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Background: Patients with hereditary angioedema (HAE) have been postulated to be at increased risk for coronavirus disease 2019 (COVID-19) infection due to inherent dysregulation of the plasma kallikrein-kinin system. Only limited data have been available to explore this hypothesis. Objective: To assess the interrelationship(s) between COVID-19 and HAE. Methods: Self-reported COVID-19 infection, complications, morbidity, and mortality were surveyed by using an online questionnaire. The participants included subjects with HAE with C1 inhibitor (C1INH) deficiency (HAE-C1INH) and subjects with HAE with normal C1-inhibitor (HAE-nl-C1INH), and household controls (normal controls). The impact of HAE medications was examined. Results: A total of 1162 participants who completed the survey were analyzed, including: 695 subjects with HAE-C1INH, 175 subjects with HAE-nl-C1INH, and 292 normal controls. The incidence of reported COVID-19 was not significantly different between the normal controls (9%) and the subjects with HAE-C1INH (11%) but was greater in the subjects with HAE-nl-C1INH (19%; p = 0.006). Obesity was positively correlated with COVID-19 across the overall population (p = 0.012), with a similar but nonsignificant trend in the subjects with HAE-C1INH. Comorbid autoimmune disease was a risk factor for COVID-19 in the subjects with HAE-C1INH (p = 0.047). COVID-19 severity and complications were similar in all the groups. Reported COVID-19 was reduced in the subjects with HAE-C1INH who received prophylactic subcutaneous C1INH (5.6%; p = 0.0371) or on-demand icatibant (7.8%; p = 0.0016). The subjects with HAE-C1INH and not on any HAE medications had an increased risk of COVID-19 compared with the normal controls (24.5%; p = 0.006). Conclusion: The subjects with HAE-C1INH who were not taking HAE medications had a significantly higher rate of reported COVID-19 infection. Subcutaneous C1INH and icatibant use were associated with a significantly reduced rate of reported COVID-19. The results implicated potential roles for the complement cascade and tissue kallikrein-kinin pathways in the pathogenesis of COVID-19 in patients with HAE-C1INH.

Funder: Takeda Pharmaceuticals International AG, Zurich, Switzerland, BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (HAE-1/2) is a chronic and debilitating disease. The unpredictable clinical course represents a significant patient burden. OBJECTIVE: To analyse longitudinal registry data from the Icatibant Outcome Survey (IOS) in order to characterize temporal changes in disease activity in patients with HAE-1/2. METHODS: Icatibant Outcome Survey (NCT01034969) is an international observational registry monitoring the clinical outcomes of patients eligible for icatibant treatment. The current analyses are based on data collected between July 2009 and July 2019. Retrospective data for attacks recorded in the 12 months prior to IOS enrolment and for each 12-month period up to 7 years were analysed. RESULTS: Included patients reported angioedema attacks without long-term prophylaxis (LTP; n = 315) and with LTP (n = 292) use at the time of attack onset. Androgens were the most frequently used LTP option (80.8%). At the population level, regardless of LTP use, most patients (52-80%) reporting

Background: The management of hereditary angioedema has rapidly changed over the past decade. With these changes there has been increased recognition of the unique challenges of diagnosing and managing hereditary angioedema in pediatric populations. The objective of this review was to identify and compare recently published consensus guidelines for the management of hereditary angioedema types 1 and 2 to identify areas of agreement and conflict. Methods: A MEDLINE database search was performed to identify guidelines that offered guidance on diagnosing or managing hereditary angioedema in pediatric populations. A limitation was placed on guidelines published in the past 5 years to reflect the most recent literature. Results: Six clinical practice guidelines were included in the analysis. Early detection of disease status, coordination with specialists, and empowering patients with self-administered medications are emphasized, with use of plasma derived C1 esterase inhibitor as first line therapy for aborting attacks. The guidelines are shifting away from attenuated androgens and tranexamic acid for long-term prophylaxis toward medications such as subcutaneous C1 esterase inhibitor, lanadelumab, and berotralstat. Conclusion: Although some differences exist based on geographic region and health system where an included guideline was published, they have very minimal differences on close review.

