Hereditary Angioedema

Hereditary Angioedema (HAE)

Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disorder due to C1 inhibitor deficiency. These episodes occur in over one-half of the patients with HAE during their lifetimes. It is characterized by recurrent angioedema attacks which affect the skin, gastrointestinal tract, and airway. Minor trauma or stress may trigger an attack, but swelling often occurs without a known trigger. The prevalence of HAE is approximately one in 80,000 people. Symptoms of HAE typically begin in childhood and get worse around twelve years of age. On average, untreated individuals have a chance of an attack every 1 to 2 weeks, and most episodes last for about 3 to 4 days. The frequency and duration of attacks vary greatly between individuals, even among people in the same family.

Fig.1 Serine proteases controlled by C1 inhibitor in pro-inflammatory cascade systems. (Longhurst, 2012)

Classification

Basically, there are three types of HAE, type I, type II, and type III. Type I and type II are the consequences of the mutation in the SERPING1 gene which encodes the C1 protease inhibitor. Type I accounts for 80-85% of HAE cases while type II 15-20%. Because of the autosomal dominant inheritance pattern, type I and type II are reported without sex predominance. As C4 functions downstream of C1 complex, a low level of C4 is detected in both types of HAE. However, the difference is that type I involves the low level of C1-inhibitor while type II is associated with C1-inhibitor engaging the biological dysfunction. Type III is not associated with C1-inhibitor. It is usually due to the mutation of the factor XII gene which results in the increasing of bradykinin and promotes swelling.

Cause of HAE

HAE is inherited as an autosomal dominant trait and results from mutations in the gene responsible for the synthesis of C1 inhibitor. However, 20-25% of the cases are estimated to be the result of spontaneous mutations. More than 200 mutations within this gene have been reported. Type I HAE is caused by the mutations that lead to a low level of C1-inhibitor. Type II HAE results from the mutations of genes which make the truncated or misfolded Ci-inhibitors. These mutations lead to the dysfunction of the protease inhibitor.

C1-inhibitor

C1-inhibitor is a protease inhibitor. It is a member of the serpin family which is found in all kingdoms of life. The primary biological activities of C1-inhibitor are to regulate the activation of the complement system and contact systems. C1 is eponymous of the inhibitor, but the activation of C1 inhibitor is not specific to C1. It is able to inhibit several complement components such as C1s, C1r derived from the classical pathway, factor XIIa, kallikrein and factor XIa derived from the contact system. Deficiency of C1-inhibitor leads to the recurrent angioedema which is potentially life-threatening.

Treatment of HAE

Currently, the treatment options for HAE including but not limited to attenuated androgens, fresh frozen plasma, and antifibrinolytics. These treatments have shown undesired effects or limited efficacy. C1 inhibitor replacement therapy has been approved by the Food and Drug Administration for the treatment of HAE. The recombinant C1-inhibitor is underway.

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Reference
1. Longhurst, H.; et al. Hereditary angio-oedema. The Lancet. 2012, 379(9814), 474-481.

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