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BMC Medical Genomics Oct 2023We conducted an investigation into the clinical and molecular characteristics of Arrhythmogenic left ventricular cardiomyopathy (ALVC) caused by a novel likely...
OBJECTIVE
We conducted an investigation into the clinical and molecular characteristics of Arrhythmogenic left ventricular cardiomyopathy (ALVC) caused by a novel likely pathogenic mutation in an Iranian pedigree with sudden cardiac death (SCD).
BACKGROUND
ALVC is a genetically inherited myocardial disease characterized by the substitution of fibro-fatty tissue in the left ventricular myocardium, predominantly inherited in an autosomal dominant pattern and is commonly associated with genes involved in encoding desmosomal proteins, specifically Desmoplakin (DSP).
METHODS
The patient and available family members underwent a comprehensive clinical assessment, including Cardiac magnetic resonance (CMR) imaging, along with Whole-exome sequencing (WES). The identified variant was confirmed and segregated by Polymerase chain reaction (PCR) and Sanger sequencing in the family members.
RESULTS
A novel likely pathogenic heterozygous variant, DSP (NM_004415.4), c.3492_3498del, p.K1165Rfs*8 was discovered in the proband. This variant is likely to be the primary reason for ALVC in this specific family. This variant was confirmed by Sanger sequencing and segregated in other affected members of the family.
CONCLUSION
We identified a novel likely pathogenic variant in the DSP gene, which has been identified as the cause of ALVC in an Iranian family. Our investigation underscores the importance of genetic testing, specifically WES, for individuals suspected of ALVC and have a family history of SCD.
Topics: Humans; Arrhythmogenic Right Ventricular Dysplasia; Iran; Genetic Predisposition to Disease; Cardiomyopathies; Death, Sudden, Cardiac; Mutation
PubMed: 37885024
DOI: 10.1186/s12920-023-01701-w -
Frontiers in Immunology 2023Autoimmune bullous diseases (AIBDs) are a group of rare cutaneous disorders affecting cornified skin and mucous membranes. They are characterized by tense or flaccid...
INTRODUCTION
Autoimmune bullous diseases (AIBDs) are a group of rare cutaneous disorders affecting cornified skin and mucous membranes. They are characterized by tense or flaccid blistering and erosions due to autoantibodies against desmosomal and hemidesmosomal structural proteins of the skin. This group of disorders can be divided into those of pemphigoid and those of pemphigus diseases. If left untreated, these autoimmune diseases can cause serious or even life-threatening complications such as loss of fluid, superinfections or impaired food intake. Due to modern standardized serological assays, the diagnosis of AIBDs can usually be confirmed in combination with their clinical appearance. Whereas for a long time corticosteroids were the major players in the treatment of these diseases, with the approval of rituximab and other immunosuppressive agents, the therapy has increasingly improved.
METHODS
In this study, we aimed to investigate epidemiologic and clinical features as well as diagnostics and therapy of bullous autoimmune diseases in Middle Franconia, a governorate within the German federal state of Bavaria. Patients diagnosed or treated because of a AIBDs between 01.04.2013 and 31.03.2019 at the dermatological department of the university hospital Erlangen were included in this retrospective study (n = 242). Patients were either diagnosed for the first time (n=176) or the diagnosis has been confirmed (n=66) at the department. The respective incidence was calculated among the 176 subjects who had been diagnosed at the center in this period. Data was taken from patient records and analyzed with Microsoft® Excel. The evaluation included the diagnoses of pemphigus vulgaris (PV), pemphigus foliaceus (PF), bullous pemphigoid (BP), mucous membrane pemphigoid (MMP), linear IgA dermatosis (LAD), epidermolysis bullosa acquisita (EBA), and dermatitis herpetiformis (DH).
RESULTS
This study shows that the incidence of each AIBDs in Middle Franconia is low and comparable (PV, PF, LAD, EBA) or lower (BP, MMP, DH) than in other studies and regions. BP is the most common newly diagnosed AIBD in Middle Franconia.
