Angiooedema, hereditary, 5 D84.1

Hereditary angioedema with mutation in ANGPT1 is caused by a heterozygous mutation in the ANGPT1 gene (601667) on chromosome 8q23.

Comment: Knowledge of rare genetic diseases such as hereditary angioedema (HAE) has evolved in parallel with the development of new molecular tools. C1 inhibitor (C1-INH) deficiency has been recognized as the major cause of HAE (HAE-C1-INH) since the 1960s. Discovery of the broad spectrum of mutations affecting the C1-INH gene (SERPING1) was not possible until the late 1980s, when Sanger sequencing became available and more readily accessible worldwide.

However, the involvement of other genes in HAE was not discovered until 2006 with the description of mutations in the F12 gene in patients with HAE and normal C1-INH. The knowledge gained through the new era of genomics has been crucial for the discovery of mutations in additional genes, improving or explaining the understanding of the complex pathogenesis of this phenotypically largely identical disease. In the last three years, advanced next-generation sequencing techniques have enabled the identification of mutations in five additional novel genes associated with hereditary angioedema variants with normal C1-INH (nC1-INH-HAE): ANGPT1 (angiopoietin-1), PLG (plasminogen), KNG1 (kininogen), MYOF (myoferlin), and HS3ST6 (heparan sulfate glucosamine 3-O-sulfotransferase 6).

In 4 affected women from an Italian family with third-generation HAE5, Bafunno et al (2018) identified a heterozygous missense mutation in the ANGPT1 gene (A119S; 601667.0002). The mutation was found by whole-exome sequencing and was confirmed by Sanger sequencing. Patients' plasma showed normal ANGPT1 levels, but there was a reduction in multimeric forms compared with wild type. The mutant protein also showed decreased binding to its membrane receptor TIE2 (600221). Bafunno et al (2018) hypothesized that altered ANGPT1 function affects bradykinin-mediated endothelial permeability.

Mostly second decade of life

Tranexamic acid treatment can effectively reduce seizure severity and frequency (Bafunno et al. 2018).

Bafunno et al (2018) reported 4 female members of a third-generation Italian family with HAE. The affected individuals had recurrent episodes of angioedema that began in the second decade. Patients reported approximately 2 episodes per year that lasted 24 to 48 hours and usually involved the skin, face, lips, oral mucosa, hands, and abdomen. Occasionally, the attacks were triggered by mechanical stimuli that were slow in onset and subsided. Nail fold capillaroscopy showed tortuous loops, microhemorrhages, and decreased skin transparency caused by edema. These changes indicated microcirculation involvement with increased capillary permeability. None of the patients responded to antihistamines or steroids; 2 patients responded well to tranexamic acid treatment.

1. Bafunno V et al (2018) Mutation of the angiopoietin-1 gene (ANGPT1) associates with a new type of hereditary angioedema. J Allergy Clin Immun 141: 1009-1017.
2. Santacroce R et al (2021) The genetics of hereditary angioedema: A review J Clin Med 10: 2023.
3. Zuraw BL (2018) Hereditary angioedema with normal C1 inhibitor: four types and counting. J Allergy Clin Immun 141: 884-885.