnston
10 min readNov 10, 2018

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A solution for most hEDS cases may be coming!
(The TPSAB1 copy number genetic trait discovery)

last edited November 9, 2018
by Russell Johnston

Thanks to a well-publicized 2016 discovery, a very effective treatment or cure for many or most with hEDS may arrive sooner than one might expect. There’s a link to the full paper disclosing the new genetic trait just below, but fair warning, this is a VERY difficult paper to untangle, and every other interpretations of it that I’ve read all got something badly wrong, including the first published version of this paper. So don’t feel you have to read the link. However, I don’t guarantee that my take on it here isn’t still flawed, too.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5397297/
The abstract is here:
https://www.ncbi.nlm.nih.gov/pubmed/27749843

Fastest possible summary: For a large population with hEDS/MCAS the newly discovered TPSAB1 copy number genetic trait is necessary for those illnesses, but not sufficient. That is, most people with the trait are fine.

Two years have passed with little more news re this trait; but that could change radically at any time.

(Note that there are other mechanisms that also “bump up” immune traits:)
https://www.ncbi.nlm.nih.gov/pubmed/26277449

At this point, I should perhaps mention one recent paper that concludes, as I do, here, that it is quite possible that the TPSAB1 copy number genetic trait is not just a minor discovery that will affect just a few people with hEDS:

“Allelic TPSAB1 gene duplication associated with higher basal mast cell tryptase is possibly one of the commonest autosomal dominantly inherited multi‐system diseases affecting the skin, gastrointestinal tract, circulation, musculoskeletal system and affect.”
https://onlinelibrary.wiley.com/doi/abs/10.1111/all.13657

I wanted to slip that quote in, because the most common (and vociferous) feedback to this paper I’ve gotten from this article over nearly two years is that the TPSAB1 copy number trait can’t be very common even in hEDSers (based on a misreading of the original paper, which retails more than one experiment, and rather mushes them together. As I’ve said it’s a very easy paper to misread.) I welcome informed criticism, but please do read this whole paper, first, and please do note the caveats I’ve included.

The second most common kind of comment I’ve received on this paper gives caveats I also give here, as if these will be news to me — they just didn’t bother to read this whole article.

In fact, most of these commenters seem to have read only as far as my “fastest possible summary,” misread that (interpreting “large number” to indicate a percentage, which it doesn’t) and then dropped endless persistent comments all based on that first quick misapprehension. That’s our world now, too often. (I can’t swear I’ve never done the same, but rarely, and no more.)

I suspect the authors of the original 2016 paper revealing the trait are wondering why the whole hEDS world hasn’t gone stark raving bonkers over their discovery, shouting it from the roof-tops and still endlessly discussing it. Of course, the study authors have a lot to lose in the academic community by drawing a line under what they’ve very probably done, and what they’ve made possible. But since I don’t have much to lose, I’m going to provide the following loose summary, as best I can. Brain fog permitting.

First, (most of) what the paper says, in quick, fairly ordinary English:

1) “Elevated basal serum tryptase levels are present in 4–6% of the general population” (this was found in their previous work — note that elevated tryptase is often found with MCAS, but it’s tough to test for accurately except by a researcher.)

2) These scientists studied what I’m going to calling complex hEDS, which has at least MCAS mixed in, and probably POTS, too. Everything they found is all about this group. In their words they studied a group of people with “elevated basal serum tryptase levels and complex clinical features following an autosomal dominant pattern of inheritance without evidence of mastocytosis”. But that isn’t to say that their initial focus was on that patient group. Unfortunately, that can’t be assumed. There is a common, very bad habit in academia of not following narrative order, and instead mixing up the time order to provide a more flattering picture that makes the researchers look more prescient than they were; but also making it very difficult to grasp the actual methodology and probabilities of their discoveries. This paper bears some of the marks of such a “mixmaster” narrative. If true, that helps explain why it is so very difficult to accurately untangle — some of the story, of what evidence led to what further evidence, may actually be missing.

3) If you have complex hEDS with MCAS and probably POTS, you turn out to have multiple-alpha-tryptase genes (in the same DNA strings — so inherited from one parent.) This from a study of 35 affected families. [from earlier reading, hope it’s so: Alpha-tryptase is unusual, most people don’t make this form of tryptase.] This is the first really big news.

