Hereditary Alpha Tryptasemia

Tryptase and Alpha Tryptasemia

Catherine R Weiler, MD, PhD

1. Tryptase:
Tryptase is an enzyme found almost exclusively in mast cells. It is used as a marker for identifying mast cells and is increased when mast cells are activated or increased in number. Examples of mast cell activation include severe allergic-type reactions causing anaphylaxis.

2. Tryptase Genes:
The genes that encode tryptase are located on human chromosome 16. There are mainly two forms of the gene, alpha (α) and beta (β). A third form, gamma tryptase (γ) is bound to the membrane of the granule and is not released from mast cells. 1 The α/β tryptase locus normally contains two genes, TPSB2, expressing only β-tryptase, and TPSAB1, expressing either α- or β- tryptase. 2 Each is expressed as a 275 amino acid pretryptase (before tryptase) that is broken down to a 257 amino acid protryptase (primitive tryptase). One portion of these protryptases is continuously secreted by unstimulated mast cells, and is the form detected in serum or plasma collected under non-anaphylactic conditions for both healthy people and patients with mastocytosis and other mast cell diseases. Another portion of the protryptases is changed to a 245 amino acid mature proteins (final protein), which is stored in mast cell granules. 3,4 Mature tryptase is stored as four chains associated with heparin in the granule, those four chains are called tetramers. α/β-Tryptases are primarily produced by mast cells. However, there is another cell that produces tryptase, and that is the basophil. Basophils contain only about 0.2% of the tryptase found in mast cells. 5

3. Levels of Tryptase in Serum:
In the general population baseline serum tryptase level is 5.1 ng/mL with a range from <1 to 31 ng/mL. In healthy twins tryptase level is related to genetics. 6 Levels of serum tryptase are affected by many factors, those include age, obesity, smoking, or alcohol consumption. Tryptase level is, however, not affected by the allergic status, 7 but can be increased in patients with active severe hives. Elevated baseline levels of total tryptase are also seen with malignancies that affect white blood cells related to the lineage of mast cells called myeloid neoplasms. 8-12 Other conditions in which tryptase is elevated include those with increased eosinophils (Hypereosinophilia) associated the FIP1L1-PDGFRA mutation. 13 End stage kidney disease, 14,15 treatment of some parasite infections (onchocerciasis), 16 systemic mastocytosis, 17 and rare familial lysosomal storage disorders such as Gaucher’s disease, 18. In clinical practice, levels above 10-11.5 ng/mL are generally considered high. For children serum tryptase level is 3.3 ng/mL (range 2.4-4.4) and is higher in younger children. 19 The baseline serum tryptase level has been utilized in diagnostic algorithms for the presence of mastocytosis in patients having or lacking typical skin lesions. 20-23 A tryptase level consistently above 20 ng/mL is one of the 2 criteria used in the diagnosis of systemic mastocytosis 23 when the patient does not have another blood neoplasm.

4. Risks Associated with High Basal Serum Tryptase Levels:
In the general population, people with elevated tryptase levels have a higher risk of anaphylaxis and food allergic reactions, reactions to drugs, contrast dye, insect stings 24-26 , and to allergy prophylactic injections for treatment of stinging insect allergies. 1,27 Tryptase in and by itself does not increase this risk; high tryptase seems to be a bystander marker for other factors involved in those reactions, such as the presence of mast cell clones. Mature tryptases are released during episodes of mast cell activation, such as anaphylaxis caused by insect stings. The severity of clinical anaphylaxis resulting from insect stings directly correlates with the increase in the level of tryptase. 28-30 However, this dramatic correlation is not found in all types of anaphylaxis, for example, food-induced anaphylaxis is associated with lower increase in serum tryptase.

