NIH scientists identify a genetic disorder that may affect 1 in 20

[Mast cells from a sinus stained in blue. Image via Wikimedia Commons & CC 2.0] 

On July 10, 2010, a DC restauranteur came down with what seemed to be food poisoning. He had no energy and no appetite. Rashes flared up. He could barely get out of bed. First hours and then days dragged by without any relief from the symptoms.

The restauranteur’s family sought out doctor after doctor, until finally they were referred to a lab at the NIH (National Institutes of Health) that studies how allergies pass down through families. 

His symptoms fit a diagnosis of Mast Cell Activation Syndrome, (MCAS)  a disorder where a type of immune cells called mast cells release chemicals that send other immune cells into a destructive frenzy. Ideally, mast cells detect infection and spur other immune cells into action. However, some people’s mast cells have a hair trigger. When mast cells release their chemical contents too often, immune cells end up attacking healthy tissue, causing allergies, stomach issues, and heart palpitations. 

[Above: An NIH-produced video about MCAS and Milner’s research into mast cell activation genetics.] 

Unfortunately, most treatments for MCAS aim at the symptoms, not the root cause.  But the NIH team delved deeper into the genetics and found a pattern:  many MCAS-related symptoms run in families.

And oddly enough, hyperflexible joints, dysautonomia, and baby teeth that fail to fall out also ran in many of those families.  [Correction 6/15: A commenter has pointed out that “hyperflexible” and “hypermobile” are not interchangeable terms. The term “hypermobile” refers to joints that can move outside the typical range of motion due to laxness in ligaments. “Hypermobility” is also sometimes called “double-jointedness.”]  Many of these symptoms skipped generations, only showing up occasionally in individuals, but genetic sequencing revealed the correlation wasn’t coincidence.

In October, NIH scientist Joshua Milner and his team described the  genetic disorder in a paper in Nature Genetics. According to the team’s paper, 4-6% of the U.S. population has the genes that predispose them to this syndrome–which has been tentatively named alpha-tryptasemia or “alpha-T”.

The symptoms can be cryptic and unrelenting: Dizziness, chronic pain, irritable bowels, and fainting. For many patients with these conditions, there’s no explanation and no treatment. “These [symptoms] are really all triggers to get an eyeroll from a doctor,” said Milner. But for a sizeable portion of population, these seemingly unrelated problems might be part of the previously undiscovered genetic disorder.

Unknowingly, patients have been struggling to manage this condition for years without being taken seriously by doctors. The symptoms associated with alpha-tryptasemia are what doctors call “nonspecific” or “unspecific,” meaning they could be caused by just about anything.

The symptoms vary quite a bit person-to-person, making it hard to spot. Often, symptoms are mild enough that people just ignore them or don’t think to mention them on the forms they fill out at the doctor’s office. In some cases, the symptoms don’t flare up until a traumatic event in adulthood, Milner says, based on his conversations with patients.

In addtion to MCAS, some people with hypermobile joints receive diagnoses of Ehler-Danlos Syndrome (Type III), and others who have problems with fainting and dizziness are diagnosed with POTS (Postural Orthostatic Tachycardia Syndrome).  EDS and POTS often occur together, but until recently, the medical research community hadn’t paid much attention.

“Patients are almost universally told, ‘It’s all in your head,’ which is awful,” said Milner.

However,  the genetic analysis revealed that many people with MCAS, EDS-III, POTS, or other unexplained autoimmune problems have duplicate (or even triplicate) copies of gene that codes for a molecule called alpha-tryptase. 

Alpha-tryptase is one of the signalling molecules that mast cells release. Doctors most often test for it when confirming allergic reactions, but tryptase also acts on connnective tissues, mast cells, and blood vessels, Milner says.

“It’s not a marker; it’s the key to ignition,” he added.

Its roles in connective tissue and immune response aren’t the only evidence that alpha-tryptase is the culprit. The gene is located in a stretch of DNA that is particularly prone to copying a section of itself and then pasting the copied DNA back into the chromosome.  As a result, some people end up with two or sometimes three copies of the gene on a single chromosome. The study found that people with more copies of the alpha-tryptase gene tended to have more problems.

In the study, the NIH researchers tested patients, their relatives, and about 200 people from the general population. About 1 in 20 people from the general population sample had elevated tryptase, and interviews revealed that many of those people had symptoms such as chronic pain and unexplained gastrointestinal problems. In many cases, the symptoms were so mild that people simply shrugged them off as signs of stress. 

(And it’s worth noting that many people with genes for alpha-tryptase don’t seem to have major problems with it. The variability in symptoms and their severity is a big part of why the syndome has gone undescribed for so long.)

