Tryptase Copy Number Variation Testing

Tryptase is a protein 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. 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.

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.

Hereditary alpha tryptasemia can be called a biochemical trait. A trait is simply a characteristic that is caused by a difference in the DNA. In the case of hereditary alpha tryptasemia, people with this trait have inherited extra copies of the alpha tryptase gene (TPSAB1), and this leads to increased levels of tryptase protein detected in the blood, whether a reaction is happening or not.

These duplications are carried on a single chromosome and can be inherited from parent to child. In some cases, both parents can carry the duplication, so that a child could have four copies. In other cases, patients actually carry three copies of TPSAB1 on a single chromosome. It appears that the more copies one inherits, the higher the blood tryptase level.

Elevated serum tryptase is present in perhaps up to 6 percent of the general population. While large studies of multiple different ethnicities need to be done, the estimate is that hereditary alpha tryptasemia may be present in a similar percentage of the general population.

Since that means that there could be millions of people carrying multiple copies of the alpha tryptase gene, it should come as no surprise that some people will have more than one explanation for their symptoms. Again, it must be stressed that there is great variability from person to person in terms of what symptoms the duplications or triplications do or do not cause.

In addition to having higher blood tryptase levels, individuals with more alpha tryptase copies also report more shared symptoms. These symptoms can be associated with multiple organ systems and may be hard to explain. These symptoms may include allergic-like symptoms such as skin itching, flushing, hives, and even anaphylaxis; gastrointestinal (GI) symptoms such as bloating, abdominal pain, diarrhea and/or constipation (frequently diagnosed as irritable bowel syndrome or IBS), heartburn, reflux, and difficulty swallowing; connective tissue symptoms such as hypermobile joints and scoliosis; cardiac symptoms such as a racing or pounding heartbeat or blood pressure swings sometimes with fainting; as well as anxiety, depression, chronic pain, panic attacks, and others.

These patients may find that others in their family have similar or related symptoms, as this is a genetic syndrome. Others may have few if any symptoms—and would be said only to have the trait and not the syndrome associated with the trait. In cases such as these, a person may only find out because a relative was more severely affected with the syndrome.

If you have a blood tryptase level above 10 ng/mL, in particular if another close relative also has a similarly elevated level, you are more likely to have hereditary alpha tryptasemia. However, a wide range of symptoms has been reported among individuals with the associated syndrome, many of which can be rather common, so it is difficult to know who has it from symptoms alone. 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

Because some people who carry the extra alpha tryptase gene copies exhibit few if any of these symptoms, we are working to determine just how common each is in people who have hereditary alpha tryptasemia, and we are studying what percentage of patients from the general population who have individual diagnoses — such as bee sting allergy, Ehlers-Danlos syndrome, or POTS —also have hereditary alpha tryptasemia.

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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. There are many similarities between patients who have been diagnosed with MCAS and those who have hereditary alpha tryptasemia syndrome. Whether hereditary alpha tryptasemia syndrome could be present in a subset of patients with MCAS is not yet known.

It is also possible that the increased tryptase itself causes the symptoms without requiring mast cells to be activated, or it could cause an abnormally increased response to otherwise normal mast cell activation, which might explain why so many patients respond to medications that target mast cells and substances released by mast cells.

There are many people who do not have hereditary alpha tryptasemia syndrome but who do have all of the symptoms listed above.

Patients who suspect that they may have hereditary alpha tryptasemia syndrome should first have a baseline blood tryptase test drawn by their doctor if they haven’t already. It should not be drawn immediately after a major allergic reaction, as that can lead to an elevated tryptase for a different reason. A serum level greater than 10 ng/ml is suggestive of alpha tryptasemia, while a level lower than 8ng/ml makes this diagnosis far less likely.

There is no commercially available test for the genetic duplication, and it cannot be identified through usual genetic testing including microarrays, whole exome sequencing, or whole genome sequencing. The research-based test that can diagnose alpha tryptasemia is under development.

Right now, the answer is no. Symptomatic treatment targeting individual symptoms is the only route for management at present. Future research will be dedicated to identifying symptoms and populations commonly associated with hereditary alpha tryptasemia and finding a treatment that specifically targets alpha tryptase and its mechanisms of action to better advise and manage those who carry multiple alpha genes.

Again, we do not yet have the answer. If your doctor suspects mastocytosis, the same tests and workup for this rare but serious disease should be performed according to published guidelines and recommendations.

While the course of symptoms can be quite variable over time and we do not know the natural history of this disease, we at present have no reason to suspect those with multiple alpha alleles will have a shortened life span. This disorder has likely been present for many generations within specific families, and, while our judgment is only based on the patients we have seen, having multiple alpha alleles appears compatible with long, productive lives.

Until therapies directly related to the genetic change are discovered, symptoms are treated individually. Because tryptase is made by mast cells, and many symptoms seen among individuals with the hereditary alpha tryptasemia syndrome have been associated with the release of mast cell-derived mediators such as histamine, several of the clinical approaches used to treat the results of mast cell activation including antihistamines may be used and often are helpful.

These approaches should be discussed with your doctor. Treatment usually requires trial and error and a lot of patience. Also, treatment may only be partially successful, but unfortunately, there are no randomized clinical trials yet to show definitive treatments that work for hereditary alpha tryptasemia syndrome.

CNV stands for Copy Number Variation. In most cases, a normal individual will have two copies of a gene – one inherited from their mother and one inherited from their father. In some cases, having more or less copies of a gene has detrimental effects on an individual. CNV testing measures the number of copies an individual has and can determine if there is a deletion (less than 2 copies) or a duplication (more than 2 copies).

A duplication is one additional copy of a gene, while a triplication is two additional copies of a gene.

Scroll to the bottom of this page and fill in the patient form. We will contact your doctor and give then information about the test.

No, a Serum Tryptase Test is a blood test that is based on your reactive state and it is also a pre-qualifier (for those that score 8 or higher) to taking the Tryptase Copy Number Variation Test.