A cost-effective algorithm for diagnosis of hereditary angioedema with normal C1 inhibitor: Applying molecular approach to clinical practice

Dias, Marina M.; Moreno, Adriana S.; Maia, Luana S.M.; Nunes, Fernanda Leonel; Campos, Wagner Narciso de; Ferriani, Mariana Paes Leme; Silva, Wilson A.; Arruda, L. Karla

doi:10.1016/j.jaip.2019.06.041

Cited by 3 publications

(13 citation statements)

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“…Initially, the symptoms of HAEs with normal C1-INH were shown to affect predominantly women and to be associated with estrogen usage; however, because it is an autosomal dominant disease, men are also affected but are often asymptomatic. 9 The 15 patients who participated in this study reported clinical features that corroborate the literature such as limb, face and genital edema, abdominal pain, diarrhea, and vomiting. Of these, 87% reported face edema as the most common symptom of HAE with normal C1-INH.…”

Section: Normal Sequence: Caatcctgacggaaaagggccatggtg Mutated Sequenc...supporting

confidence: 80%

“…(2) C1-INH dysfunction due to a mutation in exon 8 of the SERPING1 gene that results in the secretion of a non-functional protein; and (3) normal C1-INH that may be associated with mutations in the F12, ANGPT1, PLG, and Kininogen 1 (KNG1) genes, mainly found in female patients with normal C1-INH protein levels and activity. [1][2][3][4][5][6][7][8][9][10][11][12][13][14] A variant of the ANGPT1 gene was reported to interfere with the interaction between the angiopoietin protein and its natural receptor, endothelial tunica of the kinase cell-(TIE2), in endothelial cells leading to increased vascular permeability and edema. 12,15, 16 A mutation in the PLG gene has also been reported to increase fibrinolysis, which in turn causes plasmin formation and increased levels of bradykinin, leading to edema (PLG).…”

Section: Resultsmentioning

confidence: 99%

“…After that, three more mutations have been identified as related to HAE with normal C1-inhibitor, including the two mutations analyzed in this study. 9,10 This study has some limitations, particularly the small sample size. Nevertheless, the incidence of HAE in the Brazilian population is 1/160,000 and of these, only 30% have HAE with normal C1-INH.…”

Section: Normal Sequence: Caatcctgacggaaaagggccatggtg Mutated Sequenc...mentioning

confidence: 94%

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Study of angiopoietin and plasminogen genes in hereditary angioedema

Kruk

Chong-Neto

Dias

et al. 2020

Rev. Assoc. Med. Bras.

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SUMMARY OBJECTIVE To investigate the presence of the Angiopoietin 1 (ANGPT1) and Plasminogen (PLG) mutations in patients with Hereditary Angioedema (HAE) and normal C1 esterase inhibitor (C1-INH) levels, who do not harbor the F12 gene mutation. METHODS Patients clinically diagnosed with HAE but without C1-INH deficiency or dysfunction and F12 gene mutation were evaluated. DNA extraction, quantification, and dilution were performed at a concentration of 100 ng/µL, followed by a DNA amplification (PCR) for molecular evaluation of exon 2 of the ANGPT1 gene and exon 9 of the PLG gene for identification of mutations c.807G>T / p.A119S and c.988A>G / p.K330E, respectively. The PCR product was evaluated in 1% agarose gel electrophoresis. Sequencing was performed using the Sanger method. The electropherograms were analyzed using the FASTA® program. RESULTS DNA samples from 15 women were sequenced. Their ages ranged from 10 to 60 years and the normal C1 esterase and C4 inhibitor serum levels ranged from 22 to 39 mg/dL and from 10 to 40 mg/dL, respectively. No mutations were detected in the analyzed exons of ANGPT1 and PLG. However, a single-nucleotide polymorphism (SNP) was detected in two homozygotic and five heterozygotic patients. CONCLUSION Further studies are needed to evaluate these SNPs and scrutinize their potential for use as molecular markers of HAE and as novel therapeutic targets.

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Section: Normal Sequence: Caatcctgacggaaaagggccatggtg Mutated Sequenc...supporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Normal Sequence: Caatcctgacggaaaagggccatggtg Mutated Sequenc...mentioning

confidence: 94%

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Study of angiopoietin and plasminogen genes in hereditary angioedema

Kruk

Chong-Neto

Dias

et al. 2020

Rev. Assoc. Med. Bras.

