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Current Opinion in Pediatrics Aug 2015In 2010, a new classification of the congenital ichthyoses was published. At the time, the causative genes were known in many but not all instances. The goal of this... (Review)
Review
PURPOSE OF REVIEW
In 2010, a new classification of the congenital ichthyoses was published. At the time, the causative genes were known in many but not all instances. The goal of this review is to provide an update on molecular and clinical findings in congenital ichthyosis and to revise evidence-based and emerging treatments.
RECENT FINDINGS
Mutations in genes encoding for desmosomal components have recently been shown to cause three clinically overlapping entities: peeling skin disease; severe dermatitis, multiple allergies and metabolic wasting syndrome; and Netherton syndrome. Mutations in keratin 10 have been identified as the cause of ichthyosis with confetti, a rare form of ichthyosis characterized by severe erythroderma in which healthy spots gradually develop since childhood. There is no curative treatment for the congenital ichthyoses. A recent systematic review of randomized clinical trials of ichthyosis treatments revealed that research evidence of therapy is poor.
SUMMARY
The expanding phenotype and genotype of the ichthyoses facilitates accurate clinical diagnosis and permits a deeper knowledge of the epidermal pathophysiology. Although curative treatment is yet to come, N-acetylcysteine has recently been added to the therapeutic armamentarium and topical enzyme replacement therapy has emerged as a promising alternative in TG1-deficient individuals.
Topics: Administration, Topical; Cysteine; Dermatologic Agents; Gene Expression Regulation; Genes, Dominant; Genes, Recessive; Genetic Predisposition to Disease; Genetic Therapy; Humans; Ichthyosiform Erythroderma, Congenital; Mutation; Phenotype; Practice Guidelines as Topic; Randomized Controlled Trials as Topic
PubMed: 26164154
DOI: 10.1097/MOP.0000000000000239 -
Scientific Reports Jan 2017The relationship between clinical phenotypes and desmosomal gene mutations in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) is poorly... (Meta-Analysis)
Meta-Analysis Review
Genotype-phenotype relationship in patients with arrhythmogenic right ventricular cardiomyopathy caused by desmosomal gene mutations: A systematic review and meta-analysis.
The relationship between clinical phenotypes and desmosomal gene mutations in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) is poorly characterized. Therefore, we performed a meta-analysis to explore the genotype-phenotype relationship in patients with ARVC. Any studies reporting this genotype-phenotype relationship were included. In total, 11 studies involving 1,113 patients were included. The presence of desmosomal gene mutations was associated with a younger onset age of ARVC (32.7 ± 15.2 versus 43.2 ± 13.3 years; P = 0.001), a higher incidence of T wave inversion in V leads (78.5% versus 51.6%; P = 0.0002) or a family history of ARVC (39.5% versus 27.1%; P = 0.03). There was no difference in the proportion of males between desmosomal-positive and desmosomal-negative patients (68.3% versus 68.9%; P = 0.60). The presence of desmosomal gene mutations was not associated with global or regional structural and functional alterations (63.5% versus 60.5%; P = 0.37), epsilon wave (29.4% versus 26.2%; P = 0.51) or ventricular tachycardia of left bundle-branch morphology (62.6% versus 57.2%; P = 0.30). Overall, patients with desmosomal gene mutations are characterized by an earlier onset age, a higher incidence of T wave inversion in V leads and a strong family history of ARVC.
Topics: Advisory Committees; Arrhythmogenic Right Ventricular Dysplasia; Demography; Desmosomes; Genetic Association Studies; Humans; Male; Mutation; Phenotype; Prognosis
PubMed: 28120905
DOI: 10.1038/srep41387 -
JACC. Heart Failure Jun 2024Acute myocarditis is an inflammatory condition that may precede the development of dilated or arrhythmogenic cardiomyopathy. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Acute myocarditis is an inflammatory condition that may precede the development of dilated or arrhythmogenic cardiomyopathy.
OBJECTIVES
The aim of this study was to investigate the reported prevalence of pathogenic or likely pathogenic (P/LP) variants in cardiomyopathy-associated genes in patients with acute myocarditis.
