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83?Hereditary Angioedema and Normal C1-Inhibitor (HAE TYPE III): A Novel Mutation in the Coagulation Factor 12 Gene.

ABSTRACT: BackgroundHereditary angioedema with normal C1-inhibitor and mutations in the coagulation factor 12 gene is a recently described disease entity that occurs predominantly in women. Up to date, 2 different missense mutations of codon p.Thr328* in the coagulation factor 12 gene have been reported, co-segregating with clinical signs. Aim of the study was to assess the clinical symptoms, mutations in the factor 12 gene, and plasma parameters of this disease in a family with hereditary angioedema with normal C1-inhibitor.MethodsSix members of one family were studied, including 2 women with recurrent angioedema. Mutation analysis of the factor XII gene was performed.ResultsBy sequencing the factor 12 gene, a hitherto unknown mutation, the deletion of 72 base pairs (c.971_1018+24del72*), was identified in a family of Turkish origin, in 2 women with recurrent skin swellings and abdominal pain attacks, and in their symptom-free father. The novel mutation c.971_1018+24del72* caused a loss of 48 base pairs of exon 9 (coding amino acids 324* to 340*) in addition to 24 base pairs of intron 9, including the authentic donor splice site of exon 9. All carriers of this mutation had normal plasma concentrations and activity of C1-inhibitor, C4, factor XII clotting activity, and activated partial thromboplastin times.ConclusionsThe novel deletion mutation in the factor 12 gene was located in the same F12 gene region as the missense mutations p.Thr328Lys* and p.Thr328Arg* reported previously, suggesting the importance of the exon 9 to intron 9 DNA region for the development of hereditary angioedema with normal C1-inhibitor.

SUBMITTER: Bork K

PROVIDER: S-EPMC3512582 | biostudies-other | 2012 Feb

REPOSITORIES: biostudies-other

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Project description:BackgroundHereditary angioedema (HAE) is characterized by unpredictable attacks of debilitating subcutaneous and mucosal edema. Gastrointestinal attacks are painful, of sudden onset and often mistaken for acute abdomen leading to unnecessary surgery. The purpose of this study was to analyze symptom presentation of gastrointestinal angioedema in pediatric and adult HAE patients.MethodsInformation collected during the clinical development of ecallantide for treatment of acute HAE attacks included affected anatomic location, accompanying symptoms, medical history, and pain assessments. Efficacy endpoints included Treatment Outcome Score (TOS, maximum score = 100; minimally important difference = 30), a point-in-time measure of treatment response, and time to treatment response.ResultsForty-nine percent of 521 HAE attacks only involved abdominal symptoms. The most commonly reported abdominal symptoms were distension (77%), cramping (73%) and nausea (67%). The most common pain descriptors were tender, tiring-exhausting, aching, cramping and sickening. White blood cell counts were elevated (>10 × 10(9)/L) in 23% of attacks (mean ± SD: 15.1 ± 11.27 × 10(9)/L). A high proportion of patients reported a history of abdominal surgery, including appendectomy (23%), cholecystectomy (16.4%), and hysterectomy (8.2%). Mean TOS at 4 hours post ecallantide was 77 ± 33 versus 29 ± 65 for placebo. Median time to significant symptom resolution was 165 minutes (95% CI 136, 167) for ecallantide versus >4 hours (95% CI 161, >4 hours) for placebo. Anaphylactic reactions occurred in 6 of the 149 treated patients.ConclusionsHAE should be considered in the differential diagnosis of patients with recurrent discrete episodes of severe, unexplained crampy abdominal pain associated with nausea.Trials registrationThe data used in the analysis were gathered across multiple clinical trials conducted during the clinical development program for ecallantide. All of the studies were conducted using Good Clinical Practices (GCP) and in accordance with the ethical principles that have their origins in the Declaration of Helsinki. Each site that participated in the clinical trials obtained the appropriate IRB or Ethics Committee approval prior to enrolling any patients. All patients provided written informed consent prior to undergoing any study-related procedures. Pediatric patients provided written assent and their parents or guardians gave written informed consent.The following trials have been registered at http://www.clinicaltrials.gov: EDEMA2 (identifier NCT01826916); EDEMA3 (identifier NCT00262080); EDEMA4 (identifier NCT00457015); and DX-88/19 (identifier NCT00456508).

Project description:BackgroundHereditary angioedema (HAE) caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein (C1-INH-HAE) is a disabling, potentially fatal condition characterized by recurrent episodes of swelling. We have recently found that patients with C1-INH-HAE have increased plasma levels of vascular endothelial growth factors and angiopoietins (Angs), which have been associated with vascular permeability in several diseases. Among these and other factors, blood endothelial cells and vascular permeability can be modulated by extracellular or secreted phospholipases A2 (sPLA2s).ObjectiveWe sought to investigate the enzymatic activity and biological functions of sPLA2 in patients with C1-INH-HAE.MethodssPLA2s enzymatic activity was evaluated in the plasma from 109 adult patients with C1-INH-HAE and 68 healthy donors in symptom-free period and attacks. Plasma level of group IIA sPLA2 (hGIIA) protein was measured in selected samples. The effect of C1-INH-HAE plasma on endothelial permeability was examined in vitro using a vascular permeability assay. The role of hGIIA was determined using highly specific sPLA2 indole inhibitors. The effect of recombinant hGIIA on C1-INH activity was examined in vitro by functional assay.ResultsPlasma sPLA2 activity and hGIIA levels are increased in symptom-free C1-INH-HAE patients compared with controls. sPLA2 activity negatively correlates with C1-INH protein level and function. C1-INH-HAE plasma increases endothelial permeability in vitro, and this effect is partially reverted by a specific hGIIA enzymatic inhibitor. Finally, recombinant hGIIA inhibits C1-INH activity in vitro.ConclusionsPLA2 enzymatic activity (likely attributable to hGIIA), which is increased in C1-INH-HAE patients, can promote vascular permeability and impairs C1-INH activity. Our results may pave the way for investigating the functions of sPLA2s (in particular, hGIIA) in the pathophysiology of C1-INH-HAE and may inform the development of new therapeutic targets.

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83?Hereditary Angioedema and Normal C1-Inhibitor (HAE TYPE III): A Novel Mutation in the Coagulation Factor 12 Gene.

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