The Genetics of Hereditary Angioedema: A Review.
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ABSTRACT:
SUBMITTER: Santacroce R
PROVIDER: S-EPMC8125999 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hereditary angioedema (HAE) is an uncommon genetic disorder characterized by recurrent episodes of edema involving subcutaneous tissue and submucosa. The pathogenesis of HAE reflects an intricate coordinated regulation of components of complement, kinin and hemostatic pathway. Till date, mutations in 4 different genes have been identified to cause HAE which includes serine protease inhibitor G1 (SERPING1), factor XII (F12), plasminogen (PLG) and angiopoietin 1 (ANGPT 1). These mutations lead to increased bradykinin 2 receptor mediated signalling via increased production of bradykinin except mutations in ANGPT1 gene that disturbs the cytoskeletal assembly of vascular endothelial cells. In this review we aim to summarize the recent advances in the pathogenesis and genetics of HAE. We also provide an overview of possible future prospects in the identification of new genetic defects in HAE.
| S-EPMC7063419 | biostudies-literature
Project description:Hereditary angioedema (HAE) is a disease which is associated with random and often unpredictable attacks of painful swelling typically affecting the extremities, bowel mucosa, genitals, face and upper airway. Attacks are associated with significant functional impairment, decreased Health Related Quality of Life, and mortality in the case of laryngeal attacks. Caring for patients with HAE can be challenging due to the complexity of this disease. The care of patients with HAE in Canada is neither optimal nor uniform across the country. It lags behind other countries where there are more organized models for HAE management, and where additional therapeutic options are licensed and available for use. The objective of this guideline is to provide graded recommendations for the management of patients in Canada with HAE. This includes the treatment of attacks, short-term prophylaxis, long-term prophylaxis, and recommendations for self-administration, individualized therapy, quality of life, and comprehensive care. It is anticipated that by providing this guideline to caregivers, policy makers, patients and their advocates, that there will be an improved understanding of the current recommendations regarding management of HAE and the factors that need to be considered when choosing therapies and treatment plans for individual patients. The primary target users of this guideline are healthcare providers who are managing patients with HAE. Other healthcare providers who may use this guideline are emergency physicians, gastroenterologists, dentists and otolaryngologists, who will encounter patients with HAE and need to be aware of this condition. Hospital administrators, insurers and policy makers may also find this guideline helpful.
| S-EPMC4210625 | biostudies-literature
Project description:A biomarker is a defined characteristic measured as an indicator of normal, biologic, pathogenic processes, or biological responses to an exposure or intervention. Diagnostic biomarkers are used to detect a disease or a subtype of a disease; monitoring biomarkers are measured serially to assess a medical condition; response biomarkers are used to check biologic response following a medical intervention; predictive biomarkers are used to identify patients who are more likely to respond to a medical intervention; and prognostic biomarkers are used to assess the future likelihood of a clinical event. Although biomarkers have been extensively investigated and validated in many diseases and pathologies, very few are currently useful for the diagnosis, evaluation of disease activity, and treatment of hereditary angioedema (HAE). Pathophysiologic pathways involved in HAE reveal a plethora of molecules from the complement, coagulation, and fibrinolysis systems or from the vascular endothelium, which may serve as biomarkers. The most promising candidates, together with their laboratory readout systems, should be evaluated with regard to their analytical and clinical validity and utility. To be highly specific, such biomarkers should be linked to the pathomechanisms of HAE, particularly the bradykinin-generating cascade. Additionally, major advances in high-throughput omics-based technologies may facilitate the discovery of new candidate biomarkers in the future. This review will cover the existing as well as future potential biomarkers that will support the diagnosis, monitor disease activity, and can be used to assess the efficacy of new avenues of therapy of HAE and other forms of angioedema.