(This is a particularly difficult genetic trait to test for (for technical reasons) so your doctor can’t possibly request this test, now, btw.)

4) But (reversing the arrow of inference) does everyone with the multiple-alpha-tryptase genes trait have the disease, hEDS? A resounding NO, it turns out:

5) If you are in that 4–6% of the population with elevated tryptase levels, there turns out to be very roughly a fifty-fifty chance that you have the newly-found genetic trait. Out of roughly one hundred randomly sampled human genomes, 25 had elevated basal serum tryptase levels. Nine lacked sufficient DNA information, but of the remaining 16 people with high tryptase levels, nine had the multiple-alpha-tryptase genetic trait. That’s about half of those with high tryptase levels, and maybe nine percent of the general population.

6) Three of those nine had the full-blown disease of complex hEDS. Six DID NOT. That would translate to roughly one-to-three percent of the population with the trait, and complex hEDS. This matches the current estimate of EDS prevalence (which it perhaps should, since hEDS cases make up by far the bulk of EDS cases.) This gives most of us with hEDS reason to hope that they’ve truly cracked the puzzle of most and perhaps nearly all hEDS cases! Granted, these numbers are derived from an original cohort of only one hundred people (representing, sort of, the general population, I take it) so we can’t take these numbers to be all that precise. Still, so far, so good, hope-wise.

7) To repeat: “Three of those nine (in the general population) had the full-blown disease of complex HEDS. Six DID NOT.” This obviously means that just having this genetic trait doesn’t by itself cause complex hEDS. If maybe nine percent of the general population have the multiple-alpha-tryptase genetic trait — that’s about three or more times as many as have hEDS and certainly far more than have (what I’m calling) complex hEDS. Clearly, something else is going on here, where causation is concerned.

To summarize this point: even though everyone with (what I’m calling) complex hEDS who they studied was found to have the genetic trait, only some of those with the trait (in the general population) turned out to have the (full-blown, anyway) illness of hEDS. So, this newly-found genetic trait appears to be a necessary condition for complex hEDS*, but not a sufficient condition. What else might be going on?

* Note the known rare exceptions of TENX (was classified as HEDS, now removed from hEDS, I believe) and a few other hEDS familial variants traced to single genes. Speculating, one might expect TENX etc, to be permanently kept out of the hEDS basket and treated as a separate subspecies of EDS, if nearly all hEDS has a different genetic signature than TENX.

8) There are two possible explanations of why some people have the trait but not the illness: either more genes are involved that haven’t been tied to the problem yet, or environmental triggers are involved, or both. (Okay, that’s three possibilities, sorta.)

9) The authors hedge, very understandably, but they clearly think that environmental factors/triggers are very possible, perhaps taking effect epigenetically. They clearly have not ruled out additional genes, however. (Seems to me I’ve seen references to twin and identical twin studies that would rule this out, however, leaving environmental factors as the further cause.)

10) The authors mention that this genetic trait is suspected to be located nearby multiple “enhancers and other control elements” in our DNA. Likely, this refers to the fact that not just the TPSAB1 gene is copied, a section of DNA with other fellow-traveller genes is usually copied. Variants in those genes might account for most not having the disease. The first test of this, regarding the CACNA1H gene, showed no such variance of phenotype, however. Something I have now discussed elsewhere. @@ This might also suggest that these genes are especially likely to be affected by environmental variables — both epigenetically and in expression, and perhaps also by mutation. I say this because control elements are very likely to be sensitive even to the immediate environment (say epigenetically) in a way that, say, developmental genes might not need to be.

11) They suggest one possible detailed mechanism for the illness: “On the basis of clinical phenotypes, including pain and connective tissue abnormalities, a compelling case could be made for activation of protease-activated receptor 2 (PAR2)-dependent pathways.” This is a good fit, since those receptors are found where hEDS has its effects; tending to confirm the discovery (in my mind) and increasing the chances of a one-shot cure. If true this allows plenty of opportunity for environmental influence, of course, but other genes could affect these pathways, too. Still, there are a LOT of these receptors, so one is tempted to say that positing such a mechanism doesn’t rule out much.