Hereditary angioedema (HAE) is a rare condition characterized by episodic local edema involving various organs, which can be life-threatening in some cases. Among the three subtypes of the disease, HAE types I and II are known to be caused by heterozygous mutations in the SERPING1 gene encoding C1 inhibitor (C1INH). Although a number of mutations in the SERPING1 gene have been identified to date, the mechanisms how these mutations cause HAE are not completely understood. We herein performed detailed in vitro studies for a missense SERPING1 gene mutation p.S150F which we recently identified in a Japanese patient with HAE type I. We showed that the p.S150F-mutant C1INH was stably expressed within the cultured cells, while it was not secreted into the medium at all. Furthermore, we demonstrated that the mutant C1INH significantly prevented secretion of wild-type C1INH. Finally, the results suggested that the wild-type protein was not only retained but also degraded within the cytoplasm through interacting with the mutant protein. Our study clearly revealed a dominant-negative effect of the p.S150F-mutant C1INH against the wild-type C1INH.

To review the various types of angioedema including diagnosis and treatment.PubMed search of articles in the English language of various types of angioedema.Articles on the subject matter were selected and reviewed.Herein, a case-based approach is presented for discussing the major types of angioedema, including the following: hereditary angioedema types I and II and normal complement, acquired angioedema, angiotensin-converting enzyme-induced angioedema, and histaminergic and nonhistaminergic angioedema. Emerging treatments of hereditary angioedema including targets of prekallikrein, DNA vector technology replacing C1-INH protein, and CRIPSR technology targeting prekallikrein among many others are explored. In addition, other causes and mimickers of angioedema are briefly reviewed. Finally, a novel algorithm is proposed to help guide the treating physician through the workup and management of patients with suspected idiopathic angioedema unresponsive to conventional therapy with antihistamines.Over the years, many strides have been made in both understanding the pathophysiology of various types of angioedema and expansion of treatment options. It is important for clinicians to be aware of current and emerging treatment options. We provide a novel practical algorithm to guide clinicians in challenging cases of idiopathic angioedema refractory to antihistamines.

Hereditary angioedema (HAE) is a rare disease that causes episodic attacks of subcutaneous and submucosal edema, which can be painful, incapacitating, and potentially fatal. These attacks are mediated by excessive bradykinin production, as a result of uncontrolled activation of the plasma kallikrein/kinin system, which is caused by a C1 esterase inhibitor deficiency or dysfunction in HAE types 1 and 2, respectively. For many years, treatment options were limited to therapies with substantial adverse effects, insufficient efficacy, or difficult routes of administration. Increased insights in the pathophysiology of HAE have paved the way for the development of new therapies with fewer side effects. In the last two decades, several targeted novel therapeutic strategies for HAE have been developed, for both long-term prophylaxis and on demand treatment of acute attacks. This article reviews the advances in the development of more effective and convenient treatment options for HAE and their anticipated effects on morbidity, mortality, and quality of life. The emergence of these improved treatment options will presumably change current HAE guidelines, but adherence to these recommendations may become restricted by high treatment costs. It will therefore be essential to determine the indications and identify the patients that will benefit most from these newest treatment generations. Ultimately, current preclinical research into gene therapies may eventually lead the way towards curative treatment options for HAE. In conclusion, an increasing shift towards the use of highly effective long-term prophylaxis is anticipated, which should drastically abate the burden on patients with hereditary angioedema.

