Hereditary angioedema with normal C1 Inhibitor associated with Carboxypeptidase N deficiency

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Vincent, Denis | Parsopoulou, Faidra | Martin, Ludovic | Gaboriaud, Christine | Demongeot, Jacques | Loules, Gedeon | Fischer, Sascha | Cichon, Sven | Germenis, Anastasios, E | Ghannam, Arije | Drouet, Christian

Edité par CCSD ; American Academy of Allergy, Asthma & Immunology -

International audience. Background: Hereditary angioedema (HAE) is a potentially life-threatening disordercharacterized by recurrent episodes of subcutaneous or submucosal swelling. HAE withnormal C1 Inhibitor (HAE-nC1-INH) is an under-diagnosed condition. Although theassociation with genetic variants has been identified for some families, the genetic causes inmany patients with HAE-nC1-INH remain unknown. The role of genes associated withbradykinin catabolism is not fully understood.Objective: We investigated the biological parameters and the genes related to kallikrein-kininsystem (KKS) in families with a clinical phenotype of HAE-nC1-INH and presenting with acarboxypeptidase N (CPN) deficiency.Methods: This study includes four families presenting with HAE-nC1-INH and CPNdeficiency. Patients’ clinical records were examined, biological parameters of KKS measured,genetics was analyzed by next-generation sequencing and Sanger sequencing. Predictivealgorithms (HSF®, SIFT®, Polyphen-2®, MutationTaster®, ClinPred®) were used to classifyvariants as affecting splicing, as benign to deleterious, or as disease-causing.Results: Patients presented with angioedema and urticaria, mainly on face/lips, but also withabdominal pain or laryngeal symptoms. Affected patients displayed low CPN activity –30 to50% of median value in plasma. We identified three variants of the CPN1 gene encoding thecatalytic 55-kDa subunit of CPN at: c.533G>A, c.582A>G and c.734C>T. CPN deficiencyassociated with genetic variants segregated with HAE-nC1-INH symptoms in affected familymembers.Conclusions: CPN1 gene variants are associated with CPN deficiency and HAE-nC1-INHsymptoms in four unrelated families. Genetic CPN deficiency may contribute to bradykininand anaphylatoxins accumulation, with synergistic effects in angioedema and urticarialsymptoms.

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