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“…Presence of the supportive evidence shown in the boxes with blue outlines is not required for a confirmed diagnosis of HAE. 1 , 45 , 46 …”

Section: Diagnosis Of Hae-ni-c1-inhmentioning

confidence: 99%

Managing Diagnosis, Treatment, and Burden of Disease in Hereditary Angioedema Patients with Normal C1-Esterase Inhibitor

Jones¹,

Zafra²,

Anderson³

2023

JAA

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Hereditary angioedema (HAE) is a rare, chronic, and debilitating genetic disorder characterized by recurrent and unpredictable swelling episodes that primarily affect the subcutaneous and/or submucosal tissues of the extremities, larynx, face, abdomen, and genitals. Most cases of HAE are caused by mutations in the serpin family G member 1 gene ( SERPING1 ), which encodes C1-esterase inhibitor (C1-INH) protein. Mutations in SERPING1 lead to deficient (type I HAE-C1-INH) or dysfunctional (type II HAE-C1-INH) C1-INH protein and subsequent dysregulation of the kallikrein–bradykinin cascade. However, some patients present with a third type of HAE (HAE-nI-C1-INH), which was first described in the year 2000 and is characterized by an absence of mutations in SERPING1 . Although mutations in the coagulation factor XII, angiopoietin-1, plasminogen, kininogen-1, myoferlin, and heparan sulfate-glucosamine 3-O-sulfotransferase-6 genes have been identified in some patients with HAE-nI-C1-INH, genetic cause is still unknown in many cases, hindering full elucidation of the pathology of this HAE subtype. Diagnosis of HAE-nI-C1-INH is also further complicated by the fact that patients typically demonstrate normal plasma levels of C1-INH and complement component 4 protein and normal C1-INH functionality during laboratory analysis. Therefore, we review the challenges associated with diagnosing, treating, and living with HAE-nI-C1-INH. We conclude that raising awareness of the presenting features of HAE-nI-C1-INH within the clinical setting and among the general public is critical to aid earlier suspicion and diagnosis of the disease. Furthermore, adopting an individualized approach to HAE-nI-C1-INH treatment is essential to help address the current and significant unmet needs in this patient population.

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“…: <http://ghr.nlm.nih.gov/gene/F12> Localização do gene F12 indicada pela seta amarela na figura.Foram descritas duas mutações de sentido trocado c.983C>A e c.983C>G, uma deleção de 72 pares de base (c.971_1018+24del72), uma duplicação de 18 pares de bases (c.892_909dup), ambas localizadas no éxon 9 do gene F12 e associadas à clínica de AEH(Moreno et al 2015; Bork et al 2017;Dias et al 2019). Segundo o site GENE CARDS DE HUMAN GENE DATABASE(https://www.genecards.org/cgi-bin/carddisp.pl?gene=F12, recuperado em 14 de agosto de 2020) o gene F12 já tem 2952 SNPs (Polimorfismo de nucleotídeo único) e 70 mutações descritas nos éxons 9 e 10.A mutação do gene ANGPT1 faz com que ocorra uma substituição c.807G>T p.A119S resultando em uma perca patogênica na função da proteína, afetando sua capacidade de formação de multímetros, assim ocasionando uma capacidade reduzida de ligação do receptor das células endoteliais (TIE2).…”

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Investigação genética relacionada a fisiopatologia e sintomas clínicos do Angioedema Hereditário

Kruk

Fortunato

Moraes

et al. 2020

RSD

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Angioedema Hereditário (AEH) é uma doença pouco conhecida por profissionais da saúde, portanto subdiagnosticada. O objetivo do estudo, foi analisar artigos referentes à temática abordada dos últimos 5 anos. AEH é uma doença genética rara e grave do sistema imunológico, de caráter autossômico dominante, causada pela deficiência de inibidor de C1 esterase (C1-INH). Classificada em 3 fenótipos: deficiência quantitativa do inibidor de C1-INH, disfunção de C1-INH e C1-INH normal. Mutações em diversos genes estão associadas ao fenótipo do AEH, pacientes com deficiência e disfunção da proteína C1-INH possuem mutações no gene SERPING1 e pacientes com C1-INH normal, podem apresentar mutações nos genes F12, angiopoietina (ANGPT1), plasminogênio (PLG) ou cininogênio (KNG1). Os sintomas do AEH são caracterizados por edemas recorrentes em várias partes do corpo, tanto em pele como órgãos internos. Para a elaboração deste estudo realizou-se uma revisão integrativa da literatura, os artigos foram pesquisados em três bases de dados eletrônicas, Google Scholar, PubMed e Scielo, utilizando os descritores “angioedema hereditário”, “mutações”, “bradicinina”, “C1-INH”, “SERPING1”, “plasminogênio”, “angiopoietina”, “F12” e “cininogênio”, conectados por operadores boleanos AND e OR. A pesquisa no banco de dados revelou um total de 874 artigos, após triagem, 32 artigos foram avaliados. Com a pesquisa tornou-se possível compreender não somente os mecanismos percursores que levam ao desenvolvimento da doença, mas também as mutações genéticas responsáveis pelas diversas formas de manifestações clínicas do AEH, corroborando a construção de conhecimento dos profissionais envolvidos no diagnóstico e tratamento da patologia.

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A cost-effective algorithm for diagnosis of hereditary angioedema with normal C1 inhibitor: Applying molecular approach to clinical practice

Cited by 3 publications

References 28 publications

Study of angiopoietin and plasminogen genes in hereditary angioedema

Study of angiopoietin and plasminogen genes in hereditary angioedema

Managing Diagnosis, Treatment, and Burden of Disease in Hereditary Angioedema Patients with Normal C1-Esterase Inhibitor

Investigação genética relacionada a fisiopatologia e sintomas clínicos do Angioedema Hereditário

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