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Multiple copies of the alpha tryptase gene are associated with IBS, hypermobility, POTS, etc

A.B.

Senior Member
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3,780
Scientists at the National Institutes of Health have identified a genetic explanation for a syndrome characterized by multiple frustrating and difficult-to-treat symptoms, including dizziness and lightheadedness, skin flushing and itching, gastrointestinal complaints, chronic pain, and bone and joint problems. Some people who experience these diverse symptoms have elevated levels of tryptase — a protein in the blood often associated with allergic reactions. Multiple copies of the alpha tryptase gene drive these tryptase elevations and may contribute to the symptoms, according to a new study led by investigators at NIH’s National Institute of Allergy and Infectious Diseases (NIAID).

https://www.nih.gov/news-events/new...over-genetic-explanation-frustrating-syndrome
 

Sidereal

Senior Member
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4,856
Affected individuals had multiple comorbid
symptoms, including those often considered ‘functional’ in nature
because of the lack of pathological findings
. Gastrointestinal dys-
motility was common, most often manifesting as irritable bowel
syndrome (IBS), defined by Rome III criteria (49%) or symptoms
of chronic gastroesophageal reflux (65%), with both present at a
prevalence approximately three- to fivefold greater than that in the
general population12,13. Connective tissue abnormalities were also
common; the overall prevalence of joint hypermobility (Beighton ≥
4, ages 12–76 years) was 28% (approximately twice the prevalence
for the general population14), while congenital skeletal abnormali-
ties (26%) and retained primary dentition (21%) were also frequently
identified. These findings were associated with chronic arthralgia
(45%) and headache or body pain (47%). Complaints suggestive of
autonomic dysfunction, including postural orthostatic tachycardia
syndrome (POTS), were common.
Forty-six percent of individuals
had elevated composite autonomic symptom scores by validated
measure (COMPASS 31), of whom 11 (34% of those with elevated
scores) were validated by tilt-table testing (Supplementary Fig. 2a).
Additional symptoms included recurrent cutaneous flushing and
pruritus (51%), which in some cases associated with urticaria,
concomitant with complaints of sleep disruption (39%). Systemic
reaction to stinging insects (for example, Hymenoptera), an occur-
rence known to be associated with elevated basal serum tryptase
levels15, was increased by two- to threefold (16%) over the frequency
of such reactions in the general population16 (Table 1).

Another psychosomatic disorder bites the dust.
 

A.B.

Senior Member
Messages
3,780
Tryptase is secreted by activated mast cells. I wonder if this could explain food and chemical sensitivities.

PS: Wikipedia says mast cells mainly produce beta tryptases, whereas basophils mainly produce alpha tryptase.
 
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Sidereal

Senior Member
Messages
4,856
Tryptase is secreted activated mast cells. I wonder if this could explain food and chemical sensitivities.

PS: Wikipedia says mast cells mainly produce beta tryptases, whereas basophils mainly produce alpha tryptase.

It's an explanation, but not THE explanation. Many people with MCAS have normal tryptase levels. Nonetheless, this is an interesting paper. Seems to be describing the clinical syndrome we've seen anecdotally reported online thousands of times involving the trifecta of joint hypermobility, dysautonomia and MCAS, plus attendant features like migraine and GI disturbance.
 
Tryptase sounds like nasty stuff. Lactoferrin is a potent tryptase inhibitor, btw:

http://www.atsjournals.org/doi/full/10.1164/ajrccm.156.2.9607012
The child in me was amused by this
Wikipedia said:
Lactoferrin (LF), also known as lactotransferrin (LTF), is a multifunctional protein of the transferrin family. Lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa that is widely represented in various secretory fluids, such as milk, saliva, tears, and nasal secretions.
I know where I'd prefer to get it from. Sorry, I'll let the adults continue with the discussion now.. :)
 

Jenny TipsforME

Senior Member
Messages
1,184
Location
Bristol
A couple of questions:

Can I tell if I have these mutations/extra copies from 23andme data? I've had a quick look and drew a blank, but maybe wasn't looking for the right thing.

Lactoferrin sounds interesting anyway. Something I hadn't heard of. I drink that lactofree cows' milk - will the lactoferrin have been taken out with the lactose? /am I likely to react to lactoferrin seeing as I get symptoms from lactose? I don't really fancy getting it from snot!

Does anyone here already take lactoferrin for another reason?
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
But they probably wouldn't be able to handle extra copies anyhow.
My guess is that snp testing is the wrong type of test for this. We are looking at duplicate genes, not gene defects. Such gene duplication is actually common. Indeed, the evolution of grass, if I recall correctly, required four entire genomes be duplicated.

