Managing Diagnosis, Treatment, and Burden of Disease in Hereditary Angioedema Patients with Normal C1-Esterase Inhibitor.

Hereditary angioedema (HAE) is a rare, chronic, and debilitating genetic disorder characterized by recurrent and unpredictable swelling episodes that primarily affect the subcutaneous and/or submucosal tissues of the extremities, larynx, face, abdomen, and genitals. Most cases of HAE are caused by mutations in the serpin family G member 1 gene ( SERPING1 ), which encodes C1-esterase inhibitor (C1-INH) protein. Mutations in SERPING1 lead to deficient (type I HAE-C1-INH) or dysfunctional (type II HAE-C1-INH) C1-INH protein and subsequent dysregulation of the kallikrein-bradykinin cascade. However, some patients present with a third type of HAE (HAE-nI-C1-INH), which was first described in the year 2000 and is characterized by an absence of mutations in SERPING1 . Although mutations in the coagulation factor XII, angiopoietin-1, plasminogen, kininogen-1, myoferlin, and heparan sulfate-glucosamine 3-O-sulfotransferase-6 genes have been identified in some patients with HAE-nI-C1-INH, genetic cause is still unknown in many cases, hindering full elucidation of the pathology of this HAE subtype. Diagnosis of HAE-nI-C1-INH is also further complicated by the fact that patients typically demonstrate normal plasma levels of C1-INH and complement component 4 protein and normal C1-INH functionality during laboratory analysis. Therefore, we review the challenges associated with diagnosing, treating, and living with HAE-nI-C1-INH. We conclude that raising awareness of the presenting features of HAE-nI-C1-INH within the clinical setting and among the general public is critical to aid earlier suspicion and diagnosis of the disease. Furthermore, adopting an individualized approach to HAE-nI-C1-INH treatment is essential to help address the current and significant unmet needs in this patient population.
Competing Interests: Douglas Jones reports being a consultant for and receiving consulting fees from AstraZeneca, BioCryst, Pharming Technologies BV, Pharvaris, Sanofi-Regeneron, and Takeda Pharmaceutical Company Ltd. He also participates in the medical advisory board for KalVista. Heidi Zafra is a member of the BioCryst Advisory Board, and the Takeda Advisory Board. John Anderson affiliates with AllerVie Health and is a speaker bureau member for CSL Behring, Pharming, BioCryst, and Takeda; and has received consulting fees from and is a clinical trial investigator for BioCryst, CSL Behring, Pharming, Takeda, KalVista, Pharvaris, and BioMarin, and consultation fees from Cycle Pharmaceuticals. The authors report no other conflicts of interest in this work.
(© 2023 Jones et al.)