METHODS
For this systematic review and meta-analysis, the PubMed and Embase databases were searched on March 4, 2023. Observational studies evaluating the prevalence of P/LP variants in cardiomyopathy-associated genes in patients with acute myocarditis were included. Studies were stratified into adult and pediatric age groups and for the following scenarios: 1) complicated myocarditis (ie, presenting with acute heart failure, reduced left ventricular ejection fraction, or life-threatening ventricular arrhythmias); and 2) uncomplicated myocarditis. The study was registered with the International Prospective Register of Systematic Reviews (CRD42023408668) and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.
RESULTS
Of 732 studies identified, 8 met the inclusion criteria, providing data for 586 patients with acute myocarditis. A total of 89 P/LP variants in cardiomyopathy-associated genes were reported in 85 patients. For uncomplicated myocarditis, the pooled prevalence was 4.2% (95% CI: 1.8%-7.4%; I = 1.4%), whereas for complicated myocarditis, the pooled prevalence was 21.9% (95% CI: 14.3%-30.5%; I = 38.8%) and 44.5% (95% CI: 22.7%-67.4%; I = 52.8%) in adults and children, respectively. P/LP variants in desmosomal genes were predominant in uncomplicated myocarditis (64%), whereas sarcomeric gene variants were more prevalent in complicated myocarditis (58% in adults and 71% in children).
CONCLUSIONS
Genetic variants are present in a large proportion of patients with acute myocarditis. The prevalence of genetic variants and the genes involved vary according to age and clinical presentation.
Topics: Humans; Myocarditis; Acute Disease; Prevalence; Cardiomyopathies
PubMed: 38573261
DOI: 10.1016/j.jchf.2024.02.012 -
Annual Review of Medicine Jan 2019Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease characterized by fibrofatty replacement of the ventricular myocardium, a high risk... (Meta-Analysis)
Meta-Analysis
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease characterized by fibrofatty replacement of the ventricular myocardium, a high risk of ventricular arrhythmias, and progressive ventricular dysfunction. The clinical course is highly variable, and optimal approaches to management remain undefined. ARVC is associated with pathogenic variants in genes encoding the cardiac desmosome. Genetic testing facilitates identification of at-risk family members, but penetrance of ARVC in pathogenic variant carriers is difficult to predict. Participation in endurance exercise is a known key risk factor. However, there remains significant uncertainty about which family member will develop disease and how best to approach longitudinal screening. Our clinically focused review describes how new insights gained from natural history studies, improved understanding of pathogenic mechanisms, and appreciation of genetic and environmental modifiers have set the stage for developing personalized approaches to managing both ARVC patients and their at-risk family members.
Topics: Arrhythmogenic Right Ventricular Dysplasia; Genetic Predisposition to Disease; Genetic Testing; Humans; Needs Assessment; Precision Medicine; Prognosis; Survival Analysis
PubMed: 30355260
DOI: 10.1146/annurev-med-041217-010932 -
International Journal of Cardiology Aug 2017Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disorder of cardiac desmosomes associated with ventricular arrhythmias and sudden cardiac death.... (Review)
Review
BACKGROUND
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disorder of cardiac desmosomes associated with ventricular arrhythmias and sudden cardiac death. The clinical diagnosis is problematic and relies on a complex criteria composed of clinical and non-clinical parameters. In 2010, the original 1994 Task Force Criteria (TFC) was revised with particular attention given to the imaging parameters.
METHODS
Five retrospective studies compared the diagnostic concordance between the 1994 and 2010 TFC. Three studies used cardiac magnetic resonance (CMR) and compared major and minor CMR criteria and three studies compared definite ARVC cases; one study assessed both.
RESULTS
Three studies with 1435 patients compared the 1994 imaging and the 2010 CMR criteria. Using the 1994 criteria, 123 (8.6%) and 419 (29.2%) patients satisfied major and minor criteria compared to only 52 (3.6%) and 28 (1.9%) using the 2010 criteria; 57.7% and 94.3% reduction in major and minor criteria (p value, 0.0001 and 0.0001). Three studies with 611 patients assessed for definite ARVC. Using the 1994 and 2010 criteria, 207 (33.9%) and 243 (39.8%) patients satisfied the parameters respectively. This resulted in a statistically significant 17.4% (p value, 0.0379) increase in ARVC cases driven largely by two sub-groups.
CONCLUSIONS
The 2010 revised TFC have resulted in a significant reduction in the number of patients that satisfy CMR criteria particularly those that satisfied minor imaging abnormalities using the 1994 criteria. In addition, in certain groups the revised criteria have significantly increased the number of patients diagnosed with definite ARVC.