DISCUSSION
Due to the chronic and sometimes severe course of AIBDs, repeated in-house treatments are often necessary. To date, mainly topically and systemically applied corticosteroids in combination with immunomodulators are used as first-line therapy.
Topics: Humans; Retrospective Studies; Pemphigoid, Bullous; Autoimmune Diseases; Skin Diseases, Vesiculobullous; Pemphigus; Linear IgA Bullous Dermatosis; Epidermolysis Bullosa Acquisita; Adrenal Cortex Hormones
PubMed: 37881435
DOI: 10.3389/fimmu.2023.1256617 -
Cureus Sep 2023Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an autosomal inherited cardiac condition characterized by fibroadipose tissue replacement of the right...
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an autosomal inherited cardiac condition characterized by fibroadipose tissue replacement of the right ventricular muscle, leading to structural changes and a high risk for ventricular arrhythmias, a gradual decline in right ventricular function, and sudden cardiac death. ARVC has an autosomal dominant inheritance pattern with variable expression among patients, typically affecting young adults. Genetic mutations affecting the cardiac desmosome genes have been widely reported. Intense exercise has been hypothesized as one of the drivers of ARVC's pathogenesis. Due to its non-specific presentation, it can become a diagnostic challenge for physicians with delayed care. We report a case of a male adult with a history of recurrent syncope and atypical chest pain who developed ventricular tachycardia on admission. This case aims to highlight the unspecific manifestations of ARVC and its main electrocardiographic features for an early diagnosis.
PubMed: 37881382
DOI: 10.7759/cureus.45850 -
Journal of Community Hospital Internal... 2023Arrhythmogenic cardiomyopathy (ACM) is a myocardium disease characterized by phenotypic features of myocardial scarring due to fibrofatty myocardial replacement often...
Arrhythmogenic cardiomyopathy (ACM) is a myocardium disease characterized by phenotypic features of myocardial scarring due to fibrofatty myocardial replacement often associated with global or regional ventricular dysfunction. For years after arrhythmogenic right ventricular cardiomyopathy (ARVC) was first described, the left ventricle (LV) was generally considered normal or minimally involved. In recent years, however, LV involvement has been recognized. It usually presents with early-on arrhythmias more than heart failure symptoms compared to dilated cardiomyopathy. It can be right ventricular, biventricular, or left ventricular. The underlying pathophysiology involves either desmosomal or non-desmosomal mutations. Phospholamban (PLN) mutation is one of those and is associated with more severe arrhythmias and SCD. Primary prevention with ICD implantation should be considered in these patients, even the ones with an ejection fraction greater than 35%. In addition, if such patients progress to Stage D heart failure, they need to be evaluated for advanced heart failure therapies.
PubMed: 37868239
DOI: 10.55729/2000-9666.1174 -
SAGE Open Medical Case Reports 2023Hereditary palmoplantar keratoderma is a rare heterogenous group of genodermatoses characterised by hyperkeratosis of the palms and soles. Genetic alterations affecting...
Hereditary palmoplantar keratoderma is a rare heterogenous group of genodermatoses characterised by hyperkeratosis of the palms and soles. Genetic alterations affecting proteins of the keratin cytoskeleton, cornified cell envelope, desmosomes and gap junction proteins have been implicated in the pathogenesis of inherited palmoplantar keratoderma. Reports of palmoplantar keratoderma in the African population are scarce. Herein, we report a case of a 29-year-old HIV-infected African female, who presented to a tertiary hospital with complaints of a painful left fourth toe, secondary to a constriction band. Her background history is significant for prior constriction bands involving her toes, some of which progressed to auto-amputations and childhood-onset thickening of the palmoplantar skin. Examination revealed diffuse transgrediens palmoplantar keratoderma with associated clinical findings of pseudo-ainhum and knuckle pads. A systemic workup was non-contributory. Next-generation sequencing genetic testing detected two variants of undetermined significance in gap junction protein beta 4, a connexin-encoding gene, and in the rhomboid 5 homolog 2 gene. Her phenotype remains discordant with our genetic findings. Her clinical features are instead consistent with overlapping phenotypes of gap junction protein beta 2-related connexin disorders: Vohwinkel syndrome and Bart-Pumphrey syndrome. Our case underlines the genetic heterogeneity of palmoplantar keratoderma and the diagnostic challenges it presents. Our patient required surgical amputation of the affected toe and is receiving ongoing dermatological management. Early recognition, appropriate referral and management are required to avert the debilitating consequences of mutilating keratoderma and improve the quality of life.
