Abstract
Hereditary angioedema is a rare inherited disorder characterized by recurrent episodes of the accumulation of fluids outside of the blood vessels, causing rapid swelling of tissues in the hands, feet, limbs, face, intestinal tract, or airway. Mutations in SERPING1, the gene that encodes C1-INH (C1 esterase inhibitor), are responsible for the majority of cases of hereditary angioedema. C1 esterase inhibitor (C1-INH) is a major regulator of critical enzymes that are implicated in the cascades of bradykinin generation, which increases the vascular permeability and allows the flow of fluids into the extracellular space and results in angioedema. Moreover, a dominantly inherited disease has been described that has a similar clinical picture to C1-INH-HAE (Hereditary angioedema due to C1 inhibitor deficiency), but with normal C1-INH level and activity. This new type of HAE has no mutation in the SERPING1 gene and it is classified as nC1-INH-HAE (HAE with normal C1-INH). Currently mutations in six different genes have been identified as causing nC1-INH-HAE: factor XII (F12), plasminogen (PLG), angiopoietin 1 (ANGPT1), Kininogen 1 (KNG1), Myoferlin (MYOF), and heparan sulfate (HS)-glucosamine 3-O-sulfotransferase 6 (HS3ST6). In this review we aim to summarize the recent advances in genetic characterization of angioedema and possible future prospects in the identification of new genetic defects in HAE. We also provide an overview of diagnostic applications of genetic biomarkers using NGS technologies (Next Generation Sequencing).
Highlights
It has been documented that an increased release of bradykinin is the cause of angioedema via its action on B2 receptors leading to an increase in vascular permeability [12,13]
C1 esterase inhibitor (C1-INH)-hereditary angioedema (HAE), but with normal C1-INH level and activity. This new type of HAE has no mutation in the SERPING1 gene and it is classified as nC1-INH-HAE (Figure 1)
The autosomaldominant mode of inheritance has been described for C1-INH-HAE when one of the two alleles of the C1-INH gene (SERPING1) is mutated [14,15,16]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The clinical expression is highly variable, from asymptomatic individuals to patients suffering from disabling and life-threatening attacks with a demonstrated humanistic and economic burden [1]. The severity and frequency of acute attacks of angioedema are variable, ranging from once/year to three attacks/week [3]. A series of predisposing circumstances, including trauma, fluctuating hormone level ( increased estrogen), infection, and severe emotional stress have been identified, most acute episodes of angioedema seem apparently spontaneous. An acute episode of angioedema has been estimated to occur in up to 7.4% of subjects during their lifetime [4]. The diagnosis is based on the clinical description, the identification of triggers for the attacks, the response to medications during an acute episode, and possible familial history. Depending on the results of history, physical examination and laboratory investigations, it may be classified as drug-induced angioedema, hereditary angioedema, or acquired angioedema
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