Topics: Advisory Committees; Arrhythmogenic Right Ventricular Dysplasia; Echocardiography; Humans; Magnetic Resonance Imaging, Cine; Retrospective Studies
PubMed: 28342631
DOI: 10.1016/j.ijcard.2017.03.069 -
Frontiers in Physiology 2021Cardiomyocyte death in the form of apoptosis and necrosis represents a major cellular mechanism underlying cardiac pathogenesis. Recent advances in cell death research...
Cardiomyocyte death in the form of apoptosis and necrosis represents a major cellular mechanism underlying cardiac pathogenesis. Recent advances in cell death research reveal that not all necrosis is accidental, but rather there are multiple forms of necrosis that are regulated. Necroptosis, the earliest identified regulated necrosis, is perhaps the most studied thus far, and potential links between necroptosis and Cullin-RING ligases (CRLs), the largest family of ubiquitin E3 ligases, have been postulated. Cullin neddylation activates the catalytic dynamic of CRLs; the reverse process, Cullin deneddylation, is performed by the COP9 signalosome holocomplex (CSN) that is formed by eight unique protein subunits, COPS1/CNS1 through COPS8/CNS8. As revealed by cardiomyocyte-restricted knockout of (Cops8-cko) in mice, perturbation of Cullin deneddylation in cardiomyocytes impairs not only the functioning of the ubiquitin-proteasome system (UPS) but also the autophagic-lysosomal pathway (ALP). Similar cardiac abnormalities are also observed in Cops6-cko mice; and importantly, loss of the desmosome targeting of COPS6 is recently implicated as a pathogenic factor in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Cops8-cko causes massive cardiomyocyte death in the form of necrosis rather than apoptosis and rapidly leads to a progressive dilated cardiomyopathy phenotype as well as drastically shortened lifespan in mice. Even a moderate downregulation of Cullin deneddylation as seen in mice with Cops8 hypomorphism exacerbates cardiac proteotoxicity induced by overexpression of misfolded proteins. More recently, it was further demonstrated that cardiomyocyte necrosis caused by Cops8-cko belongs to necroptosis and is mediated by the RIPK1-RIPK3 pathway. This article reviews these recent advances and discusses the potential links between Cullin deneddylation and the necroptotic pathways in hopes of identifying potentially new therapeutic targets for the prevention of cardiomyocyte death.
PubMed: 34262479
DOI: 10.3389/fphys.2021.690423 -
Journal of Medical Genetics May 2016Inherited desmosomal diseases are characterised by skin and/or cardiac features. Dermatological features might be a clue in the determination of the underlying... (Review)
Review
Combination of palmoplantar keratoderma and hair shaft anomalies, the warning signal of severe arrhythmogenic cardiomyopathy: a systematic review on genetic desmosomal diseases.
Inherited desmosomal diseases are characterised by skin and/or cardiac features. Dermatological features might be a clue in the determination of the underlying life-threatening cardiac disease. This article aims to propose a dermatological algorithm for the diagnosis of desmosomal diseases after a systematic review of published articles. Palmoplantar keratoderma (PPK), hair shaft anomalies and skin fragility are the major features in the 458 patients analysed. Isolated PPK or isolated hair shaft anomalies are associated with a desmosomal disease limited to skin. The combination of PPK and hair shaft anomalies was recorded in 161 patients, and this association is at high risk of cardiac disease (129/161, 80.1%). Skin features had led to cardiac monitoring in only 2.3% of those patients. We delineated three major phenotypes: the PPK-hair shaft anomalies-non-fragile skin subtype (77%), always associated with cardiac involvement; the PPK-hair shaft anomalies-skin fragility-normal cardiac function subtype (19.9%), frequently associated with PKP1 mutations; the PPK-hair shaft anomalies-skin fragility-cardiac involvement subtype (3.1%), always due to DSP mutations. Three mutation hotspots in DSP and JUP account for 90.8% of the patients with cardiac involvement. The combination of PPK and hair shaft anomalies justifies long-term cardiac monitoring.
Topics: Adolescent; Adult; Arrhythmias, Cardiac; Cardiomyopathies; Child; Child, Preschool; Desmoplakins; Desmosomal Cadherins; Desmosomes; Female; Hair Diseases; Humans; Infant; Infant, Newborn; Keratoderma, Palmoplantar; Male; Mutation; Plakophilins; Prognosis; Syndrome; Young Adult
PubMed: 26399581
DOI: 10.1136/jmedgenet-2015-103403 -
Revista Espanola de Cardiologia... Apr 2019Dilated cardiomyopathy is inherited in nearly 50% of cases. More than 90 genes have been associated with this disease, which is one of the main causes of heart...
