Hereditary alpha tryptasemia (HαT)

HαT is common and has been found to be present in approximately 5% of people in Western Europe and the United States. HαT is caused by extra inherited copies of the gene TPSAB1 that makes extra α-tryptase and leads to high tryptase in peripheral blood at baseline. As many as 2 out of 3 individuals with HαT are believed to have few if any symptoms that would lead to them being diagnosed with this genetic trait.

Jonathan J. Lyons, MD

Affiliations: Translational Allergic Immunopathology Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.

Funding statement: This research was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, NIH. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

Quick Facts about HαT:

• HαT is common and has been found to be present in approximately 5% of people in Western Europe and the United States.
• HαT is caused by extra inherited copies of the gene TPSAB1 that makes extra α-tryptase and leads to high tryptase in peripheral blood at baseline.
• If you have HαT, there is a 50% chance your children will inherit HαT.
• An estimated 90% of individuals in the general population with increased baseline serum tryptase (BST) levels have HαT.
• While certain tryptases stored inside mast cells is believed to contribute to allergy symptoms, the version of tryptase (pro-tryptases) that can be detected in people regularly at baseline – and that is elevated in HαT – has no known function in human health or disease.
• Many symptoms have been associated with HαT, but it is difficult to prove that symptoms are caused, or even contributed to, by HαT because it is so common.
• As many as 2 out of 3 individuals with HαT are believed to have few if any symptoms that would lead to them being diagnosed with this genetic trait.
• HαT has been shown to increase the frequency and/or severity of anaphylaxis in specific settings including following certain insect stings and in patients without identifiable causes for anaphylaxis (idiopathic) and/or the clonal mast cell disease systemic mastocytosis (SM).
• A small increase in the number of mast cells in bone marrow and the lining of the GI tract has been consistently shown among symptomatic individuals with HαT.
• Patients with SM are more likely to have HαT compared to the general population, but this may result from an increase in symptoms seen in patients that have both SM and HαT.
• HαT does not appear to be a risk factor for classical irritable bowel syndrome (IBS) but does appear to modify some of the symptoms in patients with this disorder.

What We Know

Hereditary alpha-tryptasemia (HαT) is a common genetic trait

In clinical genetics, a trait is a characteristic of an individual that may be inherited genetically, acquired from the environment, or result from an interaction between individual genetics and environmental exposures. Hereditary alpha-tryptasemia (HαT) is a common genetic trait that affects approximately 5% of populations in which it has been studied – that to date have been predominantly Caucasian. The genetic change responsible for HαT is one or more extra copies of the TPSAB1 gene encoding the protein α-tryptase. This kind of change is considered a structural variant as there is a change in the number of copies of a gene, rather than in the genetic sequence itself. HαT is inherited in a dominant manner, meaning that receiving one extra copy from one parent is sufficient to result in the clinical trait or phenotype – in this case, elevated basal serum tryptase (BST) levels generally greater than 8 ng/mL. Because the TPSAB1 gene is located on chromosome 16 (as opposed to the X or Y sex chromosomes), and because when one extra copy of the gene is present the trait is expressed, it is called an autosomal dominant.

Interestingly, in the studies that have examined elevated BST in the general population (usually defined as greater than 11.4 ng/mL), the frequency of increased BST levels among Western populations have been found to be approximately 6%. Thus, best current estimates indicate that HαT likely accounts for a little over 90% of individuals with elevated BST in the general population. Based upon population prevalence data, significant kidney disease is estimated to account for another ~7% of people with elevated BST, and rare conditions including but not limited to clonal myeloid diseases such as mastocytosis – an acquired expansion of mast cells with unrestrained growth potential frequently associated with symptoms of immediate allergic reactions – account for the remainder of individuals.

Baseline serum tryptase (BST) is determined by pro-tryptase release from mast cells

Mast cells are born in the bone marrow, but leave as precursors and move into tissues, mainly the skin and lining of the gastrointestinal and respiratory tracts. Once they are in the tissues, they mature into bona fide mast cells. Not all mast cells are the same, or make all of the same proteins, but one of the most abundant proteins in a mast cell is an enzyme that cuts other proteins, or protease, called tryptase. In order for the tryptase enzyme to work properly, it must be assembled from 4 building blocks called pro-tryptases, into active “mature” tetramers (four-part proteins). Pro-tryptases are protein precursors that have no known biological function; these kinds of molecules that can ultimately be converted into active proteases are frequently called zymogens.

Once mature tryptases are formed, they are stored in special compartments called secretory granules along with other molecules that lead to symptoms of immediate allergic reactions, such as histamine. Because the contents of these granules are powerful, they are highly regulated and require significant stimulation to be released under normal conditions. During severe systemic immediate allergic reactions (i.e., anaphylaxis) due to mast cell secretory granule release – something also commonly referred to as mast cell activation or degranulation – serum tryptase levels can be used to confirm mast cells as the cause of the reaction. However, tryptase does not always increase during an allergic reaction, even when we believe that mast cells are the cause. More research is needed to understand why tryptases don’t always increase, and to identify new tests that can help in diagnosing patients during allergic reactions of all kinds.

