Hereditary angioedema with<i>F12</i>mutation: factors modifying the clinical phenotype

Charignon, Delphine; Ghannam, Arije; Defendi, Federica; Ponard, D.; Monnier, Nicole; López-Trascasa, Margarita; Launay, David; Caballero, Teresa; Djenouhat, Kamel; Fain, Olivier; Cichon, Sven; Martin, Ludovic; Drouet, Christian

doi:10.1111/all.12515

Cited by 31 publications

(29 citation statements)

References 36 publications

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“…In symptomatic F12 mutation carriers, we always observed increased spontaneous amidase activity, again supporting the concept that increased kinin formation would be indicative of disease occurrence [24]. In addition to oestrogen intake, the clinical presentation of these AOs could be strongly influenced by a low BK catabolism depending on ACE activity, a situation distinct from that observed for C1-INH-HAO depending on APP activity [23,31,33]. …”

Section: Discussionsupporting

confidence: 68%

“…This has certainly introduced a recruitment bias and subsequent over-evaluation of the frequency of these cases. We believe however that BK-AO is actually a syndromic condition caused by multiple, inherited or acquired, factors that are often combined to determine both the onset of AO and occurrence of attacks [23,31,34]. These factors may determine increased BK production and/or decreased BK catabolism in a synergistic fashion, and/or interact with kinin receptors or with drugs targeting the kinin metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…In order to investigate the kinin catabolism, the plasma activities of the three major enzymes involved in kinin degradation (kininases) were evaluated, i.e. carboxypeptidase N (CPN), angiotensin I-converting enzyme (ACE) and aminopeptidase P (APP) as previously reported [23,31]. Whenever possible, measurements were performed in the course of an AO attack.…”

Section: Methodsmentioning

confidence: 99%

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Distinct Conditions Support a Novel Classification for Bradykinin-Mediated Angio-Oedema

Dessart

Defendi²,

Humeau³

et al. 2015

Dermatology

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Background: Angio-oedema (AO) can be attributable to bradykinin (BK) accumulation, as is the case for prototypical hereditary AO (HAO) due to C1 inhibitor (C1-INH) deficiency. However, our clinical experience in a reference centre has shown that some patients display a clinical history suggestive of HAO, but exhibit normal C1-INH function, have no mutation in the causative genes associated with HAO (SERPING1, F12), and report no intake of drugs known to promote AO. Objective: We sought to determine the frequency and distribution of different AO subtypes suspected to be BK-mediated AO (BK-AO) and defined by clinical, history and biological criteria (enzyme activities implicated in BK formation and catabolism). Methods: The files of all patients referred to our centre for suspected BK-AO were retrospectively analysed. Results: The distribution of patients (n = 162) was 16 and 4% with a hereditary deficiency of C1-INH or a gain of factor XII function, respectively, 29% with iatrogenic BK-AO, 21% with non-iatrogenic defective kininase activity and 30% with idiopathic increased kinin formation. Conclusion: BK-AO may be caused by multiple inherited or acquired factors triggering BK accumulation. Therefore, we propose a novel typology for BK-AO based on the imbalance of production/catabolism of BK.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Distinct Conditions Support a Novel Classification for Bradykinin-Mediated Angio-Oedema

Dessart

Defendi²,

Humeau³

et al. 2015

Dermatology

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“…Spontaneous amidase activity in plasma as a surrogate marker for serine protease activity of the CP and fibrinolytic system has been shown to be increased in patients with FXII-HAE regardless the clinical severity (60). Interestingly, ACE and CPN activity levels inversely correlated with disease severity pointing to the important role of BKdegrading enzymes in the pathogenesis of HAE type III, but most probably in other forms as well (61).…”

Section: C1-inhibitor Regulates Bk Generationmentioning

confidence: 99%

Hereditary and acquired C1-inhibitor-dependent angioedema: from pathophysiology to treatment