5. Alpha Tryptasemia:
In 2014, Lyons et al. from NIH, published a report of a multiple families with high levels of serum tryptase. 31 The inheritance pattern was consistent with an autosomal dominant Mendelian inheritance. Autosomal dominant inheritance means that if a parent has one gene causing a high tryptase level, each child has a 50% chance of having high tryptase regardless of the gender of the child. The patients and their blood relatives, described in this report also had problems with connective tissues. About 87% of
the patients with high tryptase suffered from episodic hives, flushing, and/or abdominal pain with diarrhea. One third of those patients had a history of anaphylaxis, 94% had a history of environmental allergies or asthma, and about 70% had problems with connective tissues some with hypermobile joint disorder. One third of the patients with elevated tryptase experienced chronic musculoskeletal pain, another third experienced orthostatic hypotension with tachycardia (POTS), and half had a neuropsychiatric diagnosis. There was a direct correlation of the symptoms from each organ system (skin, gastrointestinal tract, connective tissue and allergic disorders) with the level of tryptase. In a separate report, familial hypertryptasemia in one family was also described. One of the affected family members in this report had clonal mutation of c-KIT (Asp816Val) consistent with clonal mast cell activation syndrome. 32 Calculations based on the referral pattern suggested that about 4-6% of the general population have elevated tryptase. In this report, Lyons et. al. identified duplications and triplications (increase in the copy number of the α-tryptase gene by two or three times) in the TPSAB1 gene encoding alpha-tryptase. This increase in gene copy number was associated in increase of serum tryptase level. Thirty five families were presented with this multi-organ symptom complex. The higher the number of gene copies, the higher the basal serum levels of tryptase and the worse the symptoms. Two additional family groups were identified in this report totaling 172 individuals. Findings from the NIH group showed direct link between duplications in TPSAB1 with irritable bowel syndrome, skin complaints, connective tissue abnormalities, and autonomic dysfunction. 333

In 2017, Lyons et. al. reported an overlap between a gene that encodes a calcium channel and alpha tryptase. This calcium channel contributes to sensations of pain and itching. It is related to movement in the intestinal wall, anxiety, and control of blood pressure. The gene for this calcium channel is called CACNA1H. Because it overlaps with the human tryptase locus (site) it could explain the symptoms associated with increased copies of the tryptase gene. However, even though a link in the genetic inheritance between this calcium channel and tryptase gene was identified, no clinical differences were observed in association with the CACNA1H haplotype. This means that we still do not know the cause of symptoms related to different organ systems in patients with alpha-tryptasemia 34

6. Summary:
In summary, hereditary alpha tryptasemia is an autosomal dominant genetic disorder caused by increase in number of copies of genes encoding alpha-tryptase. Individuals with this trait have increased basal serum tryptase levels. Some have symptoms associated related to other organ systems that do not appear directly caused by tryptase. The higher tryptase gene copy number (TPSAB1) is associated with higher levels of basal serum tryptase and also associated with more severe the clinical symptoms. 35
Finally, a patient with five copies of the tryptase gene TPSAB1 was found recently found to have a clonal mast cell disorder. 36