About a third of people don’t make alpha-tryptase at all. (There are five other forms of tryptase encoded in the human genome.) Since alpha-tryptase appears to be nonessential, it may be possible to target or counteract it in people whose mast cells make too much.

Treatments for alpha-tryptasemia are still years away.

However, Milner says that just knowing there’s a genetic cause behind their mysterious chronic pains comes as a huge relief to patients.  The symptoms of alpha-tryptasemia aren’t life-threatening but they’re chronic, untreatable, disruptive, and frustrating.  As the number of symptoms mounts, patients become more overwhelmed, and all the while, doctors keep telling them there’s no explanation and nothing that can be done. 

When you tell people, there’s a genetic disorder behind a lot of this, patients usually start crying when they hear that, because they feel validated,” Milner said.



  1. Murray Meetze

    Joints in EDS aren’t “overly flexible,” they’re hypermobile. Muscles are flexible, joints have extra mobility due to lax connective tissue. This article needs to correct that point. Hypermobility and flexibility are not interchangeable terms.

    1. Post
      Diana Crow

      Ok. Added a correction in the 5th paragraph (2nd below the NIH video) and changed the other mention from “overly flexible” to “hypermobile.” Hope that is satisfactory.

  2. Michele

    Wow, this article is the best description of MCAS I’ve ever read. It’s a perfect explanation of life with mast cell activation syndrome.

  3. Nikki

    What an excellent article…the mcas, pots, eds combination is horrific …good to know that scientists are pushing forward

  4. Erin Fraser

    Symptoms can be life-threatening if the airway is involved in an anaphylactic reaction resulting from this disorder.

  5. Christi

    I agree with Erin, there are many people, including my daughter that experience atypical anaphylaxis from mcas.

    1. Tracie

      My daughter experiences the same thing. We were part of the study with the NIH and found out that she has 3 copies of the TPSAB1 gene, which is why she has the most symptoms. My oldest daughter and husband have duplicate copies. She was just in the hospital 2 weeks ago with rebounding anaphylaxis and we still don’t know what the trigger was. We usually don’t. This disease is incredibly frustrating and so hard to watch. This article does a really good job of explaining mast cell disease in a way that is easily understood. Have you found anything that helps your daughter?

  6. Jeannine Cline

    How does a person get genetically checked for alpha-tryptase? Are there any research studies involving alpha-tryptase ? Is there a way to find a list of doctors who treat it? Thank you

    1. Post
      1. Aidan

        I had the tryptase test done in the UK it came back at 10 only but it can be elevated at other times. Anything over 8 Milner did say is highly likely multiple copies of tryptase the tryptase level used is actually just a cut-off point it is not a definitive test as it really has no level…

        1. Meagan

          This is a great article, thank you!!
          I spoke with an immunologist who began mast cell stabilizers, clearly having EDS, she said the tryptase test is often not reliable indicator for those with EDS.

  7. Dorothy

    yes Good Article, important to note Aidan’s comment that tryptase level might only be elevated during a specific histamine event. So just checking a current tryptase level when the body is calm won’t be sufficient. Need to check it during the histamine event. Alpha Tryptasemia is being researched even by Dr Lawrence Afrin regarding TPSAB1. However more articles are needed to see if it can also be linked to a gene called FUT2+/+ rs 601338 non secretor which can cause increased LPS and IL4 cytokine expression.

  8. mark

    I don’t think this applies to everyone who has mast cell activation, because many do not have genetics to point the finger at, and don’t have hypermobile joints either. There is a difference between mystocytosis and mast cell activation connected to a specific event that might occur only once after a lifetime of having none of these symptoms.

  9. Talk Hay Fever

    I often look around the internet these days looking help to my alergies. I like to research about new ideas, things that I may not have tried before. I really loved reading the posts on your site. Thank you for sharing.

  10. Dana

    I just received test results confirming the existence of the single extra copy of alpha-tryptase I’ve been carrying around. It’s wonderful to have validation for what I’ve been going through, given all of the flack I’ve taken from some of my lousy doctors. Living in this body ain’t easy.

    Thank you for the article, Diana!

  11. Adonnya

    I just sent my gene kit to GenebyGene. They test for hATS. It not covered by insurance and costs $165, but if it tells me why I go into analphalaxis, I will be happy.

    1. Post
      Diana Crow

      I don’t know. They’re different molecules. I’m going to have to punt this one to someone with a better understanding of biochemical naming systems.

Leave a Reply

Your email address will not be published. Required fields are marked *

Website Protected by Spam Master