The Importance of Complement Testing in Acquired Angioedema Related to Angiotensin-Converting Enzyme Inhibitors

Balla, Zsuzsanna; Zsilinszky, Zsuzsanna; Pólai, Zsófia; Andrási, Noémi; Kőhalmi, Kinga Viktória; Csuka, Dorottya

doi:10.1016/j.jaip.2020.08.052

Cited by 19 publications

(16 citation statements)

References 37 publications

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“…Here, we report the mutational spectrum of a large cohort of Hungarian C1-INH-HAE patients diagnosed in the Hungarian Angioedema Center of Reference and Excellence, the national center caring all Hungarian C1-INH-HAE patients. This is an update of the whole Hungarian cohort diagnosed in the past almost 50 years including families with previously published genetic background ( 3 , 24 , 32 – 34 , 37 , 38 ), but extended with further family members and also newly diagnosed patients with the identified SERPING1 mutations. By applying conventional molecular genetic methods such as Sanger sequencing and MLPA, a pathogenic SERPING1 variation could be explored in almost all families: C1-INH deficiency was caused by a missense or nonsense mutation in 47.1% (32/68), by a small deletion, insertion, or delins in 26.5% (18/68), by a large deletion or duplication in 13.2% (9/68) or by an intronic variation in 10.3% (7/68) of the analyzed pedigrees.…”

Section: Discussionmentioning

confidence: 99%

Overview of SERPING1 Variations Identified in Hungarian Patients With Hereditary Angioedema

et al. 2022

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BackgroundHereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare autosomal dominant disorder, characterized by recurrent, unpredictable edematous symptoms involving subcutaneous, and/or submucosal tissue. C1-INH-HAE may be caused by more than 700 different mutations in the gene encoding C1-INH (SERPING1) that may lead to decreased protein synthesis or to functional deficiency.MethodsConcentrations of C1-INH, C4, C1q, and anti-C1-INH antibodies, as well as functional C1-INH activity were determined in subjects suffering from edematous symptoms and admitted to the Hungarian Angioedema Center of Reference and Excellence. In those patients, who were diagnosed with C1-INH-HAE based on the complement measurements, SERPING1 was screened by bidirectional sequencing following PCR amplification and multiplex ligation-dependent probe amplification. For detecting large deletions, long-range PCRs covering the entire SERPING1 gene by targeting 2–7 kb long regions were applied.ResultsAltogether 197 individuals with C1-INH deficiency belonging to 68 families were identified. By applying Sanger sequencing or copy number determination of SERPING1 exons, 48 different mutations were detected in 66/68 families: 5 large and 15 small insertions/deletions/delins, 16 missense, 6 nonsense, and 6 intronic splice site mutations. Two novel variations (p.Tyr199Ser [c.596A>C] and the duplication of exon 7) were shown to cosegregate with deficient C1-inhibitor level and activity, while two other variations were detected in single patients (c.797_800delinsCTTGGAGCTCAAGAACTTGGAGCT and c.812dup). A series of long PCRs was applied in the remaining 2 families without an identified mutation and a new, 2606 bp long deletion including the last 91 bp of exon 6 (c.939_1029+2515del) was identified in all affected members of one pedigree. In the remaining one family, a deep intronic SERPING1 variation (c.1029+384A>G) was detected by a targeted next-generation sequencing panel as reported previously.ConclusionsSequencing and copy number determination of SERPING1 exons uncover most pathogenic variants in C1-INH-HAE patients, and further methods are worth to be applied in cases with unrevealed genetic background. Since knowledge of the genetic background may support the establishment of the correct and early diagnosis of C1-INH-HAE, identification of causative mutations and reporting data supporting the interpretation on the pathogenicity of these variants is of utmost importance.

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Section: Discussionmentioning

confidence: 99%

Overview of SERPING1 Variations Identified in Hungarian Patients With Hereditary Angioedema

et al. 2022

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“…Patients who are diagnosed with ACEI-AE should be tested for HAE-1/2, as the occurrence of angioedema attacks after the initiation of treatment with an ACE-inhibitor may point to previously asymptomatic HAE. 81 Angioedema attacks in patients with ACEI-AE inhibitors are thought to be bradykinin-mediated. 38 , 82 , 83 , 84 , 85 …”

Section: The Differential Diagnosis Of Haementioning

confidence: 99%

The international WAO/EAACI guideline for the management of hereditary angioedema – The 2021 revision and update

Maurer

Magerl

Betschel

et al. 2022

World Allergy Organization Journal

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“…AAE-ACEI is caused by elevated concentration of bradykinin, as the main enzyme responsible for its breakdown, the ACE, is inhibited. As no specific laboratory test is available for the identification of AAE-ACEI, this disorder can be diagnosed only by excluding other types of bradykinin-mediated angioedema ( 32 , 33 ), when the complement tests are performed at the discontinuation of ACE inhibitors ( Table 1 ) ( 32 , 34 ). Furthermore, other vasoactive peptides degraded by ACE could be involved in AAE-ACEI ( 34 ).…”

Section: Subtypes Of Angioedema From a Biochemical Point Of Viewmentioning

confidence: 99%

Angioedema Without Wheals: Challenges in Laboratorial Diagnosis

2021

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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.

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The Importance of Complement Testing in Acquired Angioedema Related to Angiotensin-Converting Enzyme Inhibitors

Cited by 19 publications

References 37 publications

Overview of SERPING1 Variations Identified in Hungarian Patients With Hereditary Angioedema

Overview of SERPING1 Variations Identified in Hungarian Patients With Hereditary Angioedema

The international WAO/EAACI guideline for the management of hereditary angioedema – The 2021 revision and update

Angioedema Without Wheals: Challenges in Laboratorial Diagnosis

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