References:
1. Vitte J. Human mast cell tryptase in biology and medicine. Mol Immunol. 2015;63(1):18-24.
2. Trivedi NN, Caughey GH. Mast cell peptidases: chameleons of innate immunity and host defense. Am J Respir Cell Mol Biol. 2010;42(3):257-267.
3. Schwartz LB, Sakai K, Bradford TR, et al. The alpha form of human tryptase is the predominant type present in blood at baseline in normal subjects and is elevated in those with systemic mastocytosis. J Clin Invest. 1995;96(6):2702-2710.
4. Kanthawatana S, Carias K, Arnaout R, Hu J, Irani AM, Schwartz LB. The potential clinical utility of serum alpha-protryptase levels. J Allergy Clin Immunol. 1999;103(6):1092-1099.
5. Jogie-Brahim S, Min HK, Fukuoka Y, Xia HZ, Schwartz LB. Expression of alpha-tryptase and beta- tryptase by human basophils. J Allergy Clin Immunol. 2004;113(6):1086-1092.
6. Sverrild A, van der Sluis S, Kyvik KO, et al. Genetic factors account for most of the variation in serum tryptase–a twin study. Ann Allergy Asthma Immunol. 2013;111(4):286-289.
7. Gonzalez-Quintela A, Vizcaino L, Gude F, et al. Factors influencing serum total tryptase concentrations in a general adult population. Clin Chem Lab Med. 2010;48(5):701-706.
8. Valent P, Sperr WR, Samorapoompichit P, et al. Myelomastocytic overlap syndromes: biology, criteria, and relationship to mastocytosis. Leuk Res. 2001;25(7):595-602.
9. Sperr WR, Drach J, Hauswirth AW, et al. Myelomastocytic leukemia: evidence for the origin of mast cells from the leukemic clone and eradication by allogeneic stem cell transplantation. Clin Cancer Res. 2005;11(19 Pt 1):6787-6792.
10. Horny HP, Sotlar K, Stellmacher F, et al. The tryptase positive compact round cell infiltrate of the bone marrow (TROCI-BM): a novel histopathological finding requiring the application of lineage specific markers. J Clin Pathol. 2006;59(3):298-302.
11. Sperr WR, El-Samahi A, Kundi M, et al. Elevated tryptase levels selectively cluster in myeloid neoplasms: a novel diagnostic approach and screen marker in clinical haematology. Eur J Clin Invest. 2009;39(10):914-923.4
12. Valent P, Orazi A, Busche G, et al. Standards and impact of hematopathology in myelodysplastic syndromes (MDS). Oncotarget. 2010;1(7):483-496.
13. Klion AD, Noel P, Akin C, et al. Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis, and imatinib responsiveness. Blood. 2003;101(12):4660-4666.
14. Sirvent AE, Gonzalez C, Enriquez R, et al. Serum tryptase levels and markers of renal dysfunction in a population with chronic kidney disease. J Nephrol. 2010;23(3):282-290.
15. Jesky MD, Stringer SJ, Fenton A, et al. Serum tryptase concentration and progression to end-stage renal disease. Eur J Clin Invest. 2016;46(5):460-474.
16. Cooper PJ, Schwartz LB, Irani AM, Awadzi K, Guderian RH, Nutman TB. Association of transient dermal mastocytosis and elevated plasma tryptase levels with development of adverse reactions after treatment of onchocerciasis with ivermectin. J Infect Dis. 2002;186(9):1307-1313.
17. Valent P, Akin C, Arock M, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol. 2012;157(3):215-225.
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20. van Doormaal JJ, van der Veer E, van Voorst Vader PC, et al. Tryptase and histamine metabolites as diagnostic indicators of indolent systemic mastocytosis without skin lesions. Allergy. 2012;67(5):683-690.
21. Alvarez-Twose I, Gonzalez-de-Olano D, Sanchez-Munoz L, et al. Validation of the REMA score for predicting mast cell clonality and systemic mastocytosis in patients with systemic mast cell activation symptoms. Int Arch Allergy Immunol. 2012;157(3):275-280.
22. Valent P, Escribano L, Broesby-Olsen S, et al. Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis. Allergy. 2014;69(10):1267-1274.
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25. Sahiner UM, Yavuz ST, Buyuktiryaki B, et al. Serum basal tryptase may be a good marker for predicting the risk of anaphylaxis in children with food allergy. Allergy. 2014;69(2):265-268.
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27. Dugas-Breit S, Przybilla B, Dugas M, et al. Serum concentration of baseline mast cell tryptase: evidence for a decline during long-term immunotherapy for Hymenoptera venom allergy. Clin Exp Allergy. 2010;40(4):643-649.
28. Schwartz LB, Metcalfe DD, Miller JS, Earl H, Sullivan T. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl J Med. 1987;316(26):1622-1626.
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30. Schwartz LB, Min HK, Ren S, et al. Tryptase precursors are preferentially and spontaneously released, whereas mature tryptase is retained by HMC-1 cells, Mono-Mac-6 cells, and human skin-derived mast cells. J Immunol. 2003;170(11):5667-5673.5
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34. Lyons JJ, Stotz SC, Chovanec J, et al. A common haplotype containing functional CACNA1H variants is frequently coinherited with increased TPSAB1 copy number. Genet Med. 2017.
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Hereditary Alpha Tryptasemia Testing

Commercial testing is now available for Hereditary Alpha Tryptasemia through Gene by Gene laboratory.
Info Here
*This test is not offered direct to consumer and must be authorized by a qualified medical professional.
*This test is not currently available for New York State residents.

This test is used to determine alpha tryptase copy number. Alpha tryptase is encoded by the TPSAB1 gene, which is on chromosome 16. The primary gene products of this gene are β-tryptase, which can be produced by TPSAB1 and TPSB2, and α-tryptase, which is only produced by the TPSAB1 gene.

Individuals who inherited one copy of α-tryptase–encoding sequence on both have normal serum tryptase levels.
This test measures both α- and β-tryptase. A normal result is any combination of α- and β-tryptase that adds up to 4.
A positive result – which means there is a duplication or triplication of α-tryptase – is a combination of α and β-tryptase that is 5 or higher.

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