This page was produced as an assignment for Genetics 564, a capstone course at UW-Madison.
What is Hereditary Angioedema?
Hereditary Angioedema (HAE) is a rare disease characterized by recurrent, unpredictable attacks of rapid swelling (angioedema) in various parts of the body. The swelling seen in all HAE patients is the result of overproduction of the protein bradykinin, which mediates vasodilation to increase blood flow and inflammation [1]. There are three main types: I, II, and III. The first two types are caused by the reduction or dysfunction of the protein C1 esterase inhibitor (C1-INH). On the contrary, Type III HAE patients have normal C1-INH concentration and function [2]. The cause of Type III HAE is strongly linked to occurrences of high estrogen levels, such as using estrogen-based oral contraceptives or pregnancy [3]. Therefore, this disorder is almost exclusively found in women [2].
What are the Signs & Symptoms of HAE?
Type III Hereditary angioedema (HAE) symptoms typically begin in childhood and worsen during puberty or after the introduction of estrogen-based oral contraceptives [2]. The duration and frequency of swelling episodes vary greatly among people. On average, untreated attacks occur biweekly with most episodes lasting about 3 to 4 days [4]. All three types of HAE have clinically indistinguishable presentation [4]. Symptoms vary between patients but typically present as nonpitting swelling, which is when pressure is applied to a swollen area but the skin does not indent [1]. The recurrent episodes of swelling seen in HAE patients most commonly develop in limbs, face, intestinal tract and airways. The airways are particularly dangerous, as it can cause death by asphyxiation. Trauma, stress or infection may trigger these attacks, but they often occur without a known cause [1].
Testing & Treatment
There are numerous clinical and genetic tests that can be performed to diagnose individuals with Type III Hereditary Angioedema (HAE). Many of these tests involve sequencing the F12 gene for mutations associated with the disease [5]. However, because HAE is so rare, often times it is not easily identified. Type III HAE cannot be treated with antihistamines or corticosteroids used to treat common swelling. In addition, treatments used for Type I and Type II HAE which include C1 inhibitor concentrate have no effect on Type III patients [2]. The first and most important treatment for women with Type III HAE is to suspend usage of oral contraceptives or hormone replacement therapies [3].
F12 & Coagulation Factor XIIF12 is a protein-coding gene for Coagulation Factor XII that can be found on the tip of chromosome 5 [6]. This extracellular protein has two main roles in the body. The first is to form blood clots (coagulation), and the second is to increase inflammation. Inactive Factor XII (FXII) circulates the blood stream until it becomes activated (FXIIa) via autoactivating induced by "contact" to a negatively charged surface. Once activated it cleaves a protein called plasma prekallikrein (PPK) into plasma kallikrein (PK). This interaction triggers the release the protein bradykinin from high molecular weight kininogen (HMWK). Bradykinin then increases the permeability of blood vessels, allowing more fluids to leak into tissue, causing inflammation [6].
In Type III HAE, there is a gain-of-function mutation in the F12 gene, causing threonine 328 in the protein to be changed into either lysine or arginine. This mutated form of Factor XII can cleave PKK at a faster rate, thus leading to uncontrolled bradykinin formation [6]. |
Inheritance and PrevalenceType III HAE is a rare disease, affecting 1 in 50,000 people worldwide [1]. It is inherited in an autosomal dominant pattern. Therefore, children have a 50% chance of inheriting it if one parent is affected. However, spontaneous mutation can occur in the genes of people with no family history of HAE [7]. Since Type III HAE is associated with high estrogen levels, it affects females almost exclusively.
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Learn more about Hereditary Angioedema:
References
[1] Sinnathamby, E.S., Issa, P.P., Roberts, L. et al. Hereditary Angioedema: Diagnosis, Clinical Implications, and Pathophysiology. Adv Ther 40, 814–827 (2023). Retrieved from: https://link.springer.com/article/10.1007/s12325-022-02401-0
[2] McKusick. (2006, November 20). Hereditary, Angioedema, 3; HAE3. Last updated June, 2021. Retrieved from: https://omim.org/entry/610618
[3] Miranda AR, Ue AP, Sabbag DV, Furlani Wde J, Souza PK, Rotta O. (2013, July). Hereditary angioedema type III (estrogen-dependent) report of three cases and literature review. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3760933/
[4] US Hereditary Angioedema Association. UpToDate. About Hereditary Angioedema. Retrieved from: https://www.haea.org/pages/p/what_is_hae
[5] NIH. Hereditary angioedema type 3. Retrieved from: https://www.ncbi.nlm.nih.gov/gtr/conditions/C1857728/#:~:text=Autosomal%20dominant%20inheritance,-MedGen%20UID%3A%20141047&text=In%20the%20context%20of%20medical,of%20inheriting%20the%20mutant%20allele.
[6] Fabregat A, Sidiropoulos K, Viteri G, Marin-Garcia P, Ping P, Stein L, D'Eustachio P, Hermjakob H. Reactome diagram viewer: data structures and strategies to boost performance. Bioinformatics (Oxford, England). 2018 Apr;34(7) 1208-1214. Retrieved from: https://reactome.org/PathwayBrowser/#/R-HSA-9657688&FLG=P00748
[7] MedlinePlus. Hereditary Angioedema. Retrieved from: https://medlineplus.gov/genetics/condition/hereditary-angioedema/.
[2] McKusick. (2006, November 20). Hereditary, Angioedema, 3; HAE3. Last updated June, 2021. Retrieved from: https://omim.org/entry/610618
[3] Miranda AR, Ue AP, Sabbag DV, Furlani Wde J, Souza PK, Rotta O. (2013, July). Hereditary angioedema type III (estrogen-dependent) report of three cases and literature review. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3760933/
[4] US Hereditary Angioedema Association. UpToDate. About Hereditary Angioedema. Retrieved from: https://www.haea.org/pages/p/what_is_hae
[5] NIH. Hereditary angioedema type 3. Retrieved from: https://www.ncbi.nlm.nih.gov/gtr/conditions/C1857728/#:~:text=Autosomal%20dominant%20inheritance,-MedGen%20UID%3A%20141047&text=In%20the%20context%20of%20medical,of%20inheriting%20the%20mutant%20allele.
[6] Fabregat A, Sidiropoulos K, Viteri G, Marin-Garcia P, Ping P, Stein L, D'Eustachio P, Hermjakob H. Reactome diagram viewer: data structures and strategies to boost performance. Bioinformatics (Oxford, England). 2018 Apr;34(7) 1208-1214. Retrieved from: https://reactome.org/PathwayBrowser/#/R-HSA-9657688&FLG=P00748
[7] MedlinePlus. Hereditary Angioedema. Retrieved from: https://medlineplus.gov/genetics/condition/hereditary-angioedema/.
Julia Carey | [email protected] | Genetics 564 Homepage | Last Updated: 02/19/2024