An autoantibody profile detects Brugada syndrome and identifies abnormally expressed myocardial proteins

Abstract Aims Brugada syndrome (BrS) is characterized by a unique electrocardiogram (ECG) pattern and life-threatening arrhythmias. However, the Type 1 Brugada ECG pattern is often transient, and a genetic cause is only identified in <25% of patients. We sought to identify an additional biomarker for this rare condition. As myocardial inflammation may be present in BrS, we evaluated whether myocardial autoantibodies can be detected in these patients. Methods and results For antibody (Ab) discovery, normal human ventricular myocardial proteins were solubilized and separated by isoelectric focusing (IEF) and molecular weight on two-dimensional (2D) gels and used to discover Abs by plating with sera from patients with BrS and control subjects. Target proteins were identified by mass spectrometry (MS). Brugada syndrome subjects were defined based on a consensus clinical scoring system. We assessed discovery and validation cohorts by 2D gels, western blots, and ELISA. We performed immunohistochemistry on myocardium from BrS subjects (vs. control). All (3/3) 2D gels exposed to sera from BrS patients demonstrated specific Abs to four proteins, confirmed by MS to be α-cardiac actin, α-skeletal actin, keratin, and connexin-43, vs. 0/8 control subjects. All (18/18) BrS subjects from our validation cohorts demonstrated the same Abs, confirmed by western blots, vs. 0/24 additional controls. ELISA optical densities for all Abs were elevated in all BrS subjects compared to controls. In myocardium obtained from BrS subjects, each protein, as well as SCN5A, demonstrated abnormal protein expression in aggregates. Conclusion A biomarker profile of autoantibodies against four cardiac proteins, namely α-cardiac actin, α-skeletal actin, keratin, and connexin-43, can be identified from sera of BrS patients and is highly sensitive and specific, irrespective of genetic cause for BrS. The four involved proteins, along with the SCN5A-encoded Nav1.5 alpha subunit are expressed abnormally in the myocardium of patients with BrS.

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A Serological Storm

Canadian Journal of General Internal Medicine ◽

10.22374/cjgim.v9i2.42 ◽

1970 ◽

Vol 9 (2) ◽

Author(s):

Bertha Wong MD ◽

Maria Bagovich MD ◽

Ivan Blasutig PhD ◽

Simon Carette MD MPhil

Keyword(s):

Differential Diagnosis ◽

Hepatitis C Virus ◽

Immune System ◽

Hepatitis C ◽

Hcv Infection ◽

Clinical Context ◽

Autoantibody Profile ◽

Life Threatening ◽

Clinically Significant ◽

Sensory Polyneuropathy

This article describes a patient presenting with a sensory polyneuropathy and multiple autoantibodies, leading to the diagnosis of hepatitis C virus (HCV) infection. His widely positive autoantibody profile in the absence of clinically significant rheumatic disease illustrates the importance of interpreting autoimmune serology in the appropriate clinical context and the concept of HCV being a non-specific activator of the immune system. In addition, it highlights the importance of considering untreated HCV infection in the differential diagnosis of rheumatic complaints, particularly if the workup reveals multiple autoantibodies, as HCV is a potentially severe and life-threatening disease, which can be appropriately managed with effective antiviral therapy.

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The Global Registry for Hereditary Angioedema due to C1-Inhibitor Deficiency

Clinical Reviews in Allergy & Immunology ◽

10.1007/s12016-021-08855-4 ◽

2021 ◽

Author(s):

Andrea Zanichelli ◽

Henriette Farkas ◽

Laurance Bouillet ◽

Noemi Bara ◽

Anastasios E. Germenis ◽

...

Keyword(s):

Hereditary Angioedema ◽

Rare Condition ◽

C1 Inhibitor ◽

C1 Inhibitor Deficiency ◽

Therapeutic Decisions ◽

Life Threatening ◽

Enhance Patient Care ◽

Electronic Support ◽

The Impact ◽

Global Registry

AbstractHereditary angioedema (HAE) is a rare condition, mostly due to genetic deficiency of complement C1 inhibitor (C1-INH). The rarity of HAE impedes extensive data collection and assessment of the impact of certain factors known to affect the course of this disabling and life-threatening disease. Establishing a global registry could assist to overcome such issues and provides valuable patient data from different countries. The HAE Global Registry is a disease-specific registry, with web-based electronic support, where data are provided by physicians and patients through a dedicated application. We collected data between January 1, 2018, and August 31, 2020. Data on 1297 patients from 29 centers in 5 European countries were collected. At least one attack was recorded for 497 patients during the study period. Overall, 1182 patients were diagnosed with HAE type 1 and 115 with type 2. At the time of database lock, 389 patients were taking long-term prophylactic medication, 217 of which were on danazol. Most recorded attacks affected the abdomen, were generally moderate in severity, and occurred in patients who were not on prophylactic treatment (70.6%, 6244/8848). The median duration of attacks was 780 min (IQR 290–1740) in patients on prophylactic medication and 780 min (IQR 300–1920) in patients not on continuous prophylactic medication. In conclusion, the establishment of a registry for C1-INH-HAE allowed collection of a large amount of data that may help to better understand the clinical characteristics of this disease. This information may enhance patient care and guide future therapeutic decisions.

