Hereditary alpha-tryptasaemia

Hereditary alpha-tryptasaemia is a clinically heterogeneous trait; presentations range from asymptomatic to debilitating multisystem complaints. Most symptoms are attributable to mast-cell activation and mediator release, with cutaneous, gastrointestinal, neurological, and psychiatric features reported alongside cardiovascular involvement and recurrent anaphylaxis.

Skin involvement frequently includes flushing, urticaria, and pruritus, while gastrointestinal symptoms encompass cramping, reflux, abdominal pain, and altered motility. Neurological features described in published cohorts include headache, paraesthesia, and chronic pain, and psychiatric symptoms ranging from anxiety to mood disturbance. Affected individuals carry an increased risk of severe systemic reactions, particularly secondary to Hymenoptera venom stings and selected drug exposures.

Clinical severity differs markedly between individuals, with inter-individual variability evident even within a single family and a substantial proportion of individuals with the trait remaining asymptomatic throughout life.

Hereditary alpha-tryptasemia (HaT) has an estimated prevalence of 4–6% in Western populations.

Hereditary alpha-tryptasaemia is caused by germline copy-number gain of TPSAB1 at 16p13.3. The gene encodes alpha-tryptase; affected individuals carry three or more alpha-tryptase copies, or two alpha-tryptase copies together with three beta-tryptase copies. Co-inherited overactive promoter elements drive over-expression of alpha-tryptase from the duplicated TPSAB1 loci, raising basal serum tryptase levels and increasing the formation of alpha/beta-tryptase heterotetramers that activate protease-activated receptor-2 and the EMR2 mechanosensory receptor, underlying many of the mast-cell-mediated clinical features.

Hereditary alpha-tryptasaemia is inherited in an autosomal dominant manner. Each first-degree relative of an affected individual has a 50% priori risk of carrying the same TPSAB1 copy-number gain. Predictive testing of at-risk relatives is technically possible once the familial variant has been characterised. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis is established by molecular genetic testing demonstrating the underlying TPSAB1 copy-number gain. Elevated basal serum tryptase (BST), with values exceeding 6.5-8 ng/mL, is the biochemical marker that prompts evaluation for tryptase genotyping in symptomatic individuals; the reported median BST with a single TPSAB1 replication is 13.6 ng/mL (95% CI 12.6 to 14.4). HaT shows clinical overlap with mast cell disorders, including systemic mastocytosis (SM), particularly with respect to elevated basal serum tryptase levels. Therefore, consideration of HαT status is important in the diagnostic evaluation of suspected SM. In individuals with confirmed HαT, the basal serum tryptase level can be adjusted according to the TPSAB1 copy number to improve the interpretation of tryptase levels.

• Establishing the diagnosis at the molecular level provides a definitive aetiological explanation for the clinical presentation.
• Establishing a diagnosis of HaT can reduce the need for invasive diagnostic procedures and plays a key role in the evaluation and management of mast cell disorders.

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