Review and Feature Article
The Genetic Basis and Clinical Impact of Hereditary Alpha-Tryptasemia

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Hereditary alpha-tryptasemia (HαT) is an autosomal dominant genetic trait found in 4% to 6% of the general population and defined by excess copies of alpha-tryptase at TPSAB1. Elevated basal serum tryptase (sBT >8 ng/mL) is a defining feature of HαT and appears to result from increased pro-alpha-tryptase synthesis and secretion rather than mast cell activation. It is estimated that approximately one-third of individuals with HαT have associated symptoms, including cutaneous, gastrointestinal, atopic, musculoskeletal, autonomic, and neuropsychiatric manifestations. HαT is found at a disproportionately high rate in systemic mastocytosis and idiopathic anaphylaxis, and is a modifying factor that independently increases the incidence and severity of anaphylaxis. The varied phenotypes associated with HαT may, in part, result from coinheritance of other genetic variants, increased expression of α-/ß-tryptase heterotetramers, and/or overexpression of pro-alpha-tryptase, although further studies are needed. There is an accurate diagnostic test available to confirm HαT in patients that can be used in combination with sBT to help risk-stratify individuals in whom bone marrow biopsy is being considered. There is no specific treatment for symptoms associated with HαT, and management is focused on controlling clinical manifestations with mast cell mediator antagonists, aspirin, inhalers, epinephrine, omalizumab, and involvement of other specialists.

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Serum Tryptase Origin and Composition

Elevated tryptase is a hallmark of HαT and is not an uncommon finding in allergy/immunology patients, or indeed the general population. Tryptases are almost exclusively MC derived. Basophils, which are the only other cell type known to secrete α- and ß-tryptase in healthy individuals, produce <1% of the tryptase that MCs produce.1 Pre-tryptase, a 274-amino-acid peptide, is processed into the 257-amino-acid pro-tryptase; some amounts of these pro-tryptases are constitutively secreted by

Tryptase Genetics

The tryptase locus on chromosome 16p13.3 contains 4 tryptase genes: TPSB2 encoding at least 3 beta tryptase isoforms (ßI, ßII, and ßIII), TPSAB1 encoding α- or ß-tryptase isoforms (with ßIII not having been reported at this locus), TPSG1 encoding γ-tryptase, and TPSD1 encoding δ-tryptase.2,5,12,31 There is an additional tryptase gene, Serine Protease 22 (PRSS22), which lies just outside the tryptase locus on chromosome 16 and encodes ε-tryptase.2 Of the 5 known major tryptase isoforms, only α-

Other Genetic Variants Frequently Associated With HαT

Given that the tryptase locus is within a gene-dense region with significant genetic recombination, coinheritance of another functional genetic variant that may contribute to some of the symptoms associated with HαT is possible. A study by Lyons et al32 demonstrated the proof of this concept by identification of a frequently co-inherited haplotype of CACNA1H gene variants that lies adjacent to the tryptase locus on chromosome 16 and encodes a T-type voltage-gated calcium channel that is

HαT—A Common Cause Of Elevated sBT

The exact mechanism underlying how increased TPSAB1 copy number results in elevated sBT has not been proven, though sBT levels increase with additional TPSAB1 copy at a level greater than would be associated with gene replication alone. Primary basophils and cultured MCs from individuals with HαT express increased levels of tryptase transcripts, and these MCs have been shown to have increased spontaneous secretion of pro-tryptases in vitro.2,5 In contrast, total intracellular tryptase levels

Pathophysiologic Effects of Tryptases

Mature tryptases have been reported to play a role in DNA modification, tissue repair, vascular permeability, neutrophil and eosinophil chemotaxis, and thrombolysis.9,33, 34, 35, 36, 37 It has been shown that tryptase does play a role in histamine release, and that blocking mature tryptase decreases the detection of urinary histamine metabolites.38 ßI and ßII mature tetramers are peptidases and are important for neutrophil chemotaxis; less is known about ßIII, although based on sequence

Other Symptoms Reported Among Individuals With HαT

Whereas sBT levels are above 8 ng/mL in virtually all individuals who have been reported with HαT, associated symptoms are variably expressed and can manifest at any age, and the majority of individuals may not present with symptoms. In the only study to examine this, one-third of otherwise healthy adults with HαT had significant symptoms, one-third had mild-to-moderate symptoms, and one-third reported symptoms at the same frequency as healthy volunteers.5 Among symptomatic families recruited

HαT and Elevated sBT in the Context of Clonal and Nonclonal MC Disorders

It had been observed that numerous clinical similarities exist between individuals with HαT and individuals with clonal and non-clonal MC disorders, including MC activation syndrome (MCAS) and SM. Multiple studies have now demonstrated an increased prevalence of HαT in clonal and non-clonal MC disorders, and that this in turn is associated with increased anaphylaxis severity and frequency, as well as increased MC mediator symptoms among individuals with SM.9,10

The evolving diagnosis of MCAS

HαT is a Heritable Risk Factor for Severe Anaphylaxis and Modifies MC Disorders

Elevated tryptase is associated with an increased prevalence and severity of anaphylaxis, food-induced allergic reactions in children, and adverse reactions to drugs, contrast, insect stings, and venom immunotherapy.11,51, 52, 53, 54 In the initial studies describing patients with HαT, anaphylaxis was common; triggers included insect stings in 16% to 20% of individuals—a rate of 2 to 4 times that of the general population—as well as foods, drugs, radiocontrast, venom immunotherapy.2,5,55 In a

Treatment Approaches for Individuals With HαT

Treatments implemented for individuals with HαT are currently symptom-based. Because many of the symptoms are suggestive of MC mediator release, and there are data to support enhanced immediate hypersensitivity reactions in these individuals, H1 and H2 antagonists, leukotriene antagonists, MC stabilizers, and high-dose aspirin in specified cases are often used as first-line agents. Inhaled albuterol can be prescribed for those with bronchospasm. If there are severe symptoms consistent with

Conclusions

HαT is a common autosomal dominant genetic trait wherein excess α-tryptase encoding TPSAB1 copy number results in elevated sBT. HαT is associated with a variety of both allergic and non-allergic conditions, which is important for the allergist/immunologist to be aware of. Recently it has been shown that HαT is present in 4% to 6% of the general population and appears to account for the significant majority of individuals with elevated sBT.2,6, 7, 8, 9, 10, 11 Associated symptoms are variably

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    This research was supported in part 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 US Government.

    Conflicts of interest: K. T. Luskin and J. J. Lyons declare no relevant conflicts of interest. A. A. White has served on the advisory boards for Blueprint Pharmaceuticals, Genentech, GSK, and Regeneron; is on the speaker's bureau for GSK, Astra Zeneca, and Optinose; and is a grant recipient from AstraZeneca.

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