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Intraorbital Abscess: A Rare Cause of Orbit Compression

FACE ◽

10.1177/27325016211005062 ◽

2021 ◽

pp. 273250162110050

Author(s):

Samuel Ruiz ◽

Rizal Lim

Keyword(s):

Pediatric Population ◽

Rare Complication ◽

Disease Process ◽

Rare Condition ◽

External Drainage ◽

Direct Extension ◽

Life Threatening ◽

History Of ◽

High Index Of Suspicion ◽

Prompt Diagnosis

Introduction: Intraorbital abscess is a rare complication of rhinosinusitis that affects most commonly the pediatric population. It is thought to be caused by direct extension or venous spread of infections from contiguous sites and can lead to life-threatening complications, like permanent visual loss and cerebral abscesses. Objectives: Intraorbital abscess is a rare condition that requires prompt diagnosis and treatment to avoid serious complications. Our objectives are to provide an overview of this rare disease process and its management including our successful treatment experience. Case Description: We present a 2 case report of a 13-year-old pediatric male and a 66-year-old male with history of chronic sinusitis who presented with a right intraorbital abscess successfully treated with external drainage with decompression of the orbit. Conclusion: When intraorbital abscess is encountered, a high index of suspicion is needed to allow prompt and accurate diagnosis for this infrequent condition. Timely surgical drainage of the abscess is needed to prevent the development of fatal complications.

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Low rate of life‐threatening events and limitations in predicting invasive and noninvasive markers of symptoms in a cohort of type 1 Brugada syndrome patients: Data and insights from the GenBra registry

Journal of Cardiovascular Electrophysiology ◽

10.1111/jce.14732 ◽

2020 ◽

Vol 31 (11) ◽

pp. 2920-2928 ◽

Cited By ~ 1

Author(s):

Luciana Sacilotto ◽

Mauricio I. Scanavacca ◽

Natália Olivetti ◽

Carolina Lemes ◽

Gabrielle D. Pessente ◽

...

Keyword(s):

Brugada Syndrome ◽

Life Threatening ◽

Noninvasive Markers ◽

Low Rate

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Successful Management of Acquired Hemophilia A Associated with Bullous Pemphigoid: A Case Report and Review of the Literature

Case Reports in Hematology ◽

10.1155/2017/2057019 ◽

2017 ◽

Vol 2017 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

Quentin Binet ◽

Catherine Lambert ◽

Laurine Sacré ◽

Stéphane Eeckhoudt ◽

Cedric Hermans

Keyword(s):

Bullous Pemphigoid ◽

Neutralizing Antibodies ◽

Hemophilia A ◽

Rare Condition ◽

Term Treatment ◽

Acquired Hemophilia A ◽

Acquired Hemophilia ◽

Short Term Treatment ◽

Life Threatening ◽

Dose Levels

Background. Acquired hemophilia A (AHA) is a rare condition, due to the spontaneous formation of neutralizing antibodies against endogenous factor VIII. About half the cases are associated with pregnancy, postpartum, autoimmune diseases, malignancies, or adverse drug reactions. Symptoms include severe and unexpected bleeding that may prove life-threatening.Case Study. We report a case of AHA associated with bullous pemphigoid (BP), a chronic, autoimmune, subepidermal, blistering skin disease. To our knowledge, this is the 25th documented case of such an association. Following treatment for less than 3 months consisting of methylprednisolone at decreasing dose levels along with four courses of rituximab (monoclonal antibody directed against the CD20 protein), AHA was completely cured and BP well-controlled.Conclusions. This report illustrates a rare association of AHA and BP, supporting the possibility of eradicating the inhibitor with a well-conducted short-term treatment.

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Novel SCN5A and GPD1L Variants Identified in Two Unrelated Han-Chinese Patients With Clinically Suspected Brugada Syndrome

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.758903 ◽

2021 ◽

Vol 8 ◽

Author(s):

Meng Yuan ◽

Yi Guo ◽

Hong Xia ◽

Hongbo Xu ◽

Hao Deng ◽

...

