Hereditary angioedema-4 (HAE4) is an autosomal dominant disorder characterized by episodic subcutaneous or submucosal edema, usually occurring in adulthood (see also Angioedema/Overview).
Hereditary angioedema-4 (HAE4) is caused by a heterozygous mutation in the PLG gene (173350) located on chromosome 6q26. A common mutation is the K330E mutation in the PLG gene (173350.0011).
Although the disorder is autosomal dominant, there is evidence of incomplete penetrance, variable expression, and a preponderance of females.
The pathogenesis is thought to be due to altered plasmin function leading to increased release of bradykinin. Remarkably, in 14% of affected women, the first symptoms occurred after taking oral contraceptives . In other patients, the triggering of symptoms may be due to the use of ACE inhibitors or angiotensin II receptor blockers.
The mean age at onset of symptoms is 30.5 years (5-72 years) (Bork K et al. 2018)
Circulating C1 inhibitor (C1INH) levels and function, as well as plasminogen levels and activity, are normal.
Molecular genetics: In 60 patients from 13 unrelated families of European ancestry with HAE4, Bork et al (2018) identified a heterozygous missense mutation in exon 9 of the PLG gene(K330E; 173350.0011). The mutation, found by whole-exome sequencing or next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in families. Dewald (2018) identified heterozygosity for the K330E mutation in the PLG gene in 18 patients from three unrelated multigenerational German families with HAE4. Isoelectric focusing of patient plasma identified PLG protein bands that differed from those of controls. The results suggest that the mutation has somequantitative and qualitative effects on the glycosylation of plasminogen. The K330E substitution is located in the so-called kringle-3 domain, which is important for binding and allows plasminogen or plasmin to interact with other protein ligands. It is thought that the mutation may affect the affinity of binding partners and thus have functional effects, particularly on the kinin signaling pathway that regulates circulating vasoactive substances. Belbezier et al (2018) identified the K330E mutation in 10 patients from 3 unrelated French families with HAE4. Farkas et al (2021) reported a 60-year-old woman with HAE4 and the common K330E mutation. She was identified from 124 patients with HAE of unknown origin. Her son, who also carried the K330E mutation, was asymptomatic.
Successful clinical treatment has been achieved with tranexamic acid, which inhibits plasmin, and ikatibant, a selective bradykinin B2 receptor antagonist (113503) (abstract in Farkas et al., 2021).
The median duration of angioedema episodes is 20.6 years according to a larger study (Bork K et al. 2018)
Bork et al (2018) reported 18 affected individuals from 4 unrelated multigenerational families (families A-D) with hereditary angioedema and normal C1INH levels. Subsequently, 9 additional unrelated subjects were identified, resulting in a total of 60 symptomatic patients from 13 families. There were 47 affected women and 13 affected men. The mean age at onset of symptoms was 30.5 years (range 5-72 years), and the mean duration of angioedema episodes was 20.6 years (range 1-72 years). Patients had recurrent swelling of the skin, most commonly affecting the face, lips, and tongue; sometimes the larynx was also affected. Tongue swelling occurred frequently and was sometimes associated with dyspnea, voice changes, and impending asphyxia. Two women died at the ages of 36 and 47 years, respectively, from choking due to tongue swelling with upper airway obstruction. Some patients had swelling of the arms or hands, feet or legs, and abdomen; none had swelling of the genital area. In 14% of women, the first symptoms occurred after they began taking oral contraceptives, suggesting estrogen influence, although onset or exacerbation during pregnancy was not reported. Plasminogen activity was within the normal range in 3 women. Two patients were successfully treated with tranexamic acid, which is an antifibrinolytic and inhibits plasmin. These results suggest a role for fibrinolysis in the pathogenesis of the disease.
Dewald (2018) reported on three unrelated multigenerational German families in which a total of 13 women and 5 men had HAE. Clinical details were limited, but all had recurrent episodes of angioedema, often involving the tongue. C1 inhibitor levels were normal.
Yakushiji et al (2018) reported on two unrelated Japanese families in which two members each had HAE4. The proband in family 1 was a 97-year-old woman in whom angioedema of the tongue first appeared at age 94 years. She had been taking an ACE inhibitor and discontinued it. Angioedema occurred a second time 3 months later and required intubation because of airway obstruction. Her 65-year-old son had a single episode of labial angioedema after surgery at age 35. Reportedly, several other family members were affected but either died or did not consent to genetic testing. The proband in the second family was a 46-year-old woman in whom angioedema first appeared at age 26. Over the years, she had numerous attacks, usually affecting the tongue and face, less commonly the larynx or abdomen, which could be triggered by travel or lack of sleep. She was successfully treated with tranexamic acid. An older sister had 2 seizures during dental treatment that resolved without treatment. All had normal C1 inhibitor levels.
Belbezier et al (2018) reported 10 patients from 3 unrelated French families with HAE4. Seven patients were women. The median age at onset was 23 years (range, 6-64 years) with a median delay in diagnosis of 24 years (range, 5-47 years). Most had seizures of the face, lips, ENT, tongue, and abdomen. The extremities were not affected. C1INH was normal in all, and plasminogen activity was normal in all but one patient. Four patients reported triggering by taking ACE inhibitors or angiotensin II receptor blockers. Oral contraceptives exacerbated seizures in 2 patients. Long-term prophylaxis with tranexamic acid was effective in 2 patients. Icatibant also resulted in clinical improvement.
Farkas et al (2021) reported on a 60-year-old woman with HAE4 who carried the common K330E mutation in the PLG gene (173350.0011). She had her first episode at age 17 years and was asymptomatic for the next 20 years until she started taking an ACE inhibitor because of hypertension, which was associated with reactivation of episodes. The condition, which manifested mainly as recurrent edema of the tongue, face, and larynx, was also known to run in her family. Her son, who also carried the K330E mutation, was asymptomatic.