Hereditary Angioedema (HAE) is a rare autosomal dominant immunodeficiency disease with mutation in C1 inhibitor gene (Thirty-four patients with clinical phenotype of recurrent edematous attacks in face, upper and lower limbs, hands, and upper airway entered the study. Mutations inTwenty-three patients were diagnosed with HAE type I and 11 with HAE type II. Fourteen distinctive pathogenic variations including five frameshift (p.G217Vfs*, p.V454Gfs*18, p.S422Lfs*9, p.S36Ffs*21, p.L243Cfs*9), seven missense (p.A2V, p.G493R, p.V147E, p.G143R, p.L481P, p.P399H, p.R466C), one nonsense (p.R494*), and one splicing defect (C.51 + 2 T˃C), which three of these mutations were identified novel. However, no mutation was found in seven patients by Sanger sequencing and MLPA.Final diagnosis with mutation analysis of HAE after clinical evaluation and assessment of C1INH level and function can prevent potential risks and life-threatening manifestations of the disorder. In addition, genetic diagnosis can play a significant role in facilitating early diagnosis, pre-symptomatic diagnosis, early diagnosis of children, asymptomatic cases, and those patients who have the borderline biochemical results of C1-INH deficiency and/or C4.

Acquired angioedema due to C1-inhibitor (C1-INH) deficiency (AAE-C1-INH) is rare and is associated with underlying lymphoproliferative diseases. C1-INH deficiency may be due to neoplastic over-consumption of C1-INH and the generation of anti-C1-INH autoantibodies. Uncovering an occult malignancy can lead to earlier oncology referral and improvement of angioedema after treatment of the underlying lymphoproliferative disorder. We characterized seven patients with C1-INH-AAE that highlights the importance of recognizing the association between C1-INH-AAE and underlying malignancy. In acute attacks, patients may be resistant to C1-INH therapy due to the presence of anti-C1-INH autoantibodies or rapid complement consumption, and may respond better to icatibant or ecallantide, which directly affect bradykinin. Treatment of the underlying malignancy also improves AAE-C1-INH symptoms and supports the role of lymphoproliferative B cells in AAE-C1-INH pathophysiology. Monitoring levels of C4, C1-INH function and level, and C1q may be predictive of AAE-C1-INH control and be used as surrogates for treatment efficacy. With close monitoring, low-dose danazol can be effective for long-term prophylaxis. Annual evaluation in AAE-C1-INH is recommended if an underlying malignancy is not found, as angioedema may precede the development of malignancy by several years. Our single-center study has aided in standardization of comprehensive AAE-C1-INH diagnosis, treatment, and monitoring strategies towards future therapeutic clinical trials.

Hereditary angioedema (HAE) is a rare autosomal dominant life-threatening disease characterized by low levels of C1 inhibitor (type I HAE) or normal levels of ineffective C1 inhibitor (type II HAE), typically occurring as a consequence of a SERPING1 mutation. In some cases, a causal mutation remains undetected after using a standard molecular genetic analysis. Here we show a long methodological way to the final discovery of c.1029 + 384A > G, a novel deep intronic mutation in intron 6 which is responsible for HAE type I in a large family and has not been identified by a conventional diagnostic approach. This mutation results in de novo donor splice site creation and subsequent pseudoexon inclusion, the mechanism firstly described to occur in SERPING1 in this study. We additionally discovered that the proximal part of intron 6 is a region potentially prone to pseudoexon-activating mutations, since natural alternative exons and additional cryptic sites occur therein. Indeed, we confirmed the existence of at least two different alternative exons in this region not described previously. In conclusion, our results suggest that detecting aberrant transcripts, which are often low abundant because of nonsense-mediated decay, requires a modified methodological approach. We suggest SERPING1 intron 6 sequencing and/or tailored mRNA analysis to be routinely used in HAE patients with no mutation identified in the coding sequence.

Low levels of C1 inhibitor, the main inhibitor of the classic complement system, result in paroxysmal angioedema attacks that can be incapacitating or even life-threatening in affected individuals. Molecular defects in the gene for C1 inhibitor cause hereditary angioedema. In recent years, new insights in the pathways leading to angioedema due to a deficiency of C1 inhibitor have been gathered. Bradykinin, which is formed upon activation of the kallikrein-kinin system under insufficient regulation by C1 inhibitor, plays a crucial role. Whereas C1 inhibitor also occupies a central mediatory role in other plasma systems, such as the contact activation system of coagulation and the fibrinolytic plasminogen-plasmin system, a C1 inhibitor deficiency may also cause enhanced activation of these pathways. Novel therapeutic modalities for treatment and prevention of hereditary angioedema are now available, such as different forms of C1 inhibitor concentrate and novel agents that interfere in the kallikrein-kinin system.