PubMed: 37846342
DOI: 10.1177/2050313X231204197 -
Nature Communications Oct 2023The most prevalent genetic form of inherited arrhythmogenic cardiomyopathy (ACM) is caused by mutations in desmosomal plakophilin-2 (PKP2). By studying pathogenic...
The most prevalent genetic form of inherited arrhythmogenic cardiomyopathy (ACM) is caused by mutations in desmosomal plakophilin-2 (PKP2). By studying pathogenic deletion mutations in the desmosomal protein PKP2, here we identify a general mechanism by which PKP2 delocalization restricts actomyosin network organization and cardiac sarcomeric contraction in this untreatable disease. Computational modeling of PKP2 variants reveals that the carboxy-terminal (CT) domain is required for N-terminal domain stabilization, which determines PKP2 cortical localization and function. In mutant PKP2 cells the expression of the interacting protein MYH10 rescues actomyosin disorganization. Conversely, dominant-negative MYH10 mutant expression mimics the pathogenic CT-deletion PKP2 mutant causing actin network abnormalities and right ventricle systolic dysfunction. A chemical activator of non-muscle myosins, 4-hydroxyacetophenone (4-HAP), also restores normal contractility. Our findings demonstrate that activation of MYH10 corrects the deleterious effect of PKP2 mutant over systolic cardiac contraction, with potential implications for ACM therapy.
Topics: Humans; Arrhythmogenic Right Ventricular Dysplasia; Actomyosin; Mutation; Cardiomyopathies; Plakophilins
PubMed: 37833253
DOI: 10.1038/s41467-023-41981-5 -
Frontiers in Cardiovascular Medicine 2023Familial dilated cardiomyopathy (DCM) causes heart failure and may lead to heart transplantation. DCM is typically a monogenic disorder with autosomal dominant...
BACKGROUND
Familial dilated cardiomyopathy (DCM) causes heart failure and may lead to heart transplantation. DCM is typically a monogenic disorder with autosomal dominant inheritance. Currently disease-causing variants have been reported in over 60 genes that encode proteins in sarcomeres, nuclear lamina, desmosomes, cytoskeleton, and mitochondria. Over half of the patients undergoing comprehensive genetic testing are left without a molecular diagnosis even when patient selection follows strict DCM criteria.
METHODS AND RESULTS
This study was a retrospective review of patients referred for genetic testing at Blueprint Genetics due to suspected inherited DCM. Next generation sequencing panels included 23-316 genes associated with cardiomyopathies and other monogenic cardiac diseases. Variants were considered diagnostic if classified as pathogenic (P) or likely pathogenic (LP). Of the 2,088 patients 514 (24.6%) obtained a molecular diagnosis; 534 LP/P variants were observed across 45 genes, 2.7% (14/514) had two diagnostic variants in dominant genes. Nine copy number variants were identified: two multigene and seven intragenic. Diagnostic variants were observed most often in (45.3%), (6.7%), (6.7%), and (5.2%). Clinical characteristics independently associated with molecular diagnosis were: a lower age at diagnosis, family history of DCM, paroxysmal atrial fibrillation, absence of left bundle branch block, and the presence of an implantable cardioverter-defibrillator.
CONCLUSIONS
Panel testing provides good diagnostic yield in patients with clinically suspected DCM. Causative variants were identified in 45 genes. In minority, two diagnostic variants were observed in dominant genes. Our results support the use of genetic panels in clinical settings in DCM patients with suspected genetic etiology.
PubMed: 37795486
DOI: 10.3389/fcvm.2023.1254272 -
Dermatology Reports Sep 2023Pemphigus is a chronic autoimmune bullous disease associated with the production of autoantibodies directed against desmosomal proteins, such as desmogleins 1 and 3....
