First, at least for me [Cort Johnson], 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
- 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.
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.
Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. (I’ve included the study itself below this article)
The researchers zeroed in 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.
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.
Mast cells have often been implicated in certain functional disorders; however,
- our patients did not have evidence of clonal mast cell disease or evidence of mast cell activation,
- many did have connective tissue manifestations overlapping with those seen in EDS III.
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.
Extra Sequences Spell Trouble
Further testing found that individuals containing multiple copies of a tryptase encoding sequence were highly, highly likely (p<.000001) to have high tryptase levels.
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.).
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.
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.
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 Heads” 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’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
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.
This is true of most incurable chronic and often painful chronic illnesses, conditions, or syndromes.
Next up for this group: developing a diagnostic test to detect alpha tryptase gene copies and finding ways to block tryptase production.
The study mentioned above:
Elevated basal serum tryptase levels are present in 4–6% of the general population, but the cause and relevance of such increases are unknown.
Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including
- cutaneous flushing and pruritus,
- functional gastrointestinal symptoms,
- chronic pain, and
- connective tissue abnormalities, including joint hypermobility.
Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints.
Individuals harboring alleles encoding three copies of α-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect.
Further, we found in two additional cohorts (172 individuals) that elevated basal serum tryptase levels were exclusively associated with duplication of α-tryptase–encoding sequence in TPSAB1, and affected individuals reported symptom complexes seen in our initial familial cohort.
Thus, our findings link duplications in TPSAB1 with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia.
Information from the NIH:
What is tryptase?
Tryptase is a pro/tein that can circulate in your bloodstream.
It is made primarily by cells that are present around blood vessels and in the bone marrow called mast cells, and it is used largely as a marker for mast cell activation, as it can be easily measured by a blood test, especially after certain allergic reactions.
What is a mast cell and what does it do?
A mast cell is a cell that is made in the bone marrow and is associated with allergic reactions; it matures in places like the skin, lungs, and gastrointestinal tract.
Mast cells may play a role in protecting us from parasites but also can contribute to allergic responses by releasing molecules such as histamine in response to allergens.
How do I know if I have hereditary alpha tryptasemia, or hereditary alpha tryptasemia syndrome?
Several features that may be shared among those who have hereditary alpha tryptasemia syndrome are multiple symptoms affecting a variety of systems including (but not limited to) these:
- Chronic skin flushing, itching, or hives
- Bee sting allergy
- Dizziness and/or difficulty maintaining a normal pulse and blood pressure, sometimes diagnosed as dysautonomia or postural orthostatic tachycardia syndrome (POTS)
- Chronic head, back, and joint pain
- Hypermobile joints, scoliosis, retained primary teeth or other skeletal abnormalities, sometimes diagnosed as Ehlers-Danlos syndrome, Type III, hypermobile type
- GI disturbances including heartburn, IBS, and numerous food and drug reactions and intolerances
- Anxiety, depression, and/or behavioral disturbances
Is hereditary alpha tryptasemia syndrome a form of mast cell activation syndrome (MCAS)?
This is an area of ongoing research. It is not clear the extent to which activated mast cells contribute to this disease, nor whether mast cell activation plays any role in symptoms
What happens if my tryptase level is normal, but I have these symptoms and/or so do multiple other family members?
There are many people who do not have hereditary alpha tryptasemia syndrome but do have all of the symptoms listed above. We do not know yet the association, but this is an area of active research.
How can I get tested for hereditary alpha tryptasemia syndrome?
Patients who suspect they may have hereditary alpha tryptasemia syndrome should first have a baseline blood tryptase test drawn by their doctor, if they haven’t already.
Will being tested positive for hereditary alpha tryptasemia change how my symptoms and disease are managed?
Right now, the answer is no.
How can I get treated for hereditary alpha tryptasemia syndrome?
Until therapies directly related to the genetic change are discovered, symptoms are treated individually.