Hereditary alpha-tryptasemia: Brief overview of current knowledge and proposal of indications

Abstract

Human tryptases are serine proteases, which are synthesized nearly exclusively by mast cells (MCs). Immature pro-tryptases, under the form of α- and β-monomers are constantly released by MCs, can be measured in the serum of normal individuals and constitute the basal serum tryptase (bST) level, usually below 6μg/L. By contrast, tetramers of tryptases, which are the mature forms of the enzyme, are normally retained in the secretory granules of MCs. These mature (α- and β-tetramers of tryptase) are only released when MC are activated by different stimuli, leading to a transient increase in serum tryptase level. Such event occurs for instance after IgE-mediated MC degranulation (immediate hypersensitivity reaction). The mature tryptases, through their various biological activities, account for the pathophysiology of immediate hypersensitivity. Of note, recent studies have reported that around 5% of the general population present with increased bST levels related to a genetic trait called hereditary α-tryptasemia (HαT). While there is still a debate on the fact that HαT+ patients may present more frequently various clinical phenotypes, it is now clearly established that the clinical phenotype of patients with primary (clonal) MC disorders, including mastocytosis, is modified by the presence of the HαT trait. In addition, HαT penetrance seems clearly increased in such patients (up to 18% of the cases), leading to the conclusion that HαT is a disease penetrance and phenotype modifier. In the present manuscript, we will describe briefly the genetic patterns of HαT and the clinical phenotypes encountered in HαT+ patients harboring or not a clonal MC disorder. Finally, we will describe the situations when the search for HαT in human can be considered and the preferred method to be used for such investigation.