Editor’s Note: This post was reviewed and updated on 7/29/19. Thank you.
Meet hereditary-a tryptasemia. Never heard of it? That’s because it’s brand-spanking-new, birthed by a group of NIH researchers studying families with multiple members who are afflicted with common health problems. What is hereditary-a tryptasemia? Quite likely, it is the disease currently labeled by its symptoms rather than what the scientists who discovered hereditary-a tryptasemia now believe to be the cause of them all, such as ME/CFS, EDS-H, FM, MCAS, POTS, IBS, MCS, IBS, dysautonomia, intersticial cystitis, and more.
One Gene Many Disorders: Genetic Finding Could Help Explain POTS, EDS, IBS, FM, ME/CFS and Others
Written and posted by Cort Johnson on Phoenix Rising
First, at least for me, there was chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM). Then I learned about irritable bowel syndrome (IBS), then POTS and in the last five years Ehler’s-Danlos (EDS) and Mast Cell Activation Syndrome (MCAS).
The more researchers looked the more they seemed to uncover a large group of syndromes which tended to flock together. Anyone who has ME/CFS or FM now has to consider whether they also might have dysautonomia, IBS, POTS, MCAS and a host of other disorders (interstitial cystitis, migraine, multiple chemical sensitivities, small fiber neuropathy).
Obviously, this suite of disorders is connected somehow, but the question – what is the tie that binds? – has remained. The wide range of symptoms – from flushing to gut problems to chronic pain to orthostatic intolerance to connective tissue problems – had defied understanding – and helped psychologists to get their feet in the door.
Now the NIH of all groups – never really a friend to any of these – may have uncovered a link – that may explain them for some people.
The researchers did what a Simmaron Research Foundation study is currently doing with ME/CFS; they zeroed on a set of families with these problems and studied them intensively. First, increased levels of an immune factor called tryptase which is sometimes associated with mast cell activation showed up. Researchers did not find signs of altered mast cell growth or morphology or increased IgE degranulation or tryptase expression; i.e., they said they found no indication of mastocytosis or mast cell activation disease (MCAS). Despite the high tryptase levels they believed the disease they uncovered was more akin to connective tissue disorders such as Ehlers-Danlos Syndrome (EDS) than MCAS.
Of the 96 people from 35 family’s studies, almost 50% met the criteria for IBS, 65% met the criteria for chronic gastroesophageal reflux, 28% had joint hypermobility, 48% had arthritis, 47% had headache, or body pain, a full quarter had congenital skeletal problems, 46% had autonomic issues and 34% had POTS. Other common issues included flushing and pruritus (51%), itching and sleep disruption (39%) and exaggerated reactions to venom.
Fatigue wasn’t measured but since fatigue is common in all these disorders, it was likely quite high. (Many of these individuals probably would have met the criteria for fibromyalgia or chronic fatigue syndrome (ME/CFS). )
Extra Sequences Spell Trouble
The group’s genetic secrets were not yielded easily. First exome and genome sequencing found no common gene variants but a linkage analysis identified a single “peak” on one chromosome – a section of the chromosome containing the 4 genes responsible for producing tryptase.
Further testing found that individuals containing multiple copies of a tryptase encoding sequence were highly, highly, (highly) likely (p<.000001) to have high tryptase levels. This is the kind of probability that’s probably considered a slam dunk in genetics; everyone who carried multiple copies of this tryptase-producing sequence had high tryptase levels and a wide range of sometimes bizarre symptoms. Plus, the more copies of the copies of the sequence an individual had, the worse they were off symptomatically. None of the family members without these sequences had any symptoms.
Tryptase is the most common enzyme found in mast cells and is often used as a marker for mast cell activation. Interestingly, none of the individuals had evidence of mast cell activation syndrome. If tryptase was causing their symptoms, it was doing so in a different way than is ordinarily associated with MCAS. (MCAS is apparently called a syndrome for a reason.).
After identifying a genetic anomaly associated with high tryptase levels in families it was time to see if it showed up in other groups. A retrospective analysis of people who’d had genomic analyses done for other disorders indicated that all the individuals with increased serum tryptase levels had multiple copies of the tryptase encoding sequence.
Next, the researchers turned to a healthy control group, and again found that all the individuals with increased tryptase levels had multiple copies of the tryptase encoding gene. (Three of the “healthy controls” turned out to have similar symptoms as the original cohort; the rest were either normal or had minor problems).
It’s rare that genetic effects are so clear. In fact, the genetic effects were so clear that the condition is now called hereditary-a tryptasemia. This disease is “exclusively caused” by increased copy numbers of the tryptase-producing sequence.