Pemphigus is a chronic autoimmune bullous disease associated with the production of autoantibodies directed against desmosomal proteins, such as desmogleins 1 and 3. Here, we present the case of an 83-year-old woman who was referred to us with suspicious cicatricial alopecia of the scalp and a small, eroded lesion on the forehead, previously labeled as atrophic actinic keratosis after a skin biopsy. In our clinic, after a careful examination of the case, we decided to perform two new skin biopsies of the scalp on suspicion of an inflammatory disease.
PubMed: 37790654
DOI: 10.4081/dr.2023.9653 -
BioRxiv : the Preprint Server For... Sep 2023Desmosomes are transmembrane protein complexes that contribute to cell-cell adhesion in epithelia and other tissues. Here, we report the discovery of frequent genetic...
Desmosomes are transmembrane protein complexes that contribute to cell-cell adhesion in epithelia and other tissues. Here, we report the discovery of frequent genetic alterations in the desmosome in human cancers, with the strongest signal seen in cutaneous melanoma where desmosomes are mutated in over 70% of cases. In primary but not metastatic melanoma biopsies, the burden of coding mutations on desmosome genes associates with a strong reduction in desmosome gene expression. Analysis by spatial transcriptomics suggests that these expression decreases occur in keratinocytes in the microenvironment rather than in primary melanoma tumor cells. In further support of a microenvironmental origin, we find that loss-of-function knockdowns of the desmosome in keratinocytes yield markedly increased proliferation of adjacent melanocytes in keratinocyte/melanocyte co-cultures. Thus, gradual accumulation of desmosome mutations in neighboring cells may prime melanocytes for neoplastic transformation.
PubMed: 37786690
DOI: 10.1101/2023.09.19.558457 -
Frontiers in Cardiovascular Medicine 2023The present study aimed to describe the phenotypic features and genetic spectrum of arrhythmogenic cardiomyopathy (ACM) presented in childhood and test the validity of...
INTRODUCTION
The present study aimed to describe the phenotypic features and genetic spectrum of arrhythmogenic cardiomyopathy (ACM) presented in childhood and test the validity of different diagnostic approaches using Task Force Criteria 2010 (TFC) and recently proposed Padua criteria.
PATIENTS AND METHODS
Thirteen patients (mean age at diagnosis 13.6 ± 3.7 years) were enrolled using "definite" or "borderline" diagnostic criteria of ACM according to the TFC 2010 and the Padua criteria in patients <18 years old. Clinical data, including family history, 12-lead electrocardiogram (ECG), signal-averaged ECG, 24-h Holter monitoring, imaging techniques, genetic testing, and other relevant information, were collected.
RESULTS
All patients were classified into three variants: ACM of right ventricle (ACM-RV; = 6, 46.1%), biventricular ACM (ACM-BV; = 3, 23.1%), and ACM of left ventricle (ACM-LV; = 4, 30.8%). The most common symptoms at presentations were syncope ( = 6; 46.1%) and palpitations ( = 5; 38.5%). All patients had more than 500 premature ventricular contractions per day. Ventricular tachycardia was reported in 10 patients (76.9%), and right ventricular dilatation was registered in 8 patients (61.5%). An implantable cardiac defibrillator was implanted in 61.5% of cases, and three patients with biventricular involvement underwent heart transplantation. Desmosomal mutations were identified in 8 children (53.8%), including four patients with variants, two with variants, one with variant, and one with . Four patients carried compound heterozygous variants in desmosomal genes associated with left ventricular involvement.
CONCLUSION
Arrhythmias and structural heart disease, such as chamber dilatation, should raise suspicion of different ACM phenotypes. Diagnosis of ACM might be difficult in pediatric patients, especially for ACM-LV and ACM-BV forms. Our study confirmed that using "Padua criteria" in combination with genetic testing improves the diagnostic accuracy of ACM in children.
PubMed: 37781308
DOI: 10.3389/fcvm.2023.1216976