Clinical and genetic features of hereditary angioedema with and without C1-inhibitor (C1-INH) deficiency in Japan.
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ABSTRACT:
SUBMITTER: Hashimura C
PROVIDER: S-EPMC9291306 | biostudies-literature | 2021 Nov
REPOSITORIES: biostudies-literature
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Clinical and genetic features of hereditary angioedema with and without C1-inhibitor (C1-INH) deficiency in Japan.
Hashimura Chinami C Kiyohara Chikako C Fukushi Jun-Ichi JI Hirose Tomoya T Ohsawa Isao I Tahira Tomoko T Horiuchi Takahiko T
Allergy 20210812 11
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Project description:Existing evidence indicates that modifier genes could change the phenotypic outcome of the causal SERPING1 variant and thus explain the expression variability of hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE). To further examine this hypothesis, we investigated the presence or absence of 18 functional variants of genes encoding proteins involved in the metabolism and function of bradykinin, the main mediator of C1-INH-HAE attacks, in relation to three distinct phenotypic traits of patients with C1-INH-HAE, i.e., the age at disease onset, the need for long-term prophylaxis (LTP), and the severity of the disease. Genetic analyses were performed by a validated next-generation sequencing platform. In total, 233 patients with C1-INH-HAE from 144 unrelated families from five European countries were enrolled in the study. Already described correlations between five common functional variants [F12-rs1801020, KLKB1-rs3733402, CPN1-rs61751507, and two in SERPING1 (rs4926 and rs28362944)] and C1-INH-HAE severity were confirmed. Furthermore, significant correlations were found between either the age at disease onset, the LTP, or the severity score of the disease and a series of other functional variants (F13B-rs6003, PLAU-rs2227564, SERPINA1-rs28929474, SERPINA1-rs17580, KLK1-rs5515, SERPINE1-rs6092, and F2-rs1799963). Interestingly, correlations uncovered in the entire cohort of patients were different from those discovered in the cohort of patients carrying missense causal SERPING1 variants. Our findings indicate that variants other than the SERPING1 causal variants act as independent modifiers of C1-INH-HAE severity and could be tested as possible prognostic biomarkers.
| S-EPMC9300820 | biostudies-literature
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).
| S-EPMC4101849 | biostudies-literature
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.
| S-EPMC6064723 | biostudies-literature
Project description:BackgroundIn hereditary angioedema (HAE) due to C1-inhibitor deficiency (C1-INH-HAE), bradykinin-mediated submucosal and/or subcutaneous angioedema dominates the clinical picture. The deficiency of C1-inhibitor can lead to the over-activation of the complement system. Complement plays an important role in all types of hypersensitivity reactions. On the other hand, during the degranulation of mast cells, heparin is also released amongst other substances. Heparin can activate the plasma kinin-kallikrein system, leading to bradykinin generation. These observations suggest a possible connection between C1-INH-HAE and mast cell-mediated hypersensitivity reactions.ObjectiveTo assess the occurrence of hypersensitivity reactions in the Hungarian C1-INH-HAE population.MethodsPatients filled out a questionnaire of 112 questions, either online or on paper. The questions were about hypersensitivity and C1-INH-HAE symptoms, the relation between these 2, general health, and demographic data. The study protocol was approved by the institutional review board of Semmelweis University, Budapest, and informed consent was obtained from the participants.ResultsOne hundred and six patients (64 female, 42 male, median age 46 years) responded, with 63.2% having hypersensitivity. Hypersensitivity was provoked by pollen in 25.5% of patients, by contact sensitivity in 22.6%, by food in 21.7%, by insect sting in 19.8%, by pet in 15.1%, by drug in 14.2%, by dust mite in 5.7%, and by mold in 1.9%. In 11 patients, hypersensitivity symptoms appeared after the diagnosis of C1-INH-HAE. Six hypersensitive patients experienced improvement in their symptoms; 42 remained the same, but none experienced worsening after the diagnosis of C1-INH-HAE. In 7.8% of the hypersensitive patients, a C1-INH-HAE attack worsened the hypersensitivity symptoms, while 15.7% of the hypersensitive patients experienced a C1-INH-HAE attack provoked by contact with the provoking factor.ConclusionWhile 63.2% of our C1-INH-HAE patients have reported hypersensitivity symptoms, Eurostat's latest data puts the prevalence of self-reported allergies in Hungary at 19.3%. Since in our experience most Hungarian patients report hypersensitivity reactions as allergies, this may support a possible connection between the 2 diseases, but further molecular studies are needed.
| S-EPMC10618765 | biostudies-literature
Project description: Not available
| S-EPMC9682248 | biostudies-literature
Project description:Hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) type I and II is a rare and life-threatening disease caused by SERPING1 gene mutations. Previous genetic studies indicated a wide spectrum of disease-associated variants in the SERPING1 gene and often lack of correlation with patient's phenotypes. The aim of this study was to evaluate the presence, type, and localization of mutations in the SERPING1 gene in 41 Polish patients with C1-INH-HAE and their relation with case/family history, type of C1-INH-HAE, fC1-INH, age of onset, and disease severity. Sanger sequencing and MLPA method were used for detection of disease-associated variants. In 34 (82.9%) patients, mutations located in various regions of SERPING1 gene were revealed. The detected alterations in patients with C1-INH-HAE type I differed and were positioned in various exons/introns of the SERPING1 gene. The most frequent disease-associated variants appeared in exon 3 (especially in type I) and in exon 8 (type I and II). Out of 20 different disease-causing variants, 9 were not previously described. We did not find any relation between the type and location of the mutations and no type of features included in phenotype evaluation of the patients, such as case and family history, type of C1-INH-HAE, age of onset, biochemical parameters, or severity of disease.