Exactly how elevated tryptase levels are causing pain and autonomic nervous symptoms is not clear but may involve “protease-activated 2 receptor pathways” (if that’s any help (lol). The study highlights, though, that it’s not necessary to understand a disease to find a treatment for it. Knowing that elevated tryptase levels cause pain, connective tissue problems and orthostatic intolerance, even if we don’t know how, can allow researchers to develop anti-tryptase blockers that could conceivably stop these symptoms in their tracks.
Tryptase can be tested for, and in fact, around five percent of the population, or over 15 million people in the U.S. have high tryptase levels. Most of them are probably asymptomatic but those who are ill could benefit greatly from this finding. It’s very rare to find such a clear genetic link and such a clear treatment pathway.
NIH Admits It Was Not All in Their Head After All
The NIH itself noted that this study should give hope to people with complex multi-system disorders who, too often, have ended up being told their unusual symptoms must be “all in their head”. It was obviously high on this work. It’s not often that a clear cause of an illness – let alone a spectrum of illnesses – may have been found. In fact, the NIH was so excited that it produced a video about the finding, and sent out a press release featuring none other than our old “friend”, Dr. Anthony Fauci, the Director of NIAID.
Chronic fatigue syndrome’s relationship with NIAID and Fauci is a complex one; NIAID is the only Institute to ever fund ME/CFS research centers, but its abandonment of ME/CFS in the early 2000’s ushered in 15 years of declining funding. That obviously didn’t endear anyone to Fauci or NIAID, but now NIAID and NINDS do appear to be doing the lion’s share of the work in the ME/CFS Working Group at the NIH.
Plus, seeing NIAID crow over its genetic finding for a complex multi-symptom condition is a good thing. One of the reasons NIAID abandoned ME/CFS was because it was a complex multi-symptom, multi-systemic condition. The multiple system issue gave NIAID an out; because ME/CFS clearly wasn’t simply an immune disease it decided it was no longer responsible for it. Fifteen years later, ironically, as NIAID begins to welcome ME/CFS back, it has found an immune factor that causes multiple symptoms and produces a multiple system disease.
Next up for this group: developing a diagnostic test to detect alpha tryptase gene copies and finding ways to block tryptase production. For people with extra copies of this gene and who are ill the news is good indeed. Few diseases, after all, can be traced to one factor. Pharmaceutical companies are surely combing their drug databases for drugs with tryptase-inhibiting pathways.
Thanks to The SolveME/CFS Initiative for highlighting this study on their website. Without their doing that, I would have missed it entirely.
To view the original article with comments, go here.
I am absolutely fascinated that Tryptase not only provides a simple solution for the myriad ways in which the body seems to go haywire in these diseases along with their many intersections, but that it also finally explains why these diseases appear so ‘individual’ at the same time; it all depends on the number of extra copies of the tryptase producing sequence a person has as to how that individual will typically react. More copies not only means more symptoms, it can also mean greater severity of symptoms. As many of us have learned from first hand experience however, environment and diet can play a huge role in the health of the individual, as well.
The important thing to me here is that it seems to be becoming clearer to the people who do the research that these diseases are very likely of a single origin which, like many diseases, produces a plethora of symptoms. Of course the hope is that if this is the case, there will be rapid development of effective treatments, too.
Of course there was no mention in this study of two conditions of great import to some in the EDS-H community and how this discovery might effect them; gastroparesis and Cranio-Cervical Instability (CCI) with or without Chiari Malformation (CM). As I’m not a doctor, I can’t speak to this on a professional level, but I have a theory that IBS and gastroparesis are both related to the vagas nerve and if they believe finding a way to block the excess production of tryptase will prevent IBS, it too would prevent gastroparesis and it would be much the same with CCI and resulting CM’s.
However, once you have something like gastroparesis or a CM is it too late? Would such treatments effectively reverse such severe afflictions and damage already done? I don’t think a doctor would even be able to answer this for sure. Likely, it would depend not only on the amount of damage done and overall health of the individual, but it’s rather amazing what the human body is capable of when healthy. I’ve been forced to occasionally marvel at the capabilities of my own highly dysfunctional body.
No matter how you look at it, it seems some very solid hope for the future of millions who have suffered for far too long with too few answers and even less comfort. The validation that this discovery could bring many of us would be some amazing succor in itself.
While this research left many questions, over time more research which supports this theory has come up in the time since this study was released. I did an update exploring these studies and formulating a few theories of my own in Are Most Spoonies Suffering from an MCAD?