Clinical relevance of inherited genetic differences in human tryptases Hereditary alpha-tryptasemia and beyond

Objective: To describe our current understanding of hereditary alpha-tryptasemia (H alpha T), how H alpha T fits into the evo-lutionary context of tryptases and contemporary framework of mast cell-associated disorders, and to discuss the future clinical and therapeutic landscape for symptomatic individuals with H alpha T. Data Sources: Primary peer-reviewed literature. Study Selections: Basic, clinical, and translational studies describing tryptase gene composition, generation, secretion, and elevation and the associated clinical impacts of H alpha T and treatment of such individuals were reviewed. Results: H alpha T is a common autosomal dominant genetic trait caused by increased TPSAB1 copy number encoding alpha-tryptase. Approximately 1 in 20 White individuals have H alpha T, making it by far the most common cause for elevated basal serum tryptase levels. Although many individuals with H alpha T may not manifest associated symptoms, the prevalence of H alpha T is increased in patients with clonal and nonclonal mast cell-associated disorders wherein it is linked to more prevalent and/or severe anaphylaxis and increased mast cell mediator-associated symptoms. Increased generation of mature alpha/beta-tryptase hetero-tetramers, and their unique physiochemical properties, may be responsible for some of these clinical findings. Conclusion: H alpha T is a common modifier of mast cell-associated disorders and reactions. Nevertheless, whether H alpha T may be an independent cause of clinical phenotypes with which it has been associated remains unproven. Correct identification of H alpha T is critical to accurate interpretation of serum tryptase levels in the clinical evalua-tion of patients. Beyond H alpha T, we foresee tryptase genotyping as an important parameter in the standard workup of patients with mast cell-associated disorders and development of therapeutic modalities targeting these patients and associated clinical phenotypes. Published by Elsevier Inc. on behalf of the American College of Allergy, Asthma & Immunology.