Keyword(s):

Brugada Syndrome ◽

Missense Variant ◽

Han Chinese ◽

Chinese Patients ◽

Splicing Variant ◽

Pathogenic Variants ◽

Whole Exome ◽

Gated Channel ◽

Life Threatening ◽

Glycerol 3 Phosphate Dehydrogenase

Brugada syndrome (BrS) is a complexly genetically patterned, rare, malignant, life-threatening arrhythmia disorder. It is autosomal dominant in most cases and characterized by identifiable electrocardiographic patterns, recurrent syncope, nocturnal agonal respiration, and other symptoms, including sudden cardiac death. Over the last 2 decades, a great number of variants have been identified in more than 36 pathogenic or susceptibility genes associated with BrS. The present study used the combined method of whole exome sequencing and Sanger sequencing to identify pathogenic variants in two unrelated Han-Chinese patients with clinically suspected BrS. Minigene splicing assay was used to evaluate the effects of the splicing variant. A novel heterozygous splicing variant c.2437-2A>C in the sodium voltage-gated channel alpha subunit 5 gene (SCN5A) and a novel heterozygous missense variant c.161A>T [p.(Asp54Val)] in the glycerol-3-phosphate dehydrogenase 1 like gene (GPD1L) were identified in these two patients with BrS-1 and possible BrS-2, respectively. Minigene splicing assay indicated the deletion of 15 and 141 nucleotides in exon 16, resulting in critical amino acid deletions. These findings expand the variant spectrum of SCN5A and GPD1L, which can be beneficial to genetic counseling and prenatal diagnosis.

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Surgical treatment for secondary aortoesophageal fistula

Journal of Cardiothoracic Surgery ◽

10.1186/s13019-020-01293-x ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Kayo Sugiyama ◽

Toru Iwahashi ◽

Nobusato Koizumi ◽

Toshiya Nishibe ◽

Toshiki Fujiyoshi ◽

...

Keyword(s):

Open Repair ◽

Rare Condition ◽

Aortic Aneurysms ◽

Total Arch Replacement ◽

University Hospital ◽

Aortoesophageal Fistula ◽

Thoracic Aortic Aneurysms ◽

Life Threatening ◽

Tokyo Medical ◽

Medical University

Abstract Background Aortoesophageal fistula (AEF) is a relatively rare condition that is often life-threatening. Secondary AEF is a complication of previous surgery, which can be more critical and challenging than primary AEF. The number of secondary AEF is increasing due to increase in the number of thoracic endovascular aortic repair (TEVAR). Although TEVAR has become a successful alternative surgical strategy for thoracic aortic aneurysms, secondary AEF after TEVAR might be critical than other secondary AEF because of severe adhesion between the esophagus and residual thoracic aortic wall. Methods This study analyzed six patients with secondary AEF who were treated at Tokyo Medical University Hospital between 2011 and 2016. These participants included four patients who had undergone TEVAR and two who had undergone total arch replacement. Results Although they were subsequently hospitalized for a long period, open surgical repair was completed in two patients who had undergone total arch replacement. TEVAR alone was performed in two patients who had undergone TEVAR and they were discharged without major complications shortly. Combined repair of TEVAR as a bridge to open surgery was planned for two patients who had undergone TEVAR. However, reconstruction of the aorta and esophagus could not be completed in these patients due to severe adhesions, and they died during hospitalization. Conclusions Definitive open repair was successfully performed in patients with secondary AEF after total arch replacement. However, in the patients with secondary AEF after TEVAR, severe adhesion between the aorta and esophagus led to difficulty in performing a successful definitive open repair. The strategy for secondary AEF should, therefore, be decided considering the etiology of secondary AEF. In secondary AEF after TEVAR, definitive open repair is difficult to complete because of catastrophic complication, and palliative treatment using TEVAR without reconstruction of aorta and esophagus can be an alternative.

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Bilateral Adrenal Hemorrhage in Coronavirus Disease 2019 Patient: A Case Report

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa487 ◽

2020 ◽

Vol 105 (12) ◽

pp. 3745-3749 ◽

Cited By ~ 1

Author(s):

Meir Frankel ◽

Itamar Feldman ◽

Michal Levine ◽

Yigal Frank ◽

Naama R Bogot ◽

...

