RESUMEN
Angioedema is a prevailing symptom in different diseases, frequently occurring in the presence of urticaria. Recurrent angioedema without urticaria (AE) can be hereditary (HAE) and acquired (AAE), and several subtypes can be distinguished, although clinical presentation is quite similar in some of them. They present with subcutaneous and mucosal swellings, affecting extremities, face, genitals, bowels, and upper airways. AE is commonly misdiagnosed due to restricted access and availability of appropriate laboratorial tests. HAE with C1 inhibitor defect is associated with quantitative and/or functional deficiency. Although bradykinin-mediated disease results mainly from disturbance in the kallikrein-kinin system, traditionally complement evaluation has been used for diagnosis. Diagnosis is established by nephelometry, turbidimetry, or radial immunodiffusion for quantitative measurement of C1 inhibitor, and chromogenic assay or ELISA has been used for functional C1-INH analysis. Wrong handling of the samples can lead to misdiagnosis and, consequently, mistaken inappropriate approaches. Dried blood spot (DBS) tests have been used for decades in newborn screening for certain metabolic diseases, and there has been growing interest in their use for other congenital conditions. Recently, DBS is now proposed as an efficient tool to diagnose HAE with C1 inhibitor deficiency, and its use would improve the access to outbound areas and family members. Regarding HAE with normal C1 inhibitor, complement assays' results are normal and the genetic sequencing of target genes, such as exon 9 of F12 and PLG, is the only available method. New methods to measure cleaved high-molecular-weight kininogen and activated plasma kallikrein have emerged as potential biochemical tests to identify bradykinin-mediated angioedema. Validated biomarkers of kallikrein-kinin system activation could be helpful in differentiating mechanisms of angioedema. Our aim is to focus on the capability to differentiate histaminergic AE from bradykinin-mediated AE. In addition, we will describe the challenges developing specific tests like direct bradykinin measurements. The need for quality tests to improve the diagnosis is well represented by the variability of results in functional assays.
Asunto(s)
Angioedema/diagnóstico , Angioedemas Hereditarios/diagnóstico , Errores Diagnósticos/prevención & control , Angioedema/sangre , Angioedema/inmunología , Angioedemas Hereditarios/sangre , Angioedemas Hereditarios/genética , Angioedemas Hereditarios/inmunología , Biomarcadores/sangre , Biomarcadores/metabolismo , Bradiquinina/sangre , Bradiquinina/inmunología , Bradiquinina/metabolismo , Proteína Inhibidora del Complemento C1/análisis , Proteína Inhibidora del Complemento C1/genética , Proteína Inhibidora del Complemento C1/metabolismo , Análisis Mutacional de ADN , Diagnóstico Diferencial , Pruebas con Sangre Seca/métodos , Ensayo de Inmunoadsorción Enzimática , Factor XII/genética , Humanos , Mutación , Plasminógeno/genética , RecurrenciaRESUMEN
INTRODUCTION: HAE is a very debilitating disease that causes significant distress for patients not only during an acute attack but also constant fear for a subsequent attack. It is important to address long-term prophylactic (LTP) therapy to prevent attacks, decrease morbidity and increase the quality of life. When discussing LTP, the drug burden, convenience and efficacy must be taken into account. AREAS COVERED: We review the literature and the different phases of clinical trials leading up to approval by the US FDA of subcutaneous highly concentrated C1-Inhibitor (SC-C1-INH), called Haegarda. The dose approved is of 60 IU/kg twice weekly showing significant improvement in the reduction of attacks and need for on-demand therapy for attacks with minimal side effects. EXPERT OPINION: SC-C1-INH has added significantly to the armamentarium of physicians that treat HAE. The ability to achieve a steady state of C1-INH above 40% function is key to the success of the drug. The drug burden is an SC injection twice a week that exceeds the newly approved lanadelumab. The benefit may be that the protein that is deficient in HAE is replaced and with this the complement, fibrinolytic, coagulation pathways, and contact system are also regulated; however, evidence that this is of benefit is still lacking.