12) Dose responsive — meaning those with triple copies of alpha-tryptase were worse off than those with just two copies (pretty good evidence, re causation.) This is huge. It should mean that genetic therapy will be more straightforward than could have been the case. A very optimistic example: clip out maybe thirty percent of the extra gene copies via CRISPR, and that patient might be done with hEDS, forever. Animal studies have already successfully cured sickle-cell (genetic) trait using CRISPR — sickle-cell is somewhat similar genetically to the newly-found hEDS trait, but nothing like a one-to-one match.

12) Note that we don’t have to know what the other genes are, or the environmental triggers are, in order to cure the illness (almost certainly.) Those without more than one copy of alpha-tryptase never get complex hEDS, so strip out enough of those genes OR block or antagonize alpha-tryptase in some other way, and you’re done! This leaves a LOT of approaches to a cure, none of which seem awesomely complex. Nor do these cures have to be genetic. Manufacturing auto-immunity to alpha-trptase or blocking tryptase receptors are possible approaches that come to mind easily. Of course, the more we know, the more avenues to a cure there might be. Once upon a time, I had hoped that perhaps we’d already discovered such a treatment — toning down innate immune system function — courtesy worm studies (“Helminthic therapy.”) Unfortunately, the few anecdotal attempts to use helminthic therapy I could find, don’t really support this possibility.

13) It’s well worth looking for that environmental trigger. Presently I’m investigating lack of sunlight/UV as the possible cause. Granted, UV exposure often exacerbates MCAS in the short run (as I confess was still happening in my case, months into my experiment.) But, I am hypothesizing if enough UV light isn’t present, an overgrowth of extracellular bacteria may create a very difficult situation, that extra alpha-tryptase fumbles especially badly.

Note that according to this guess of mine, once extra-cellular bacteria (etc) have built up, any UV exposure would kill so much bacteria that the clean up could make you awfully sick — discouraging further exposure and worsening the illness. Something of an addictive situation, in other words.

It does look like extra-cellular bacteria, not mere lack of sun exposure, is the cause of most Vitamin D deficiencies, for example. One reference re sunlight as therapy; today using sunlight to treat illness is a mostly-abandoned therapy (although there’s a recent higher-tech version called photobiomodulation.) But Theodore Roosevelt used it to overcome an illness that included asthma at a minimum, and he’s not the only one:

“Sunlight has much anecdotal use in ancient scriptures. In the late eighteenth century, Niels Ryberg Finsen pioneered the use of red and blue light to treat various human ailments, especially Lupus vulgaris. He was awarded the Nobel Prize in medicine and physiology in 1903 for his pioneering demonstration that concentrated chemical rays from sunlight could be bactericidal as well as stimulating surrounding tissue.2 Although this seminal work received much attention from physicians and scientists, the lack of mechanistic explanation relegated it non-mainstream medicine. The second major milestone in therapeutic use of light began with the invention of laser technology in the early 1960s.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4390214/

I may be far off in my guesses as to where a cure might lie, of course. But if you have hEDS and think of an environmental trigger you can test, by all means do that, and report back. Research medicine is not particularly good at divining elusive environmental variables (or combinations of them) because there are so many such variables, and testing for all of them would be hella, hella expensive. I think I can say that historically, discoveries of important environmental are more likely to come from observation, including independent patient reports, as well as wide-ranging clinical studies.

November 2018 addition:

I’m continuing UV exposure and have a significant tan by now, and the evidence that melanin is a critical part of the innate immune system continues to accumulate. But no, I haven’t written all those study links up yet. I have reported on my experience with UV and hEDS and MCAS so far, here:

https://medium.com/@russjj/year-two-of-living-dangerously-with-ehlers-danlos-syndrome-and-mcas-e7c1e022655e

As it happens, I’ve now focused more of my attention on a factor I’d overlooked the importance of; as a result I’ve had a couple of remissions this year, but I need at least one more before I’ll be writing that experience down.

Meanwhile, good luck to the genetic searchers, and good luck to the independent, sometimes too-highly-motivated searchers who have hEDS, too.

Next article:
Cannabis for allergies, etc — there’s a risk re viruses;
(and this might be true of antihistamines, too.)

Previous article:
Year Two of Living Dangerously With Ehlers-Danlos Syndrome and MCAS!

Full list of my medical articles:
https://medium.com/@russjj

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Russell Irvin Johnston

I've read at least the abstracts of (far) more than 250,000 peer-reviewed medical articles, I studied the history and philosophy of science at University.