One thing that snp testing might lead to though, if the genes are duplicated, is some copies might be one type, and other copies another type, so you might have multiple different snps, maybe quite a few.
 

taniaaust1

Senior Member
Messages
13,054
Location
Sth Australia
It's an explanation, but not THE explanation. Many people with MCAS have normal tryptase levels. Nonetheless, this is an interesting paper. Seems to be describing the clinical syndrome we've seen anecdotally reported online thousands of times involving the trifecta of joint hypermobility, dysautonomia and MCAS, plus attendant features like migraine and GI disturbance.

nods very interesting paper as Ive believed for a while there is genetic link between mast cell disorders, ME/CFS, Autism and EDS ...mutual genes all crossing over. So this study is a further link in my thoughts of these conditions are all related by genes.

I have the severe ME/CFS, dysautonomia, Autism (aspergers is no longer a diagnoses here) and Im 95% sure some kind of mast cell disorder and have been diagnosed as having a connective tissue disorder but they dont know what exactly.

daughter has EDS (hyper flexible) and Autism and skeletal deformatories, my father has autism

uncle (fathers brother) has systemic mastocytosis (severe mast cell disorder) I think he has dysautonomia too.
that uncles daughter has same ME/CFS symptoms as I do but is without a diagnoses as their family believe she has mast cell disorder. She could easily be given ME/CFS diagnoses
another uncle also has a daughter with ME/CFS

Connective tissue abnormalities were also
common; the overall prevalence of joint hypermobility (Beighton ≥
4, ages 12–76 years) was 28% (approximately twice the prevalence
for the general population14), while congenital skeletal abnormali-
ties (26%)

I do not currently (well didnt last time I was tested and the time before) have elevated trypase. My uncle though when tested for trypase his first 2 tests were normal though his symptoms were severe .. it took 3 tests over time to find an abnormal typase going on (it took his life threatening mast cell issue 10 years for a diagnoses).
 

taniaaust1

Senior Member
Messages
13,054
Location
Sth Australia
It is a standard test for mastocytosis which is a severe disorder quite distinct from MCAS.

I think that many who are getting MCAS diagnoses probably do actually have mastocytosis as it can be very hard to get diagnosed with it and the trypase testing which the doctors usually use to test to see if one can have it can be negative as its been found in my family in member which later turned out to actually have systemic mastocytosis. His first two trypase for it were negative.

He's told me that many with this take many years to get diagnoses and that the trypase test is unreliable for finding it. (the gold standard is bone marrow testing but then even then it can missed if it turns out the sample is in a place where there wasnt as much build up of mast cells).
 

anciendaze

Senior Member
Messages
1,841
I think that many who are getting MCAS diagnoses probably do actually have mastocytosis as it can be very hard to get diagnosed with it and the trypase testing which the doctors usually use to test to see if one can have it can be negative as its been found in my family in member which later turned out to actually have systemic mastocytosis. His first two trypase for it were negative.

He's told me that many with this take many years to get diagnoses and that the trypase test is unreliable for finding it. (the gold standard is bone marrow testing but then even then it can missed if it turns out the sample is in a place where there wasnt as much build up of mast cells).
Mastocytosis involves a runaway process producing mast cells, paralleling runaway production of white blood cells in leukemia. There is no official etiology for mastocytosis.

Nobody knows why mast cells proliferate to life-threatening levels. We do know that nobody with a serious shortage of mast cells has ever been found, indicating these are necessary for life. We also know they are more densely clustered near sensitive tissues like the eyes. Since they cluster around wounds, and appear to play a role in healing, there is some reason to believe they multiply in response to signals indicating damage to healthy tissues.

Without a firm etiology, the question of whether or not proliferation of mast cells has become a runaway process is a subjective call by the doctor. Precautions for emergency personnel are the same for mastocytosis and MCAS, leading some people with MCAS to wear Medic Alert tags for mastocytosis even if the doctor who knows them best does not believe they have excessive numbers of mast cells. (This doesn't stop them from having a higher percentage of active mast cells.)

Until we have some idea of underlying causes the distinction between the two will be somewhat arbitrary.
 

Hutan

Senior Member
Messages
1,099
Location
New Zealand
http://www.prohealth.com/library/showarticle.cfm?libid=29620

A nice write up of the study by Cort.
One Gene, Many Disorders: Could One Gene Help Explain ME/CFS, FM, POTS, IBS, EDS, IBS and Others

One interesting point from the study for me was this:
The high degree of identity between sequences encoding the a-tryptase and b-tryptase isoforms, and the presence of multiple paralogs in a single locus, makes detection of copy number variation difficult, likely precluding genome-wide association studies or quantitative arrays from detecting TPSAB1 copy number variation.

So, I assume massive genome studies like MEGA would not pick up this complex copy number variation which required some special techniques to identify.