[6] People diagnosed with Hereditary Angioedema have recurrent swelling in the extremities, genitals, face, lips, larynx or GI tract.
Involvement of respiratory structures, such as the throat or larynx, can cause difficulties in breathing and life-threatening airway obstruction.
[7][8] Episodes that attack the gastrointestinal tract can cause a number of complications including vomiting, crampy abdominal pain, diarrhea, and dehydration.
The autosomal dominant inheritance pattern with regards to hereditary angioedema requires receipt of only one copy of the mutated C1 inhibitor gene to have symptomatic disease.
[9][10][11][12] Further, hereditary angioedema with C1 inhibitor deficiency types 1 and 2 have complete penetrance, meaning all of those who inherit the dysfunctional gene will have symptomatic disease.
However, hereditary angioedema with normal C1 inhibitor levels (Type 3 disease) has incomplete penetrance, and men may be asymptomatic carriers despite inheriting a mutated gene.
[7] This activation leads to vascular endothelial cadherin (a type of cell adhesion molecule) phosphorylation, internalization and degradation.
Cadherin degradation leads to actin cytoskeleton contraction and increased pore size of the vascular endothelial cells.
[7] Recognizing HAE is often difficult due to the wide variability in disease expression, with the diagnosis often delayed for years.
This disease may be similar in its presentation to other forms of angioedema resulting from allergies or other medical conditions, but it is significantly different in cause and treatment.
To avoid potentially fatal consequences such as upper airway obstruction and unnecessary abdominal surgery, the importance of a correct diagnosis cannot be overemphasized.
[7] In HAE type II, there is a qualitative deficiency, with normal - sometimes even elevated - C1-inhibitor protein levels, but decreased functional C1-inhibitor measurements.
As a result, it is not uncommon to observe patients with primary recurrent angioedema attacks and C1-inhibitor deficiency where both parents are unaffected.
[26] The mutant plasminogen protein has been shown to be a highly efficient kininogenase that directly releases bradykinin from high- and low-molecular-weight kininogen.
[27] Tongue swellings are a very frequent and characterizing symptom in patients with hereditary angioedema due to a plasminogen mutation.
[7] Treatment with ACE inhibitors is contraindicated in this condition, as these drugs can lead to bradykinin accumulation, which can precipitate disease episodes.
[28][29] People in whom episodes occur at least once a month or who are at high risk of developing laryngeal edema require long-term prevention.
[30] In 2018, the US Food and Drug Administration (FDA) approved lanadelumab, an injectable monoclonal antibody, to prevent attacks of HAE types I and II in people twelve years of age and older.
Lanadelumab inhibits the plasma enzyme kallikrein, which liberates the kinins bradykinin and kallidin from their kininogen precursors and is produced in excess in individuals with HAE types I and II.
[31][32] Berotralstat was approved in the US in December 2020, for the prevention of attacks of hereditary angioedema in people twelve years of age and older.
Ruconest is a recombinant C1 inhibitor approved in the US and the EU that does not carry the risk of infectious disease transmission due to human blood-borne pathogens.
[44][45] Clinical development of several new active substances, which intervene in the disease process in different ways, is currently ongoing.
[citation needed] In October 2010, the European Medicines Agency authorized conestat alfa (brand name Ruconest), a C1-inhibitor for the treatment of acute angioedema attacks.
[46] Icatibant (marketed as Firazyr) is a selective bradykinin receptor antagonist, was authorized in the EU in July 2008,[47][48] and was approved in the US in August 2011.
The investigational antisense oligonucleotide donidalorsen significantly reduced hereditary angioedema attack rates and improved patient-reported quality of life when administered 80 mg subcutaneously every 4 or 8 weeks.