Dilated cardiomyopathy is inherited in nearly 50% of cases. More than 90 genes have been associated with this disease, which is one of the main causes of heart transplant and has been associated with an increased risk of sudden cardiac death. Risk stratification in these patients continues to be challenging. The identification of the specific etiology of the disease is very useful for the early detection of mutation carriers. Genetic study often provides prognostic information and can determine the therapeutic approach. Wide phenotypic variability is observed depending on the mutated gene, the type of mutation, and the presence of additional genetic and environmental factors.
Topics: Adaptor Proteins, Signal Transducing; Apoptosis Regulatory Proteins; Calcium-Binding Proteins; Cardiomyopathy, Dilated; Cytoskeletal Proteins; Desmosomes; Filamins; Genes; Genes, Mitochondrial; Genetic Testing; Humans; Lysosomal-Associated Membrane Protein 2; Mutation; NAV1.5 Voltage-Gated Sodium Channel; Prognosis; RNA-Binding Proteins; Risk Assessment; Sarcomeres
PubMed: 30792015
DOI: 10.1016/j.rec.2018.10.017 -
Frontiers in Pediatrics 2021Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by fibrofatty infiltration of predominantly the right ventricular...
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by fibrofatty infiltration of predominantly the right ventricular (RV) myocardium. Affected patients typically present as young adults with hemodynamically stable ventricular tachycardia, although pediatric cases are increasingly recognized. These young subjects often have a more severe phenotype with a high risk of sudden cardiac death (SCD) and progression toward heart failure. Diagnosis of ARVC is made by combining multiple sources of information as prescribed by the consensus-based Task Force Criteria. The description of Naxos disease, a fully penetrant autosomal recessive disorder that is associated with ARVC and a cutaneous phenotype of palmoplantar keratoderma and wooly hair facilitated the identification of the genetic cause of ARVC. At present, approximately 60% of patients are found to carry a pathogenic variant in one of five genes associated with the cardiac desmosome. The incomplete penetrance and variable expressivity of these variants however implies an important role for environmental factors, of which participation in endurance exercise is a strong risk factor. Since there currently is no definite cure for ARVC, disease management is directed toward symptom reduction, delay of disease progression, and prevention of SCD. This clinically focused review describes the spectrum of ARVC among children and adolescents, the genetic architecture underlying this disease, the cardio-cutaneous syndromes that led to its identification, and current diagnostic and therapeutic strategies in pediatric ARVC subjects.
PubMed: 34926342
DOI: 10.3389/fped.2021.750916 -
American Journal of Medical Genetics.... Oct 2020Rare loss of function variants in DSP, which codes for the desmosomal protein desmoplakin, have been implicated in dilated and arrhythmogenic right ventricular...
Rare loss of function variants in DSP, which codes for the desmosomal protein desmoplakin, have been implicated in dilated and arrhythmogenic right ventricular cardiomyopathies. We present a family with arrhythmogenic cardiomyopathy associated with a novel missense variant in DSP (NM_004415.4): c.877G>A, p.(Glu293Lys). The phenotype is characterized by predominant involvement of the left ventricle with systolic dysfunction, fibrosis, and life-threatening arrhythmias. We performed a systematic review of literature collecting all cardiomyopathy cases with rare missense variants in DSP. We demonstrate that the distribution of missense variants across the protein domains in cardiomyopathy cases differs from that in gnomAD (p = .04), with a case enrichment of rare missense variants in the spectrin repeat domain (36/78 [46%] in cases vs. 449/1495 [30%] in gnomAD; p = .004). Our findings highlight the predominance of cardiac arrhythmia and left ventricular involvement in desmoplakin cardiomyopathy and pinpoint to a potential mutation hotspot in DSP thereby facilitating missense variant interpretation in the diagnostic setting.
Topics: Arrhythmias, Cardiac; Arrhythmogenic Right Ventricular Dysplasia; Desmoplakins; Female; Genetic Predisposition to Disease; Genetic Variation; Heart Ventricles; Humans; Male; Mutation, Missense; Phenotype
PubMed: 32808748
DOI: 10.1002/ajmg.a.61799