Plasminogen gene mutation with normal C1 inhibitor hereditary angioedema: Three additional French families

Belbézier, Aude; Hardy, G.; Marlu, Raphaël; Defendi, Federica; Perard, Chantal Dumestre; Boccon‐Gibod, Isabelle; Launay, David; Bouillet, Laurence

doi:10.1111/all.13543

Cited by 43 publications

(48 citation statements)

References 6 publications

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“…Together with the report from Belbezier et al. , the data indicate that the majority of HAE‐PLG patients (ranging between 78–87 %) experience angioedema attacks of the tongue (Table ), and it was suggested that this was characteristic of HAE‐PLG, distinguishing it from HAE‐C1‐INH (12 %) and HAE‐FXII (33 %) . In our study, the percentage of patients who experienced swelling of the tongue was 50 %, similar to a report by Yakushiji et al.…”

Section: Discussionsupporting

confidence: 90%

“…We found the most common symptom for HAE‐PLG to be edema of the lips, experienced by 80 % of our patients, compared to 50 to 62 % in the literature (Table ). The rarest symptoms for HAE‐PLG in our patients include edema of the abdomen (10 %) and extremities (0 %).…”

Section: Discussionmentioning

confidence: 55%

“…Recently the first findings on patients with HAE-PLG were reported, describing the type of mutation and symptoms for this disease [7]. Together with the report from Belbezier et al [8], the data indicate that the majority of HAE-PLG patients (ranging between 78-87 %) experience angioedema attacks of the tongue (Table 5), and it was suggested that this was characteristic of HAE-PLG, distinguishing it from HAE-C1-INH (12 %) [13] and HAE-FXII (33 %) [7]. In our study, the percentage of patients who experienced swelling of the tongue was 50 %, similar to a report by Yakushiji et al [9], which is significantly lower than the value reported by Bork et al [7] and only somewhat higher than the average for HAE-FXII.…”

Section: Discussionmentioning

confidence: 77%

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Hereditary angioedema in a single family with specific mutations in both plasminogen and SERPING1 genes

Bork

Zibat

Ferrari

et al. 2020

J Deutsche Derma Gesell

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Summary Background Hereditary angioedema (HAE) is a group of genetic diseases characterized by recurrent, painful and potentially lethal tissue swelling. The most common form results from mutations in the SERPING1 gene, leading to reduced function of complement 1 inhibitor (C1‐INH). Rarer forms with normal C1‐INH may arise from mutations in the coagulation factor F12 gene, but mostly the genetic background is unknown. Recently, a novel HAE mutation in the plasminogen (PLG) gene was shown. Patients and methods We analyzed the various clinical manifestations of HAE in 14 related patients using clinical data, biochemical analysis for C1‐INH and C4 as well as gene sequencing. Results Patients’ symptoms were assigned to two different forms of HAE. In ten patients suffering from swelling of the lips or tongue but not of the extremities, a mutation in the PLG gene (c.988A>G) was found whereas in the only four patients with swelling of the gastrointestinal tract and extremities, a mutation in the SERPING1 gene (c.1480C>T) was identified. In two cases this was additional to PLG c.988A>G. Conclusions This unique finding of two different HAE‐specific mutations in a large family not only explains the divergent phenotypes but also supports a genotype‐phenotype correlation showing that abdominal attacks and swelling of the extremities are common with HAE‐C1‐INH but unusual with HAE‐PLG.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 77%

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Hereditary angioedema in a single family with specific mutations in both plasminogen and SERPING1 genes

Bork

Zibat

Ferrari

et al. 2020

J Deutsche Derma Gesell

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“…Secondly, there is a growing body of biochemical evidence for a role of plasmin as activator of the contact system [6,10,11] More convincingly, there good clinical experience with tranexamic acid as a maintenance therapy in both forms of HAE [7,12,13], and even in patients with (H)AE of unknown origin [14]. This may be explained by our biochemical findings that show that tranexamic acid blocks FXII activation by plasmin [6].The identification of a mutation in the plasminogen (PLG) gene in families with HAE from multiple countries gives rise to the idea that plasmin is an active contributor to bradykinin production [15][16][17]. However, the majority of patients respond well to tranexamic acid.…”