| S-EPMC8272698 | biostudies-literature
Project description:Remarkable progress has been made in the treatment of bradykinin-mediated angioedema with the advent of multiple new therapies. Patients now have effective medications available for prophylaxis and treatment of acute attacks. However, hereditary angioedema is a burdensome disease that can lead to debilitating and dangerous angioedema episodes associated with significant costs for individuals and society. The burden of treatment must be addressed regarding medication administration difficulties, treatment complications, and adverse side effects. New therapies are being investigated and may offer solutions to these challenges. This article reviews the emerging therapeutic options for the treatment of HAE.
| S-EPMC5585075 | biostudies-literature
Project description:Hereditary angioedema (HAE) with C1-inhibitor (C1-Inh) deficiency (C1-Inh-HAE) is a rare, life-threatening, and disabling genetic disorder characterized by self-limited tissue swelling caused by deficiency or dysfunction of C1-Inh. Our aim in this update is to discuss new advances in HAE therapy, focusing mainly on the various treatment options that have become available recently and also drugs that are under trial for prophylaxis to prevent attacks. There is a paradigm shift to where the treatment of HAE is headed, focusing now on prophylactic treatment rather than abortive management.
| S-EPMC5531155 | biostudies-literature
Project description:ObjectiveThis study systematically reviews the existing literature on the management of hereditary angioedema (HAE) and provides an update on the clinical presentation and specific therapies.MethodsA literature search of PubMed and Embase databases was conducted from start of the database to February 2021. Inclusion criteria included relevant systematic reviews, randomized control clinical trials, prospective and retrospective cohort studies, and outcomes research published in English and available in full-text. Out of 310 candidate articles, a total of 55 articles were included in our study.ResultsThe most common genetic form of HAE in up to 85% of cases is caused by low levels of C1 esterase inhibitor (C1-INH) protein, leading to a bradykinin-mediated increase in vascular permeability. During an attack of HAE, abortive treatment with C1-INH replacement is most commonly described, however, icatibant, ecallantide, or fresh frozen plasma are also used. Long-term prophylaxis in the form of C1-INH replacement (subcutaneous or intravenous), monoclonal antibodies targeting plasma kallikrein, attenuated androgens, and transexemic acid should be considered for those who suffer from frequent, severe attacks.ConclusionProgressively distal involvement of the upper airway, especially the larynx, has been shown to pose an increased risk of asphyxiation and death in the acute presentation of HAE. Evaluation by an otolaryngologist is often sought during the emergent clinical management of HAE; therefore, it is prudent that the consulting physician is well-versed in the prompt recognition, triage of patients, and appropriate treatment modalities.Level of evidence1A.
| S-EPMC8223449 | biostudies-literature
Project description:This is an update to the 2014 Canadian Hereditary Angioedema Guideline with an expanded scope to include the management of hereditary angioedema (HAE) patients worldwide. It is a collaboration of Canadian and international HAE experts and patient groups led by the Canadian Hereditary Angioedema Network. The objective of this guideline is to provide evidence-based recommendations, using the GRADE system, for the management of patients with HAE. This includes the treatment of attacks, short-term prophylaxis, long-term prophylaxis, and recommendations for self-administration, individualized therapy, quality of life, and comprehensive care. New to the 2019 version of this guideline are sections covering the diagnosis and recommended therapies for acute treatment in HAE patients with normal C1-INH, as well as sections on pregnant and paediatric patients, patient associations and an HAE registry. Hereditary angioedema results in random and often unpredictable attacks of painful swelling typically affecting the extremities, bowel mucosa, genitals, face and upper airway. Attacks are associated with significant functional impairment, decreased health-related quality of life, and mortality in the case of laryngeal attacks. Caring for patients with HAE can be challenging due to the complexity of this disease. The care of patients with HAE in Canada, as in many countries, continues to be neither optimal nor uniform. It lags behind some other countries where there are more organized models for HAE management, and greater availability of additional licensed therapeutic options. It is anticipated that providing this guideline to caregivers, policy makers, patients, and advocates will not only optimize the management of HAE, but also promote the importance of individualized care. The primary target users of this guideline are healthcare providers who are managing patients with HAE. Other healthcare providers who may use this guideline are emergency and intensive care physicians, primary care physicians, gastroenterologists, dentists, otolaryngologists, paediatricians, and gynaecologists who will encounter patients with HAE and need to be aware of this condition. Hospital administrators, insurers and policy makers may also find this guideline helpful.