Perhaps because mast cells make so much tryptase – though we don’t know for certain why – mast cells also constantly release moderate amounts of pro-tryptases into the area surrounding them. From this area pro-tryptases pass into the peripheral blood where they can be measured. In everyone, including individuals with the clonal mast cell disorder mastocytosis, the level of serum tryptase that can be measured in the peripheral blood at baseline (meaning not during an immediate systemic allergic reaction) is determined by the amount of pro-tryptase constantly released by mast cells. In HαT extra copies of the TPSAB1 gene result in increased production of α-tryptase and elevated BST. While in certain circumstances HαT is associated with more severe allergic reactions (discussed below), increases in BST measured in peripheral blood are not evidence of mast cells releasing granule contents and mature tryptases are not detectable in BST samples from individuals with HαT or even those with systemic mastocytosis.

Possible mechanisms explaining findings among symptomatic individuals with HαT

How α-tryptase may contribute to symptoms associated with HαT remains unclear. One possible contributing explanation that has recently been proposed relates to the composition of the mature four-part tryptase tetramers. It has been known for some time that while mature tryptases that contain four β-tryptase are enzymatically active proteases, mature tryptases that contain four α-tryptase subunits have almost no ability to cut other proteins. However, it was recently discovered that some mature tryptases contain both α-tryptase and β-tryptase subunits, so-named heterotetramers. A surprising aspect of these newly identified heterotetramers is that there are specific proteins including stimulating receptors on mast cells and the cells that line blood vessels (i.e., endothelial cells) that can only be cut by heterotetramers when tested in the laboratory. Some of these receptors may contribute to mast cell activation to certain stimuli such as vibration or make blood vessels leakier in response to mast cell degranulation, and in turn may contribute to some of the symptoms associated with HαT.

However, mature tryptases are principally released all at once following mast cell activation and are not observable in carefully handled and preserved tissue sections or baseline peripheral blood samples, making this explanation for many of the chronic symptoms somewhat unsatisfactory. It is also difficult to explain the increased numbers of mast cells that multiple studies have reported in bone marrow and in the GI epithelium based upon these findings, or the increased prevalence among SM patients – which may not entirely be explained by the aforementioned detection bias. Additional mechanism(s) potentially underlying all of these findings are active areas of research.

How is HαT Diagnosed?

The first step in diagnosing HαT involves having your physician measure a total serum tryptase level. In the large majority of individuals with HαT, serum tryptase levels are over 8 ng/mL. Most genetic sequencing techniques available for clinical use are unable to determine the number of α– and β-tryptase encoding sequences anyone has.  However, a specialized test that uses a technology called droplet digital polymerase chain reaction (ddPCR) is available for clinical use from a Clinical Laboratory Improvement Amendments (CLIA)-certified clinical laboratory: https://genebygene.com/tryptase/  The assay run for clinical use is the same assay that was developed by Lyons et al. in 2016. Tryptase genotyping by ddPCR should be considered in symptomatic individuals with elevated basal serum tryptase levels, and is currently the only test available to confirm the diagnosis of HαT.

Correct interpretation of tryptase genotyping can be a challenge even for doctors. α-Tryptase and β-tryptase sequences are encoded by the tryptase genes TPSAB1 and TPSB2 within the human tryptase locus near the end of the short arms of chromosome 16. While β-tryptase sequences can be present at either gene, only TPSAB1 is known to contain the sequences needed to make α-tryptase. Because these genes are so close together physically on chromosome 16, they are nearly always inherited as a pair, or haplotype. Each person received one haplotype from each parent. The three most common haplotypes are: αα, ββ, or αβ. Because each person inherits two of these haplotypes, the resulting tryptase genotypes that make-up approximately 95% of population are: 4β (ββ/ββ), 1α3β (ββ/αβ), or 2α2β (αβ/αβ). HαT is diagnosed when there are extra inherited copies of TPSAB1 encoding α-tryptase on a αβ haplotype, making the most common HαT-associated haplotype ααβ. Because the other inherited haplotype can be either ββ or αβ, the two most common HαT-associated genotypes are 2α3β (ααβ/ββ) and 3α2β (ααβ/αβ), respectively. The most common misunderstanding is that a 2α3β genotype results from increased β-tryptase encoding sequence. While variation in the number of β-tryptase encoding sequences has been observed, this is uncommon, and has not been associated with inherited increases in serum tryptase levels. While one extra germline TPSAB1 copy – frequently referred to as a duplication – accounts for the majority (approximately 80-90%) of individuals with HαT, as many as four extra copies of TPSAB1 encoding α-tryptase have been reported to occur.

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