Hereditary angioedema (HAE) is an autosomal dominant disease, characterized by edema attacks resulting from quantitative and/or functional deficiency of the C1 inhibitor (C1-INH), which acts in controlling the complement, coagulation, fibrinolysis, and contact systems. The exacerbation of these systems results in decreased circulating levels of kallikrein and conversion of bradykinin. In addition, thrombophilia is related to the deficiency of methylenetetrahydrofolate reductase (MTHFR) enzyme, causing an increase in homocysteine, accumulation of atheromatous plaques, and arterial and venous thrombosis. The association of these conditions in related systems brings greater clinical risks to the patient. We report a female patient, aged 23 years, with HAE and homozygous

Background: Hereditary angioedema (HAE) is a rare genetic potentially life-threatening disease characterized by episodic non-pruritic subcutaneous and submucosal edema attacks in different parts of the body. Objective: To assess the status of Romanian HAE patients after the recent introduction of a new therapy through a nationwide program. Methods: This cross-sectional observational study included patients from the Romanian HAE Registry. Results: The study included 84 patients with HAE type I (91.7%) and type II (8.3%). The mean delay in diagnosis was 2.4 years in children and 16.7 years in adults (p=0.019). Stress and tiredness were the most frequent trigger factors. The majority of the HAE episodes involved subcutaneous (89.3%), abdominal (77.4%), genital (51.2%), facial (41.7%), and laryngeal (39.3%) symptoms during the preceding 12 months. One or several misdiagnoses were reported in 83.33% patients and 44.1 % of the patients were subjected to or proposed unnecessary surgery during abdominal episodes. Plasma-derived C1-INH (pdC1-INH) and recombinant C1-INH (rhC1-INH) were respectively used in 10 (11.9%) and 13 (15.5%) of the HAE patients for life-threatening attacks over the past 12 months. Fortythree (51.19%) patients practiced home treatment with subcutaneous injection of the bradykinin B2-receptor antagonist for acute HAE attacks. Conclusion: The significantly lower delay observed in children suggests an improvement in the awareness of C1-INH-HAE among physicians in recent years. The management of HAE in Romania has been somewhat enhanced as the majority of HAE patients have recently gained access to pdC1-INH, rhC1-INH, and bradykinin B2-receptor antagonist.

Hereditary angioedema (HAE) is a rare, debilitating and potentially life-threatening disease characterized by recurrent attacks of oedema. With the development of new therapies and better availability of diagnostic tools, important advances have been made. However, the disease still remains frequently misdiagnosed and inadequately treated. Familial Mediterranean fever (FMF) is an autoinflammatory syndrome comprised of serositis, fever, arthritis and skin involvement. Both diseases can cause severe abdominal pain resembling that of acute abdomen. We report a case of three family members that presented with various symptoms that could fit in a clinical picture of both diseases, only to confirm a diagnosis of HAE type II after a diagnostic delay of many years.

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In the vast majority of patients with hereditary angioedema (HAE), angioedema attacks are due to the quantitative or functional deficiency of C1-esterase inhibitor (C1-INH), which leads to increased vascular permeability and unregulated release of bradykinin. Exogenous administration of C1-INH is a rational way to restore the concentration and functional activity of this protein, regulate the release of bradykinin, and attenuate or prevent subcutaneous and submucosal edema associated with HAE. Recent international guidelines for the management of HAE include C1-INH as an option for acute treatment of HAE. In addition, these guidelines recommend C1-INH as first-line treatment for long-term prophylaxis and as the therapy of choice for short-term/preprocedural prophylaxis. Several C1-INH products are available, with approved indications varying across regions. For the acute treatment of HAE, both plasma-derived and recombinant C1-INH formulations have been shown to be effective and well tolerated in adolescents and adults with HAE, with onset of relief within 30 min to a few hours. Plasma-derived C1-INH is approved for use in children, and recombinant C1-INH is being evaluated in this population. Intravenous (IV) and subcutaneous (SC) formulations of C1-INH have been approved for routine prophylaxis to prevent HAE attacks in adolescents and adults. Both formulations when administered twice weekly have been shown to reduce the frequency and severity of HAE attacks. The SC formulation of C1-INH obviates the need for repeated venous access and may facilitate self-administration of HAE prophylaxis at home, as recommended in HAE treatment guidelines. As with most rare diseases, the costs of HAE treatment are high; however, the development of additional acute and prophylactic medications for HAE may result in competitive pricing and help drive down the costs of HAE treatment.

