Some science behind the scenes

Hereditary angioedema

Hereditary angioedema (HAE) is a rare, autosomal dominantly inherited blood disorder.  This disorder affects approximately one in 10,000–50,000 people.  It is caused by a mutation in the C1 inhibitor - C1-INH gene or SERPING1 gene.

Because hereditary angioedema is an autosomal inheritable disease, there is no gender difference in transmission and both sexes are equally likely to receive the mutated gene from their parent(s). Mortality rates are estimated at 15–33%, resulting primarily from laryngeal edema and asphyxiation. HAE leads to 15,000–30,000 emergency department visits per year.

Symptoms

HAE causes episodic attacks of swelling that may affect the face, extremities, genitals, gastrointestinal tract and upper airways.  Swelling of the intestinal mucosa may lead to vomiting and painful, colic-like intestinal spasms that may mimic intestinal obstruction. Airway edema may be life-threatening.

Episodes may be triggered by trauma, surgery, dental work, menstruation, some medications, viral illness and stress; however, this is not always readily determined.

  • HAE type I - The most common form of the disorder is HAE type I, which is the result of abnormally low levels of certain complex proteins in the blood (C1 esterase inhibitors), known as complements. They help to regulate various body functions (e.g., flow of body fluids in and out of cells).
  • HAE type II  - is a more uncommon form of the disorder. It occurs as the result of the production of abnormal complement proteins and accounts for about 15-20% of this disorder.
  • HAE Type III is a very rare recently documented form: It predominantly affects females and it is influenced by exposure to estrogens or hormone replacement therapy (e.g. oral contraceptives and pregnancy). HAE type III is not due to C1 INH gene deficiency; it is linked to an increase in kininogenase activity leading to elevated levels of bradykinin. Some patients with type III HAE have a mutation in the F12 gene which produces a protein involved in blood clotting.

Cause

The underlying cause of HAE is attributed to autosomal dominant inheritance of mutations in the C1 inhibitor (C1-INH gene or SERPING1 gene), which is mapped to chromosome 11 (11q12-q13.1).To date there are over 300 known genetic mutations that result in a deficiency of functional C1 Inhibitor. 2-4 The majority of HAE patients have a family history; however, 25% are the result of new mutations. The low level of C1 inhibitor in the plasma leads to increased activation of pathways that release bradykinin, the chemical responsible for the angioedema due to increased vascular permeability, and the pain seen in individuals with HAE.

The prevalence of HAE is relatively low - between 1 in every 10,000 to 1 in every 50,000 persons. Most of people with HAE acquire a C1 esterase inhibitor (C1-INH) mutation from one of their parents. A parent with HAE usually has a 50% probability of transmitting this condition on to one of his/her children of either sex. In occasions when HAE is not inherited and occurs in people with no previous history of it, the cause of the mutation is unknown but is believed to be caused in the sperm or egg cell that is responsible for this specific pregnancy.

In a review of patients who do not have a history of HAE in their family, but who have relatively low levels of mutated C1-INH with persistent angioedema, 25% of new patients who had HAE had C1-INH changes that do not show signs of being inherited but rather new.

 A blood test can be used to diagnose the condition.

Although the cause of the various manifestations is a mutation in the gene, this is not in fact the actual cause, as we need to know what caused the mutation.

As the problem here is a generic one for all inherited diseases caused by mutation it is discussed in the section Inherited illness, please follow the link.

References

  • "What is Hereditary Angioedema?" HAE Canada.
  • Overview of hereditary angioedema caused by C1-inhibitor deficiency: assessment and clinical management. Bork K, Davis-Lorton M.]
  • Type III hereditary angioedema: defined, but not understood. Kaplan A. Ann Allergy Asthma Immunol. 2012 Sep;109(3):153-4. doi: 10.1016/j.anai.2012.07.007.
  • Genetic test indications and interpretations in patients with hereditary angioedema. Weiler CR, van Dellen RG. Mayo Clin Proc. 2006 Jul;81(7):958-72. Review.
  • Zingale LC, Beltrami L, Zanichelli A, et al. (October 2006). "Angioedema without urticaria: a large clinical survey". CMAJ 175 (9): 1065–70. doi:10.1503/cmaj.060535. PMC 1609157. PMID 17060655.