Keyword(s):

Adrenal Insufficiency ◽

Rare Condition ◽

Renal Vein Thrombosis ◽

Adrenal Hemorrhage ◽

Polymerase Chain Reaction Test ◽

Primary Antiphospholipid Syndrome ◽

Thromboembolic Events ◽

Adrenal Axis ◽

Bilateral Adrenal Hemorrhage ◽

Life Threatening

Abstract Context Bilateral adrenal hemorrhage is a rare condition with potentially life-threatening consequences such as acute adrenal insufficiency. Early adrenal axis testing, as well as directed imaging, is crucial for immediate diagnosis and treatment. Coronavirus disease 2019 (COVID-19) has been associated with coagulopathy and thromboembolic events. Case description A 66-year-old woman presented with acute COVID-19 infection and primary adrenal insufficiency due to bilateral adrenal hemorrhage (BAH). She also had a renal vein thrombosis. Her past medical history revealed primary antiphospholipid syndrome (APLS). Four weeks after discharge she had no signs of COVID-19 infection and her polymerase chain reaction test for COVID-19 was negative, but she still needed glucocorticoid and mineralocorticoid replacement therapy. The combination of APLS and COVID-19 was probably responsible of the adrenal event as a “two-hit” mechanism. Conclusions COVID-19 infection is associated with coagulopathy and thromboembolic events, including BAH. Adrenal insufficiency is life threatening; therefore, we suggest that early adrenal axis testing for COVID-19 patients with clinical suspicion of adrenal insufficiency should be carried out.

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6081Efficacy and limitations of quinidine therapy in patients with Brugada Syndrome

European Heart Journal ◽

10.1093/eurheartj/ehz746.0125 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

A Mazzanti ◽

E Tenuta ◽

M Marino ◽

E Pagan ◽

M Morini ◽

...

Keyword(s):

Cardiac Arrest ◽

Side Effects ◽

High Risk ◽

Brugada Syndrome ◽

Low Dose ◽

Clinical Course ◽

High Risk Group ◽

High Dose ◽

Life Threatening ◽

Patients Experience

Abstract Background Quinidine at high-dose is used in patients with Brugada Syndrome (BrS), but its efficacy to prevent life-threatening arrhythmic events (LAE) in BrS is unproven and its use is limited by side effects. Objective We assessed whether low-dose quinidine in BrS patients reduces: 1) the occurrence of a first LAE; 2) the arrhythmic burden in the high-risk group of cardiac arrest survivors. Methods We first compared the clinical course of 53 BrS patients treated with quinidine to that of 441 untreated controls, matched by sex, age, and symptoms. Furthermore, we calculated the annual incidence of LAEs off- and on-quinidine in 123 BrS patients who had survived a cardiac arrest. Results First, we compared the clinical course of 53 BrS patients treated with quinidine (i.e. “cases”: 89% males, median age 40 years) to that of 441 untreated, clinically-matched BrS patients (i.e. “controls”: 91% males, median age 41 years) present in our database of patients with inherited arrhythmias. Cases received quinidine (median dose of 450 mg per day) for 5.0±3.7 years. Quinidine was interrupted in only 3/53 cases (6%) for side effects and it conferred a nonsignificant reduction of the risk of a first LAE in cases versus controls (HR 0.74, 95% CI 0.22–2.48, P=0.62). Secondly, we calculated the annual recurrence of LAE off- and on-quinidine in 123 BrS cardiac arrest survivors, 27 of whom were treated with quinidine for 7.0±3.5 years. The annual rate of recurrent LAEs decreased significantly from 14.7% while off-quinidine to 3.9% while on-quinidine (P=0.03). Notably, recurrent life-threatening arrhythmic events were recorded in 4/27 (15%) symptomatic patients while on-quinidine. Conclusion We demonstrated for the first time in the long-term that low-dose quinidine reduces the recurrence of life-threatening arrhythmias in symptomatic BrS patients, with few side effects. Remarkably, about one-fifth of symptomatic patients experience life-threatening arrhythmias while on-treatment, suggesting that quinidine cannot replace implantable defibrillators in high-risk subjects.

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A Case of Acquired Idiopathic Hemophilia Successfully Treated with Immunosuppressive Drugs and Factor VIII Concentrates

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/107602969600200314 ◽

1996 ◽

Vol 2 (3) ◽

pp. 222-223 ◽

Cited By ~ 2

Author(s):

Alessandro Bucalossi ◽

Giuseppe Marotta ◽

Franco De Regis ◽

Piero Galieni ◽

Egidio Dispensa

Keyword(s):

Factor Viii ◽

Therapeutic Strategy ◽

Rare Condition ◽

Immunosuppressive Drugs ◽

Complete Disappearance ◽

Acquired Hemophilia ◽

Number Of Patients ◽

Life Threatening ◽

Factor Viii Concentrates ◽

Definition Of

The appearance of circulating factor VIII:C (FVIII:C) inhibitors in nonhemophilic patients represents a rare condition characterized by spontaneous and often life-threatening bleeding. We describe a patient with ac quired idiopathic hemophilia in whom immunosuppres sive therapy associated with human FVIII infusion deter mined a prompt and complete disappearance of the inhib itor. Given the very low number of patients with acquired hemophilia and the lack of prospective randomized clin ical trials published, we hope to contribute to a better definition of the therapeutic strategy in these patients.

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