Hereditary alpha tryptasemia: literature overview on the genetic trait and its clinical manifestations

Hereditary Alpha Tryptasemia (HαT) is a genetic condition characterized by an increased number of copies of the TPSAB1 gene, resulting in elevated basal serum tryptase levels and an increased risk of anaphylaxis, especially in individuals with IgE-dependent allergies or systemic mastocytosis. The severity of clinical symptoms can vary and is influenced by the number of extra TPSAB1 gene copies, suggesting a gene-dose effect. Approximately two-thirds of individuals with HαT show minimal or no symptoms. The remaining individuals with HαT may present with Hymenoptera venom allergy, flushing, urticarial/angioedema, irritable bowel syndrome, gastrointestinal reflux, hypermobility, neuropsychiatric symptoms and dysautonomia. Recent studies revealed that α-tryptase which forms complexes with β-tryptase activate protease-activated receptor-2 (PAR2) receptors. Activation of these receptors may lead to hypotension, muscle contraction, inflammation, and trigger neuropeptide secretion, and in consequence, result in mast cell degranulation. This cycle of activation and degranulation may potentially contribute to the development of mast cell activation syndrome (MCAS). Mast cell activation syndromes are defined by systemic, severe and recurrent mast cell activations, usually in the form of anaphylaxis. Hereditary/ familial MCAS is a specific subtype of MCAS, which is associated with HαT. Diagnostic work-up for HαT includes determination of basal serum tryptase level and the presence of additional TPSAB1 gene copies using droplet digital polymerase chain reaction. Further research is needed, to explore the relationship between HαT and MCAS, as well as to determine if there is a distinct form of hereditary MCAS which is independent of HαT. These investigations aim to improve diagnostic approaches and treatment strategies for individuals with HαT, enhancing their management and overall quality of life.