Hereditary angioedema (HAE) due to C1-inhibitor deficiency (C1-INH-HAE) is a rare disorder with life-threatening complications if untreated. It begins during childhood, and reduces the patient's quality of life. Therefore, the availability of an easily administered agent to relieve unpredictable HAE episodes is indispensable for this age group. Areas covered: Randomized, double-blind, placebo-controlled, open-label extensions and prospective observational studies have proven the safety and efficacy of the subcutaneously administered bradykinin B2 receptor antagonist, icatibant, in the acute treatment of HAE episodes in adult C1-INH-HAE patients. Recently, a Phase 3, multicenter, open-label, non-randomized, single-arm study demonstrated the efficacy, safety, and tolerability of icatibant as an acute treatment for pediatric patients aged 2 years to less than 18 years. Expert commentary: The clinical study in pediatric patients showed that icatibant undergoes rapid absorption, reaches a therapeutic level, and promptly relieves the symptoms. It is well tolerated, and the subcutaneous preparation, presented in a pre-filled syringe, ensures ease of use. It can be administered anytime, anywhere, and instantly - even by the patients themselves, or - in the case of children and adolescents - by a caregiver. Icatibant may greatly contribute to the improvement of the quality of life of pediatric patients.

A 41-year-old woman presented with recurrent dizziness. After an attack of dizziness, she felt edematous sensations in her hands. However, according to photographs taken during the attack, the edema on the back of the patient’s hands and fingers appeared mild. Laboratory examinations revealed a low C4 and C1 inhibitor (INH) activity. A direct sequencing analysis of C1INH revealed a pathogenic gene mutation. Based on these results, she was diagnosed with hereditary angioedema (HAE) type 1. These findings indicate that HAE can cause recurrent dizziness, and it should therefore be included in the differential diagnosis in patients with recurrent neurologic symptoms, even in the absence of severe edema.

Aim: C1-INH-HAE is caused by activation of plasma kallikrein which subsequently cleaves high-molecular-weight kininogen (HMWK) to generate bradykinin and cHMWK. Materials & methods: A novel ion-pair 2D LC–MS/MS assay was developed to measure the 46 kDa cHMWK in plasma as a biomarker for C1-INH-HAE. The sample preparation included sodium dodecyl sulfate denaturation, methanol crash, chymotryptic digestion and peptide enrichment by solid phase extraction. Results: The LLOQ was 200 ng/ml. The overall cHMWK recovery combining crash and digestion was 57.5%. The precision of the method was ≤12.7% and accuracy ≤-13.8%. Conclusion: A reagent-free LC–MS assay has been developed for the quantitation of 46 kDa cHMWK, which was shown to be elevated in plasma of C1-INH-HAE patients due to C1-INH deficiency relative to that of healthy subjects.