Zeerleder

Levi

2016

Annals of Medicine

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Uncontrolled generation of bradykinin (BK) due to insufficient levels of protease inhibitors controlling contact phase (CP) activation, increased activity of CP proteins, and/or inadequate degradation of BK into inactive peptides increases vascular permeability via BK-receptor 2 (BKR2) and results in subcutaneous and submucosal edema formation. Hereditary and acquired angioedema due to C1-inhibitor deficiency (C1-INH-HAE and -AAE) are diseases characterized by serious and potentially fatal attacks of subcutaneous and submucosal edemas of upper airways, facial structures, abdomen, and extremities, due to inadequate control of BK generation. A decreased activity of C1-inhibitor is the hallmark of C1-INH-HAE (types 1 and 2) due to a mutation in the C1-inhibitor gene, whereas the deficiency in C1-inhibitor in C1-INH-AAE is the result of autoimmune phenomena. In HAE with normal C1-inhibitor, a significant percentage of patients have an increased activity of factor XIIa due to a FXII mutation (FXII-HAE). Treatment of C1-inhibitordependent angioedema focuses on restoring control of BK generation by inhibition of CP proteases by correcting the balance between CP inhibitors and BK breakdown or by inhibition of BK-mediated effects at the BKR2 on endothelial cells. This review will address the pathophysiology, clinical picture, diagnosis and available treatment in C1-inhibitor-dependent angioedema focusing on BK-release and its regulation. ä KEY MESSAGESInadequate control of bradykinin formation results in the formation of characteristic subcutaneous and submucosal edemas of the skin, upper airways, facial structures, abdomen and extremities as seen in hereditary and acquired C1-inhibitor-dependent angioedema. Diagnosis of hereditary and acquired C1-inhibitor-dependent angioedema may be troublesome as illustrated by the fact that there is a significant delay in diagnosis; a certain grade of suspicion is therefore crucial for quick diagnosis. Submucosal edema formation in hereditary and acquired C1-inhibitor-dependent angioedema is potentially life threatening and can occur at any age. To date effective therapies for acute and prophylactic treatment are available. ARTICLE HISTORY

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“…57 Por último, está el icatibant, un antagonista potente del receptor B2 de la bradiquinina, con afinidad y especificidad elevadas por los receptores de las quininas, disponible en jeringas precargadas de 30 mg para administración subcutánea durante el ataque agudo, con una aplicación máxima de 90 mg/24 horas. [58][59][60] En otras partes del mundo existen otras opciones de tratamiento, algunas reemplazan la proteína deficiente, como el C1 inhibidor humano derivado del plasma y el C1 inhibidor recombinante; [61][62][63] así como el ecallantide, un inhibidor reversible de la calicreína plasmática.…”

Section: Tratamientounclassified

Angioedema

Holguín-Gómez

Vásquez-Ochoa

Cardona

2016

RAM

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Angioedema is defined as edema of the skin or mucosa, including the respiratory and the gastrointestinal mucosa, which is self-limiting, and in most cases is completely resolved in less than 72 hours. It occurs due to increased permeability of the mucosal and submucosal capillaries and postcapillary venules, with resulting plasma extravasation. There are different types of angioedema: histaminergic (which may be mediated by immunoglobulin E), hereditary, from acquired C1 inhibitor deficiency, from angiotensin converting enzyme inhibitor, bradykinin-mediated, and nonhistaminergic idiopathic angioedema. Treatment depends on the cause of angioedema, age, and the frequency and severity of manifestations. The main measures are avoiding external triggers or causes, giving antihistamines, steroids, or adrenaline for histaminergic angioedema; replacing the deficient protein or blocking the action of bradykinin in C1 inhibitor deficiency and angioedema from angiotensin converting enzyme inhibitor.

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Hereditary angioedema withF12mutation: factors modifying the clinical phenotype

Abstract: The FXII-HAE is associated with modifiers, for example kinin catabolism enzymes, ACE and CPN, different from those recognized in HAE with C1Inh deficiency.

Cited by 31 publications

References 36 publications

Distinct Conditions Support a Novel Classification for Bradykinin-Mediated Angio-Oedema

Distinct Conditions Support a Novel Classification for Bradykinin-Mediated Angio-Oedema

Hereditary and acquired C1-inhibitor-dependent angioedema: from pathophysiology to treatment

Angioedema

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