Asunto(s)
Angioedemas Hereditarios/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Calidad de Vida , Angioedemas Hereditarios/sangre , Ensayos Clínicos como Asunto , Proteína Inhibidora del Complemento C1/metabolismo , HumanosRESUMEN
BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disorder mainly caused by mutations in the SERPING1 gene, determining a deficit of C1 inhibitor (C1-INH). In approximately 10% of the cases, HAE with C1-INH deficiency (C1-INH-HAE) is caused by large gene rearrangements, which are not detected by Sanger sequencing. Here we present the exon quantification technique (EQT), a molecular diagnostic test for the detection of large genetic rearrangements in SERPING1, mapping the exact size and location of the deletion caused by the recombination of Alu elements. EQT analysis was performed on total DNA extracted from blood of patients belonging to two Brazilian families with a medical history of HAE, low plasma levels of C4 and C1-INH and no pathogenic alteration in SERPING1 analyzed by Sanger sequencing. RESULTS: Two large deletions were found, one of 1356 pb and one of 1804 pb, which resulted from recombination of two Alu elements present in introns 3 and 4 of the gene. CONCLUSION: These results showed that the EQT could be used as a simple, rapid, and efficient diagnosis test for analysis of large deletions and insertions involving SERPING1, otherwise not detected by Sanger sequencing, serving as a support technique for molecular diagnosis of HAE.
Asunto(s)
Elementos Alu , Angioedemas Hereditarios/genética , Mapeo Cromosómico , Proteína Inhibidora del Complemento C1/genética , Orden Génico , Eliminación de Secuencia , Angioedemas Hereditarios/sangre , Brasil , Complemento C4 , Exones , Sitios Genéticos , Humanos , IntronesRESUMEN
Hereditary angioedema (HAE) is a heterogeneous genetic disease caused by a deficit in C1 inhibitor (C1-INH) and clinically characterized by sudden events of edema, swelling, and pruritus. Here, we describe the first SERPING1 genotyping in 22 subjects from 4 non-related families, all from southern Colombia. The previously reported heterozygous gene mutations, c.1081C>T (p.Gln361*), c.1396C>G (p.Arg466Gly), c.1029+84G>A, or c.106_107del (p.Ser36Phefs*21), were found in 12 patients. Of note, a single patient clinically characterized as severe HAE type 2 expressed mutations in exon 8 and intron 6, whereas all the others have type 1 HAE and expressed one pathogenic variant. One of the subjects, a 5-year-old girl was discovered to have a pathogenic variant, and she is still asymptomatic. This is the first report focused on HAE genetic analysis in a Colombian population.
Asunto(s)
Angioedemas Hereditarios/diagnóstico , Angioedemas Hereditarios/genética , Proteína Inhibidora del Complemento C1/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Variación Genética , Genotipo , Adolescente , Adulto , Angioedemas Hereditarios/sangre , Biomarcadores , Niño , Preescolar , Colombia , Complemento C4 , Femenino , Estudios de Asociación Genética/métodos , Humanos , Lactante , Masculino , Persona de Mediana Edad , Linaje , Adulto JovenRESUMEN
BACKGROUND: Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) is a rare condition with clinical features similar to those of HAE with C1-INH deficiency. Mutations in the F12 gene have been identified in subsets of patients with HAE with normal C1-INH, mostly within families of European descent. OBJECTIVES: Our aim was to describe clinical characteristics observed in Brazilians from 42 families with HAE and F12 gene mutations (FXII-HAE), and to compare these findings with those from other populations. METHODS: We evaluated a group of 195 individuals, which included 102 patients clinically diagnosed with FXII-HAE and their 93 asymptomatic relatives. RESULTS: Genetic analysis revealed that of the 195 subjects, 134 individuals (77.6% females) carried a pathogenic mutation in F12. The T328K substitution was found in 132 individuals, and the c.971_1018+24del72 deletion was found in 2 patients. The mean age at onset of symptoms in patients with FXII-HAE was 21.1 years. The most common symptoms were subcutaneous edema (85.8% of patients), abdominal pain attacks (69.7%), and upper airway edema (32.3%). Of male individuals carrying F12 mutations, 53.3% (16 of 30) were symptomatic. Compared with reports from Europe, fewer female patients (68.6%) reported an influence of estrogen on symptoms. CONCLUSIONS: Our study included a large number of patients with FXII-HAE, and, as the first such study conducted in a South American population, it highlighted significant differences between this and other study populations. The high number of symptomatic males and patients with estrogen-independent FXII-HAE found here suggests that male sex and the absence of a hormonal influence should not discourage clinicians from searching for F12 mutations in cases of HAE with normal C1-INH.