Background Hereditary angioedema (HAE) is a rare genetic disorder with substantial morbidity and mortality. Despite expanded choices for effective acute treatment, prophylactic options are more limited. Intravenous C1 esterase inhibitor (C1-INH[IV]) is licensed and used to prevent HAE symptoms. Objective To better understand patient experiences with using C1-INH(IV), including level of satisfaction and types and frequency of complications. Methods Fifty adult members (≥18 years of age) of the US HAE Association who had HAE type I or II completed a self-administered internet survey. Eligible participants were experiencing at least 1 HAE attack per month and must have been receiving treatment with C1-INH(IV) as prophylaxis or acute therapy. Results Almost all respondents (n = 47; 94%) were using C1-INH(IV) for HAE prophylaxis. Most patients reported administration of C1-INH(IV) through a peripheral vein (n = 34) and 19 were currently (n = 17) or previously (n = 2) using a central venous port. Most respondents (62%) who used a peripheral vein to administer treatment reported having difficulty finding a usable vein or getting the infusion to work properly at least some of the time. Issues accessing veins, exhausted veins, and frequency of attacks were the main reasons physicians recommended ports to respondents. Although ports allow easier administration of therapy, 47% of respondents with ports experienced problems such as occlusion, thrombosis, and infection. Respondents using C1-INH prophylaxis reported a mean of 2.3 attacks per month during the previous 6 months. Conclusion The survey results identified clinical challenges with IV HAE medication use, including venous access issues and ongoing monthly attack occurrence despite prophylactic C1-INH(IV) administration.

Prevenció; Atac d'angioedema; Inhibidor C1 Prevención; Ataque de angioedema; Inhibidor C1 Prevention; Angioedema attack; C1 inhibitor BACKGROUND: Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS: We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS: Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P

Background: The activity of hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) varies between patients and within individual patients. Objective: This study aims to develop a disease activity scale for C1-INH-HAE (HAE-AS) with sound measurement properties. Methods: Eleven countries participated in a prospective multicenter cohort study. A clinical questionnaire was self-completed by 290 adult patients with C1-INH-HAE. Patients also completed 2 quality of life scales, the SF-36v2 and the HAE-QoL. Rasch analysis and classic psychometric methods were used to preselect a series of clinical items: number of attacks by location and number of treated attacks, emergency room visits, psychological/psychiatric treatment, missed school/workdays in the previous 6 months; general health; and impairment in everyday work/activities due to pain. Results: The mean (SD) age was 41.5 (14.7; range, 18-84) years, and 69% were females. The final 12-item Rasch model showed that the HAE-AS had satisfactory reliability (person separation index, 0.748), local item independence, unidimensionality, and no item bias by age or sex. The HAE-AS provided scores in a linear measure, with a mean of 10.66 (3.92; range, 0-30). Further analysis with classic psychometric methods indicated that the HAE-AS linear measure presented moderate-to-high convergent validity with quality of life scales (SF-36v2: physical component, r=–0.33; mental component, 0.555; HAE-QoL, –0.61), and good discriminative validity by age, sex, and disease severity (P

Hereditary angioedema is a disabling, life-threatening condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein (C1-INH-HAE) leading to bradykinin accumulation and recurrent episodes of edema attack. Vascular leakage is a complex process sustained by the coordinated production of several permeabilizing factors including vascular endothelial growth factors (VEGFs), angiopoietins (ANGPTs) and phospholipase A2 enzymes (PLA2). We previously reported that patients with C1-INH-HAE in remission have increased plasma levels of VEGFs, ANGPTs and secreted PLA2. In this study, we sought to analyze plasma levels of these mediators in 15 patients with C1-INH-HAE during the acute attack compared to remission. Plasma concentrations of VEGF-A, VEGF-C and VEGF-D were not altered during attack compared to remission. Moreover, VEGF-D concentrations were not altered also in remission phase compared to controls. Concentrations of ANGPT1, a vascular stabilizer, were increased during attacks compared to symptoms-free periods, whereas ANGPT2 levels were not altered. The ANGPT2/ANGPT1 ratio was decreased during angioedema attacks. Platelet activating factor acetylhydrolase activity was increased in patients with C1-INH-HAE in remission compared to controls and was decreased during angioedema attacks. Our results emphasize the complexity by which several vasoactive mediators are involved not only in the pathophysiology of C1-INH-HAE, but also during angioedema attacks and its resolution.

Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent edema attacks associated with morbidity and mortality. HAE results from variations in the SERPING1 gene that encodes the C1 inhibitor (C1INH), a serine protease inhibitor (serpin). Reduced plasma levels of C1INH lead to enhanced activation of the contact system, triggering high levels of bradykinin and increased vascular permeability, but the cellular mechanisms leading to low C1INH levels (20%-30% of normal) in heterozygous HAE type I patients remain obscure. Here, we showed that C1INH encoded by a subset of HAE-causing SERPING1 alleles affected secretion of normal C1INH protein in a dominant-negative fashion by triggering formation of protein-protein interactions between normal and mutant C1INH, leading to the creation of larger intracellular C1INH aggregates that were trapped in the endoplasmic reticulum (ER). Notably, intracellular aggregation of C1INH and ER abnormality were observed in fibroblasts from a heterozygous carrier of a dominant-negative SERPING1 gene variant, but the condition was ameliorated by viral delivery of the SERPING1 gene. Collectively, our data link abnormal accumulation of serpins, a hallmark of serpinopathies, with dominant-negative disease mechanisms affecting C1INH plasma levels in HAE type I patients, and may pave the way for new treatments of HAE.

We present a case with extremely late diagnosis of type II hereditary angioedema (HAE). Given recent advances in HAE treatment, we want to bring physician awareness to this condition and aid in earlier detection. HAE is a disorder associated with episodes of angioedema of the face, larynx, lips, abdomen, or extremities. Late diagnosis of HAE can lead to significant morbidity and is severely impairing due to recurring attacks. The diagnosis of HAE is ordinarily made during childhood and adolescence. Delayed diagnoses in early and middle adulthood have been documented in the literature. Gastrointestinal symptoms are common features of HAE and can be misdiagnosed as disease of primary gastrointestinal pathology, such as irritable bowel syndrome, recurrent pancreatitis, or appendicitis. These attacks are characterized by recurrent attacks of subcutaneous and submucosal edema without the presence of urticaria.We present a case of an elderly veteran whose diagnoses was extremely delayed into the eighth decade of life subsequent to unexplained abdominal symptoms. After diagnosis, the patient's symptoms were well controlled with medication due to advances in HAE treatment. To prevent further atypically delayed diagnoses, physicians should consider HAE in patients with recurrent attacks of unexplained abdominal pain.

Hereditary angioedema as a result of deficiency of the C1 inhibitor (HAE-C1INH; MIM# 106100) is a rare autosomal disorder and affected individuals are generally heterozygous for dominant negative variants in theSERPING1gene. Homozygosity forSERPING1pathogenic variants was long considered to be embryonically lethal; however, five nonrelated families with a recessive HAE pattern have been described in the last decade. in this report, we functionally characterized two newly reported nonrelated, consanguineous families with a recessive presentation of HAE attributed toSERPING1variants in the reactive center loop (family D; S438F) and gate (family A; I379T) regions. S438F heterozygotes (family D) showed variable levels of intact 105-kDa and cleaved/inactive 96-kDa isoforms of C1INH, whereas their homozygous relative presented only the 96-kDa band. Functional studies showed that S438F reduced C1INH interaction with target proteases in heterozygous (C1s, 32-38% of controls and FXIIa, 28-35% of controls) and homozygous (C1s, 18-24% of controls and FXIIa, 4-8% of controls) carriers, which is consistent with the more severe presentation of HAE in the family and decreased C1q levels in homozygous patients. By contrast, plasma C1INH from I379T heterozygotes (family A) showed normal C1INH/C1s binding (84-94% of controls) and no significant reduction in C1INH/FXIIa complexes (50-70% of controls). However, the homozygote failed to inhibit both C1s (25-42% of controls) and FXIIa (14-18% of controls). This profile is concordant with the less severe presentation of HAE in the family and the conserved C4 and C1q levels in heterozygous and homozygous patients., [ER19P7AC7541/2019], We thank Dr Alper Ozdemir, Arda Kula, Suat Hopanci and Betul Hopanci for obtaining the patient's serum samples. Alberto Lopez Lera is supported by grant ER19P7AC7541/2019 from Centre for Biomedical Network Research or Rare Diseases (CIBERER).