| S-EPMC7790005 | biostudies-literature
Project description:BackgroundHereditary angioedema (HAE) is a life-threatening, autosomal dominant disorder characterized by unpredictable, episodic swelling of the face, upper airway, oropharynx, extremities, genitalia, and gastrointestinal tract. Almost all cases of HAE are caused by mutations in the SERPING1 gene resulting in a deficiency in functional plasma C1 esterase inhibitor (C1EI), a serine protease inhibitor that normally inhibits proteases in the contact, complement, and fibrinolytic systems. Current treatment of HAE includes long-term prophylaxis with attenuated androgens or human plasma-derived C1EI and management of acute attacks with human plasma-derived or recombinant C1EI, bradykinin, and kallikrein inhibitors, each of which requires repeated administration. As an approach to effectively treat HAE with a single treatment, we hypothesized that a one-time intravenous administration of an adeno-associated virus (AAV) gene transfer vector expressing the genetic sequence of the normal human C1 esterase inhibitor (AAVrh.10hC1EI) would provide sustained circulating C1EI levels sufficient to prevent angioedema episodes.MethodsTo study the efficacy of AAVrh.10hC1EI, we used CRISPR/Cas9 technology to create a heterozygote C1EI-deficient mouse model (S63±) that shares characteristics associated with HAE in humans including decreased plasma C1EI and C4 levels. Phenotypically, these mice have increased vascular permeability of skin and internal organs.ResultsSystemic administration of AAVrh.10hC1EI to the S63± mice resulted in sustained human C1EI activity levels above the predicted therapeutic levels and correction of the vascular leak in skin and internal organs.ConclusionA single treatment with AAVrh.10hC1EI has the potential to provide long-term protection from angioedema attacks in affected individuals.
| S-EPMC6752709 | biostudies-literature
Project description:Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency is a rare disease characterized by recurrent swellings. This study aims to determine (i) the clinical characteristics of the HAE patient population from Poland, and (ii) real-life patients' treatment practices. A cross-sectional study involved 138 adult HAE patients (88 females, 50 males) treated in six regional HAE centers in Poland. Consecutive patients during routine follow-up visits underwent a structured medical interview on the clinical characteristics of the course and treatment of HAE attacks within the last six months. A total of 118 of 138 patients was symptomatic. They reported in total 2835 HAE attacks predominantly peripheral and abdominal, treated with plasma-derived C1-INH (61.4%), icatibant (36.7%) and recombinant C1-INH (1.9%). An amount of 116 patients carried the rescue medication with them while traveling, and 74 patients self-administrated on demand treatment. There were twice as many symptomatic women (n = 78) as there were men (n = 40). Women treated their HAE attacks significantly more often than men. Older patients (≥65 years) reported a longer delay in diagnosis, and practiced the self-administration of rescue medication less frequently in comparison to other patients. Clinical features of the surveyed population are similar to other European, but not Asian, HAE patient groups. Self-administration still remains an unmet medical need. Some distinct HAE patients may require special attention due to the severe course of the disease (females) or a delay in diagnosis (the elderly).
| S-EPMC8658320 | biostudies-literature
Project description:BackgroundTreatment of hereditary angioedema (HAE) in 'older adults' (those aged ≥65 years) has not been well studied. The international Berinert Patient Registry collected data on the use of intravenous plasma-derived, pasteurized, nanofiltered C1-inhibitor concentrate (pnfC1-INH; Berinert®/CSL Behring) in patients of any age, including many older adults.MethodsThis observational registry, conducted from 2010 to 2014 at 30 US and seven European sites, gathered prospective (post-enrollment) and retrospective (pre-enrollment) usage and adverse event (AE) data on subjects treated with pnfC1-INH.ResultsThe registry documented 1701 pnfC1-INH infusions in 27 older adults. A total of 1511 HAE attacks treated with pnfC1-INH administration were reported among 25 of the 27 (92.6 %) older adults. Among the older adults, mean (standard deviation [SD]) (8.8 [4.1] IU/kg) and median (6.4 IU/kg) pnfC1-INH doses were lower than those reported for 252 'younger adults' (those aged <65 years: 12.9 [6.2], 12.5 IU/kg, respectively). A total of 19 AEs occurred in 8 of 23 (34.8 %) older adults with prospective data, for rates of 0.83 events per subject and 0.02 events per infusion, similar to corresponding rates in younger adults (0.91 and 0.03, respectively). None of the AEs were considered related to pnfC1-INH, and all but two events (prostatectomy, gastrointestinal bleeding) were mild or moderate in severity. Administration of pnfC1-INH outside of a healthcare setting was reported for 1609 infusions in 16 older adults, representing 94.6 % of all pnfC1-INH infusions in this age group. There were no recorded instances of difficulty with self-administration of intravenous pnfC1-INH.ConclusionsThese findings suggest a high degree of safety with intravenous pnfC1-INH use in older adults with HAE, regardless of administration setting. Trial Registration Clinicaltrials.gov NCT01108848.
| S-EPMC5107191 | biostudies-literature
Project description: Not available
| S-EPMC6691520 | biostudies-literature