Asunto(s)
Angioedemas Hereditarios/genética , Factor XII/genética , Adolescente , Adulto , Anciano , Angioedemas Hereditarios/sangre , Brasil , Niño , Preescolar , Proteína Inhibidora del Complemento C1/análisis , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mutación , Linaje , Adulto JovenRESUMEN
Hereditary Angioedema is an autosomal dominant inherited disease leading to oedema attacks with variable severity and localization predominantly caused by C1-INH deficit. More than 400 mutations have been already identified, however no genetic analysis of a Brazilian cohort of HAE patients with C1-INH deficiency has been published. Our aim was to perform genetic analysis of C1-INH gene (SERPING1) in Brazilian HAE patients. We screened the whole SERPING1 coding region from 30 subjects out of 16 unrelated families with confirmed diagnosis of HAE due to C1-INH deficiency. Clinical diagnosis was based on symptoms and quantitative and/or functional analysis of C1-INH. We identified fifteen different mutations among which eight were not previously described according to databases. We found five small deletions (c.97_115del19; c.553delG; c.776_782del7; c.1075_1089del15 and c.1353_1354delGA), producing frameshifts leading to premature stop codons; seven missense mutations (c.498C>A; c.550G>C; c.752T>C; c.889G>A; c.1376C>A; c.1396C>T; c.1431C>A); one nonsense mutation (c.1480C>T), and two intronic alterations (c.51+1G>T; c.51+2T>C). Despite the small number of participants in this study, our results show mutations not previously identified in SERPING1 gene. This study represents the first Brazilian HAE cohort evaluated for mutations and it introduces the possibility to perform genetic analysis in case of need for differential diagnosis.
Asunto(s)
Angioedemas Hereditarios/genética , Proteínas Inactivadoras del Complemento 1/genética , Mutación , Adolescente , Adulto , Anciano , Angioedemas Hereditarios/sangre , Angioedemas Hereditarios/diagnóstico , Brasil , Niño , Proteína Inhibidora del Complemento C1 , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Hereditary angioedema (HAE) is accompanied by an overproduction of bradykinin (BK) as the primary mediator of swelling. Although many proteins may be involved in regulating the wide spectrum of HAE symptoms, most studies have only focused on C1-INH and FXII. For the first time, a next generation sequencing (NGS) method was applied to develop a robust, time- and cost-effective diagnostic and research tool to analyze selected genes related to HAE. The entire coding region and the exon-intron boundaries of 15 genes from 23 subjects of a Brazilian family, nine of whom were symptomatic, were analyzed by NGS. One new mutation found uniquely in the nine symptomatic patients, p.Ala457Pro in the SERPING1 gene, was estimated as likely to be pathogenic (PolyPhen-2 software analysis) and is the main candidate to be responsible for HAE in these patients. Alterations identified in a few asymptomatic individuals but also found in almost all symptomatic patients, such as p.Ile197Met (HMWK), p.Glu298Asp (NOS3) and p.Gly354Glu (B2R), may also be involved in modulating patient-specific symptoms. This NGS gene panel has proven to be a valuable tool for a quick and accurate molecular diagnosis of HAE and efficient to indicate modulators of HAE symptoms.
Asunto(s)
Angioedemas Hereditarios/genética , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Adulto , Angioedemas Hereditarios/sangre , Angioedemas Hereditarios/diagnóstico , Brasil , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) is a rare disorder. Mutations of the gene encoding coagulation factor XII have been identified in a subset of patients with this condition. Our aim was to investigate mutations in the F12 gene in patients with HAE with normal C1-INH from Brazil. METHODS: We studied 5 Brazilian families with index female patients who presented with recurrent angioedema with normal C1-INH and C4 levels. Genomic DNA was isolated from whole blood and PCR was performed. Mutations were detected by the sequencing of exon 9 of the F12 gene and allelic discrimination. RESULTS: The c.983C>A (p.Thr328Lys) mutation was identified in 16 subjects, from 4 of the 5 families studied, including 8 patients with symptoms of HAE with normal C1-INH (87.5% women) and 8 subjects asymptomatic for HAE (25% women). Mean age at onset of symptoms among the FXII-HAE patients was 13.8 years (range 6-25 years). Recurrent abdominal pain (100%) and subcutaneous angioedema (87.5%) were the most frequent clinical presentations. Two patients presented with associated laryngeal edema. In keeping with previous observations in patients with both C1-INH-HAE and HAE with normal C1-INH, all 7 women with FXII-HAE reported triggering or worsening of symptoms upon intake of estrogen-containing oral contraceptives and/or pregnancy. CONCLUSIONS: We report for the first time in Brazil a mutation in the F12 gene as a likely cause of HAE with normal C1-INH in patients with recurrent attacks of angioedema and/or abdominal pain. A higher frequency of abdominal pain attacks and onset of symptoms at a younger age were observed among Brazilian patients when compared to those from other parts of the world.
