Hereditary alpha-tryptasemia (HαT) extends the symptom spectrum to cardiovascular, pain and neuropsychiatric symptoms in patients with mast cell-related conditions Free

Background: Elevated baseline serum tryptase levels (BST ≥11.5 µg/L) are the hallmark of Hereditary alpha-Tryptasemia (HαT), which is an autosomal dominant inherited amplification of alpha-tryptase on the TPSAB1 gene. HαT is common in the general population (5-6%) and is almost exclusively found in BST levels ≥ 8.0 µg/L. Elevated BST levels are associated with severe anaphylaxis and mast cell mediator symptoms, such as pruritus, urticaria, flushing, and gastrointestinal complaints. Previous studies have linked HαT to severe Hymenoptera venom anaphylaxis (HVA) and a higher symptom burden of mast cell-associated symptoms in patients with systemic mastocytosis (SM). Mechanistically, an increased formation of α-β-tryptase heterotetramers in HαT patients may specifically activate receptors such as PAR2 and EMR2 on vascular endothelium, gut mucosa, and neurons. As these findings suggest a clinical impact of HαT in mast cell-related conditions other than SM, this study aimed to investigate the symptom burden and symptom profile of HαT-positive and HαT-negative patients in a large monocentric cohort of patients presenting with mast cell-related conditions.

Methods: We prospectively screened 332 patients with BST levels ≥ 8 µg/L presenting to the local allergy department. The reasons for presentation were noted and included urticaria/ angioedema, HVA, food and drug allergies, gastrointestinal complaints, and atopic diseases. In n=256 patients, structured symptom assessment of mast cell-associated symptoms, as well as functional symptoms (cardiovascular, pain and neuropsychiatric symptoms) conducted with a customized questionnaire was available. All participants underwent blood testing for the HαT genotype and KIT D816V mutation indicating SM.

Results: HαT was highly prevalent especially in elevated BST levels of ≥ 11.5µg/l (89,9%; 133/148). In BST levels ≥ 15µg/l, all patients were positive for HαT and/ or KIT D816V. HαT was most prevalent among females (+15%; p=0.012) and patients presenting with gastrointestinal symptoms (+16%; ns). To assess the clinical impact of HαT in patients without SM, only KIT D816V-negative patients (n=227) were analysed. HαT-positive patients reported a significantly higher symptom burden compared to HαT-negative patients (9.3 vs. 6.5 symptoms; p<0.001). In subgroup analyses, this difference was primarily observed in patients presenting with urticaria/angioedema (8.9 vs. 5.5; p=0.023) and atopic diseases (8.3 vs. 4.2; p=0.016). Patients significantly more often reported general symptoms such as fatigue (+26%; p<0.001) and sleep disturbances (+13%; p=0.049), as well as neuropsychiatric impairments such as concentration issues (+26%; p<0.001), memory impairment (+16%; p=0.020) and sadness/ lack of motivation (+22%; p=0.004). Headaches (+19%; p=0.006), abdominal pain (+21%; p=0.002), and cardiovascular symptoms such as dizziness (+14%; p=0.052), palpitations (+15%; p=0.039) or orthostatic dysregulation (+22%; p=0.002) were more frequent in HαT-positive patients. In contrast, skin and gastrointestinal symptoms, which were mostly related to the reasons for presentation (e.g., flushing, urticaria, pruritus, nausea and flatulence), did not differ between HαT-positive and HαT-negative patients. Among patients with HαT genotypes, individuals with the 3α2β genotype exhibited a significantly higher symptom burden compared to those with the 2α3β genotype (10.1 vs. 8.0; p=0.013).

Conclusion: HαT significantly impacts the symptom burden experienced by patients presenting with mast cell-related conditions. Surprisingly, HαT-positive patients displayed a symptom pattern extending to neuropsychiatric, cardiovascular and pain syndromes rather than reporting pronounced typical mast cell-associated symptoms. Our findings further suggest that not only HαT-positivity, but also the HαT genotype (i.e. the ratio of α/β-tryptase) may have a clinical impact. Together, clinicians should be aware that HαT impacts the symptom pattern and severity especially in patients presenting with mast cell-related conditions like systemic mastocytosis, anaphylaxis, urticaria, angioedema and atopic disease. Larger cohort studies are needed to further evaluate the significance of the α/β-tryptase ratio, sex or associated comorbidities on the clinical presentation of these patients.