A recent study published in the journal Internal Medicine reports on a case of a Japanese family with hereditary angioedema (HAE) caused by a missense mutation of the plasminogen gene.

The authors suggest the inheritance mode of the missense mutation p.Lys330Glu (K330E) in exon 9 of the plasminogen gene is autosomal dominant and offer insight into the clinical features of Japanese patients with this condition.

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The index patient, a 65-year-old woman, reported having attacks marked by severe tongue and lip swelling for 1 year before the hospitalization. The index patient’s mother had also suffered from unexplained suffocation, while her sister and younger brother had also experienced similar symptoms.

Suspecting HAE as a likely diagnosis, the researchers performed genetic analyses of the C1 inhibitor gene SERPING1, plasminogen, and factor XII (F12) genes for all family members. In the index patient, direct sequencing of all the exons and their flanking introns of the SERPING1 gene and the F12 gene showed no mutations. Subsequent direct sequencing of exon 9 of the plasminogen gene revealed a heterozygous missense mutation, K330E. This mutation was also detected in the index patient’s daughter, sister, brother, nephews, and nieces.

According to the information gathered, attacks occurred up to 10 times per year, and the symptoms were located in the tongue or facial area as well as the abdomen while swelling in the extremities was absent.

With regards to treatment, the study authors found bradykinin B2 receptor antagonists and to a lesser extent, plasma-derived C1-INH concentrates to be effective. Tranexamic acid was also useful in improving the symptom relief time and frequency of swelling attacks in several family members of the case family.

The pathophysiology of HAE linked to plasminogen gene mutation, which is the only non-C1-inhibitor genetic mutation detected in Japanese people with HAE at present, remains unclear. The study authors hypothesize that K330E may increase plasmin activity, leading to the activation of substances like coagulation factor XII involved in the cascade of HAE.

“Plasmin has an extremely short half-life in blood and is difficult to measure directly, but the alpha2-plasmin inhibitor-plasmin complex may permit the indirect measurement of the plasmin function. Further studies will be needed to clarify the pathophysiology,” the study authors wrote.

This is the third Asian family with HAE to have a normal expression of the C1 inhibitor and a missense mutation of the plasminogen gene. To date, 146 patients from 33 families have been reported to carry the K330E mutation in the plasminogen gene worldwide.

Reference

Yakushiji H, Yamagami K, Hashimura C, et al. A missense mutation of the plasminogen gene in a Japanese family with hereditary angioedema with normal C1 inhibitor: third family survey in AsiaIntern Med. Published online on November 23, 2022. doi: 10.2169/internalmedicine.0645-22