| S-EPMC6878678 | biostudies-literature
Project description:Hereditary angioedema (HAE) is a rare and potentially life-threatening disease with heterogeneous clinical symptoms. The metabolomic profile of HAE remains unknown. Uncovering the metabolic signatures of HAE may provide inspiration for a comprehensive understanding of HAE pathogenesis and may help explore potential new metabolic biomarkers. We performed a comprehensive metabolic analysis using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Urine samples from 34 HAE patients and 82 healthy controls (HCs) were collected to characterize the metabolic signatures associated with HAE. The metabolomes of HAE patients carrying different mutation types were also compared. A total of 795 metabolites were accurately detected and quantified. We considered 73 metabolites as differential metabolites in HAE patients (with an importance in projection (VIP) value > 1.0, q-value < 0.05, and fold change (FC) ≥ 1.2 or FC ≤ 0.8). Several metabolites associated with riboflavin metabolism, the citrate cycle, oxidative stress, and inflammation, including xanthine, oxypurinol, vitamin B2, and isocitrate, were significantly altered in HAE patients. No significantly different metabolites were found in HAE patients carrying different mutation types. The present study highlights that metabolic disturbances in the purine metabolism, riboflavin metabolism, and TCA cycle may be involved in the pathogenesis of HAE. Although biochemical significance requires further experimental verification, these findings may help to identify novel candidate metabolite biomarkers associated with HAE.
| S-EPMC9696332 | biostudies-literature
Project description:The unpredictable nature of attacks of tissue swelling in hereditary angioedema requires the identification of reliable biomarkers to monitor disease activity as well as response to therapy. At present, one can assess a C4 level (by ELISA) to assist in diagnosis but neither C4 nor C1 inhibitor levels reflect clinical course or prognosis. We will here review a collection of plasma proteins involved in blood coagulation, fibrinolysis, and innate immunity (Figure 1). A main focus is those proteins that are key to the formation of bradykinin (BK); namely, factor XII, plasma prekallikrein/kallikrein, high-molecular weight kininogen, and BK itself since overproduction of BK is key to the disease. Considerations include new approaches to measurement of active enzymes, ELISA methods that may supersede SDS gel analysis of bond cleavages, and examples of changes outside the BK cascade that may reflect when, where, and how an attack of swelling is initiated. We will discuss their usefulness as biomarker candidates, with pros and cons, and compare the analytical methods that are being developed to measure their levels or activity.
| S-EPMC5702621 | biostudies-literature
Project description:This review aims to summarize the main pathophysiological events involved in the development of hereditary angioedema (OMIM#106100). Hereditary angioedema is a rare genetic disease inherited in an autosomal dominant manner and caused by a loss of control over the plasma contact system or kallikrein-kinin system, which results in unrestrained bradykinin generation or signaling. In patients with hereditary angioedema, BK binding to endothelial cells leads to recurrent episodes of swelling at subcutaneous or submucosal tissues that can be life threatening when affecting the upper respiratory tract. The disease can either present with hypocomplementemia owing to the presence of pathogenic variants in the gene encoding complement C1 inhibitor (hereditary angioedema with C1-inhibitor deficiency) or present with normocomplementemia and associate with elevated estrogen levels owing to gain-of-function variants in the genes encoding coagulation proteins involved in the kallikrein-kinin system (namely, coagulation FXII [FXII-associated hereditary angioedema], plasminogen [PLG-associated hereditary angioedema], and high-molecular-weight kininogen [KNG1-associated hereditary angioedema]). Moreover, in recent years, novel pathogenic variants have been described in the genes encoding angiopoietin 1 (ANGPT1-associated hereditary angioedema) and myoferlin (MYOF-associated hereditary angioedema), which further expand the pathophysiological picture of hereditary angioedema.
| S-EPMC8909245 | biostudies-literature