Asunto(s)
Angioedemas Hereditarios/genética , Proteínas Inactivadoras del Complemento 1/inmunología , Factor XII/genética , Mutación Puntual , Adolescente , Adulto , Edad de Inicio , Anciano , Alelos , Angioedemas Hereditarios/sangre , Angioedemas Hereditarios/inmunología , Brasil , Proteína Inhibidora del Complemento C1 , ADN/química , ADN/genética , Factor XII/inmunología , Femenino , Humanos , Persona de Mediana Edad , Linaje , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
BACKGROUND: Approximately 2% of angioedema (AE) patients have a hereditary or an acquired deficiency of the complement 1 (C1) esterase inhibitor (C1 INH) gene. Some case reports indicate an association between angiotensin-converting enzyme inhibitor (ACEI) use and exacerbation of hereditary AE (HAE). OBJECTIVE: The aim of this retrospective study is to investigate the association between HAE and ACEI use in a larger patient population. METHODS: A retrospective chart review of patients who presented with AE and patients with diagnostic serum assays for functional C1 INH, C1 INH antigenic protein, C1q, C1q immune complex (C1q IC), and complement 4 (C4) regardless of medical complaint. Descriptive statistics were used to analyze the data. RESULTS: A total of 1594 patients had complement levels measured (136 C1 INH, 55 C1q, 10 C1q IC, and 1500 C4), of which 156 (9.7%) patients presented with AE. Angiotensin-converting enzyme inhibitor use was documented in 747 (47%) patients. Low C1 INH was detected in one patient with recurrent AE who was not taking ACEI. Another patient who presented with recurrent AE was found to have systemic lupus erythematosus with abnormal C4, C1q, and C1q IC, but normal C1 INH. A low C4 level was present in 94 patients, 4 of which had AE. CONCLUSIONS: The risk of exacerbating HAE by ACEI might be present, but we did not find any association in this retrospective study. Further studies are needed to determine the existence of this association.
Asunto(s)
Angioedemas Hereditarios/inducido químicamente , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Adulto , Anciano , Angioedemas Hereditarios/sangre , Proteína Inhibidora del Complemento C1/metabolismo , Complemento C1q/metabolismo , Complemento C4/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Hereditary angioedema is caused by a C1-inhibitor deficiency. It is a life-threatening disease. Its management includes treating acute attacks, short-term prophylaxis, and long-term prophylaxis. We report our experience with nadroparin for the short-term prophylaxis and treatment of angioedema attacks. We indicated treatment with nadroparin 0.3-0.6 mL SC 20 min after the onset of prodromes, then every 8-12 h for 1 day; short-term prophylaxis with 0.3-0.6 mL 1 h before a triggering event and then every 12-24 h for 1 more day. For children, treatment included 0.3 mL SC 20 min after the onset of prodromes, then every 12-24 h for 1 day; short-term prophylaxis was 0.3 mL 1 h before a triggering event and 1 more dose after 24 h. For the treatment, a complete response was considered when nadroparin totally stopped an acute attack within 2 h after injection. Partial response was considered if after 2 h analgesics and/or other therapy were required. Failure was established if after 4 h no response was obtained and fresh frozen plasma and other in-patient measures were required. For short-term prophylaxis, only complete responses and failures were considered. We included 29 adults and 5 children. Functional C1-inhibitor and C4 levels rose after nadroparin. We recorded 256 treatments (89.8% complete responses, 8.2% partial responses, and 1.9% failures), and 102 short-term prophylactic regimens (90.2% complete responses, and 9.8% failures). We found 38 mild adverse events without severe hemorrhagic episodes. If our results are reproduced subsequently, nadroparin may be an alternative for the treatment and short-term prophylaxis of angioedema attacks.