mentioning

confidence: 85%

Hereditary angioedema: the plasma contact system out of control: reply

Maat

Hofman

Maas

2018

Journal of Thrombosis and Haemostasis

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We thank Drs Loffredo and Marone for their interest in our article and correspondence, which summarizes their impressive scientific contributions to the complex field of vascular biology.In our review, we provide an overview of the role of the plasma contact system, classically seen as part of the coagulation system, in hereditary angioedema [1]. The active role of the contact system in this pathology is evident, as both C1 esterase inhibitor (C1INH) deficiency and gain-of-function mutations in factor XII (FXII) result in hereditary angioedema (HAE). After decades of investigation, it became clear that clinical symptoms of C1INH deficiency are attributable to contact systemdependent bradykinin formation, rather than a complement-related disease mediator [2]. This is supported by positive clinical experience with selective kinin B2 receptor (B2R) antagonism [3], as well as prophylactic selective blockade of plasma kallikrein (PKa) in C1INH deficiency [4]. Together these findings show us that the contact system is very important in C1INH-HAE.For other types of HAE with normal C1INH activity that have been identified more recently, disease mediators are sometimes less clear. Biochemical studies by us and others have shown that mutations in the gene that encodes FXII change protein glycosylation, which lowers the threshold for binding to triggering polyanions [5]. Furthermore, several of these mutations introduce novel cleavage sites that are sensitive to plasmin. Truncation of pathogenic mutant FXII by plasmin amplifies its capacity for enzymatic activation in solution [6]. The former paper shows in vivo in mouse models that the pathogenic prop-erties of mutant FXII are dependent on prekallikrein activation [5]. The latter paper demonstrates that induction of plasminogen activation in FXII-HAE patient plasma provokes an 'explosion' of bradykinin production [6]. However, neither paper definitively demonstrates that bradykinin is a critical disease mediator in human FXII-HAE patients during a real-world angioedema attack. Fortunately, recent clinical studies have demonstrated that this is most probably the case: both infusion of additional C1INH and B2R inhibition are therapeutic in FXII-HAE patients [7].In our review, we propose that plasmin makes a significant contribution to bradykinin C1INH-HAE and FXII-HAE; firstly, levels of plasmin-a2-antiplasmin complexes are elevated during swelling attacks [8,9]. Secondly, there is a growing body of biochemical evidence for a role of plasmin as activator of the contact system [6,10,11] More convincingly, there good clinical experience with tranexamic acid as a maintenance therapy in both forms of HAE [7,12,13], and even in patients with (H)AE of unknown origin [14]. This may be explained by our biochemical findings that show that tranexamic acid blocks FXII activation by plasmin [6].The identification of a mutation in the plasminogen (PLG) gene in families with HAE from multiple countries gives rise to the idea that plasmin is an active contributor to bradykinin production [...

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“…Treatment experiences are still limited; however, case reports and studies suggest that C1INH concentrates, icatibant, and ecallantide might be beneficial for acute attacks while progestins, danazol, and tranexamic acid can be used for prophylaxis [25, 30, 32, 51, 75, 128-133]. …”

Section: Therapiesmentioning

confidence: 99%

Hereditary Angio-Oedema for Dermatologists

Bygum¹

2019

Dermatology

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Among angio-oedema patients, hereditary angio-oedema (HAE) should not be overlooked. Besides skin swellings, these patients might have very painful abdominal attacks and potentially life-threatening angio-oedema of the upper airway. They will not respond to traditional anti-allergic therapy with antihistamines, corticosteroids, and adrenaline, and instead need specific drugs targeting the kallikrein-kinin pathway. Classically, patients with HAE have a quantitative or qualitative deficiency of the C1 inhibitor (C1INH) due to different mutations in SERPING1, although a new subtype with normal C1INH has been recognised more recently. This latter variant is diagnosed based on clinical features, family history, or molecular genetic testing for mutations in F12, ANGPT1,or PLG.The diagnosis of HAE is often delayed due to a general unfamiliarity with this orphan disease. However, undiagnosed patients are at an increased risk of unnecessary surgical interventions or life-threatening laryngeal swellings. Within the last decade, new and effective therapies have been developed and launched for acute and prophylactic therapy. Even more drugs are under evaluation in clinical trials. It is therefore of utmost importance that patients with HAE are diagnosed as soon as possible and offered relevant therapy with orphan drugs to reduce morbidity, prevent mortality, and improve quality of life.

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Plasminogen gene mutation with normal C1 inhibitor hereditary angioedema: Three additional French families

Cited by 43 publications

References 6 publications

Hereditary angioedema in a single family with specific mutations in both plasminogen and SERPING1 genes

Hereditary angioedema in a single family with specific mutations in both plasminogen and SERPING1 genes

Hereditary angioedema: the plasma contact system out of control: reply

Hereditary Angio-Oedema for Dermatologists

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