RESUMEN

Pediatric skeletal muscle channelopathies include a spectrum of conditions including nondystrophic myotonias and periodic paralyses. They are rare inherited conditions that can cause significant morbidity. They are characterized by episodic stiffness and weakness. While there is significant phenotypic variability, there are distinct diagnostic features. The nondystrophic myotonias encompass myotonia congenita, paramyotonia congenita, and sodium channel myotonia caused by mutations in chloride and sodium channels. The clinical manifestations vary across age groups and a small subset with sodium channel mutations may have severe presentation with fetal akinesia, laryngospasm, or congenital myopathy. The periodic paralyses include hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and Andersen-Tawil syndrome. The phenotypic differences between the groups can be helpful in diagnosis. It is important to review the cardiac phenotype in Andersen-Tawil syndrome due to a risk of life-threatening cardiac arrhythmias. Early and accurate diagnosis utilizing clinical features aided by investigations is important across all the pediatric channelopathies, as effective symptomatic treatment is available and can substantially improve quality of life.

Asunto(s)

Canalopatías , Humanos , Canalopatías/genética , Canalopatías/diagnóstico , Niño , Enfermedades Neuromusculares/diagnóstico , Enfermedades Neuromusculares/genética , Pediatría/métodos , Miotonía/genética , Miotonía/diagnóstico , Mutación/genética

RESUMEN

Recent advances in genetic diagnosis have revealed the underlying etiology of many epilepsies and have identified pathogenic, causative variants in numerous ion and ligand-gated channel genes. This chapter describes the clinical presentations of epilepsy associated with different channelopathies including classic electroclinical syndromes and emerging gene-specific phenotypes. Also discussed are the archetypal epilepsy channelopathy, SCN1A-Dravet syndrome, considering the expanding phenotype. Clinical presentations where a channelopathy is suspected, such as sleep-related hypermotor epilepsy and epilepsy in association with movement disorders, are reviewed. Channelopathies pose an intriguing problem for the development of gene therapies. Design of targeted therapies requires physiologic insights into the often multifaceted impact of a pathogenic variant, coupled with an understanding of the phenotypic spectrum of a gene. As gene-specific novel therapies come online for the channelopathies, it is essential that clinicians are able to recognize epilepsy phenotypes likely to be due to channelopathy and institute early genetic testing in both children and adults. These findings are likely to have immediate management implications and to inform prognostic and reproductive counseling.

Asunto(s)

Epilepsia , Humanos , Epilepsia/genética , Epilepsia/diagnóstico , Epilepsia/terapia , Canalopatías/genética , Canalopatías/terapia , Canalopatías/diagnóstico

Asunto(s)

Fibrilación Atrial , Canalopatías , Humanos , Canalopatías/genética , Canalopatías/diagnóstico , Medición de Riesgo

RESUMEN

Genetic arrhythmia disorders are rare diseases; however, they are a common cause of sudden cardiac death in children, adolescents, and young adults. In principle, a distinction can be made between channelopathies and cardiomyopathies in the context of genetic diseases. This paper focuses on the channelopathies long and short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT). Early diagnosis of these diseases is essential, as drug therapy, behavioral measures, and if necessary, implantation of a cardioverter defibrillator can significantly improve the prognosis and quality of life of patients. This paper highlights the pathophysiological and genetic basis of these channelopathies, describes their clinical manifestations, and comments on the principles of diagnosis, risk stratification and therapy.

Asunto(s)

Arritmias Cardíacas , Síndrome de Brugada , Canalopatías , Humanos , Arritmias Cardíacas/genética , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/terapia , Arritmias Cardíacas/fisiopatología , Canalopatías/genética , Canalopatías/diagnóstico , Canalopatías/terapia , Síndrome de Brugada/genética , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/fisiopatología , Síndrome de Brugada/terapia , Taquicardia Ventricular/genética , Taquicardia Ventricular/terapia , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/fisiopatología , Adolescente , Niño , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/terapia , Síndrome de QT Prolongado/fisiopatología , Muerte Súbita Cardíaca/prevención & control , Muerte Súbita Cardíaca/etiología , Adulto , Desfibriladores Implantables , Electrocardiografía

RESUMEN

Cardiac channelopathies are a group of heritable disorders that affect the heart's electrical activity due to genetic variations present in genes coding for ion channels. With the advent of new sequencing technologies, molecular diagnosis of these disorders in patients has paved the way for early identification, therapeutic management and family screening. The objective of this retrospective study was to understand the efficacy of whole-genome sequencing in diagnosing patients with suspected cardiac channelopathies who were reported negative after whole exome sequencing and analysis. We employed a 3-tier analysis approach to identify nonsynonymous variations and loss-of-function variations missed by exome sequencing, and structural variations that are better resolved only by sequencing whole genomes. By performing whole genome sequencing and analyzing 25 exome-negative cardiac channelopathy patients, we identified 3 pathogenic variations. These include a heterozygous likely pathogenic nonsynonymous variation, CACNA1C:NM_000719:exon19:c.C2570G:p. P857R, which causes autosomal dominant long QT syndrome in the absence of Timothy syndrome, a heterozygous loss-of-function variation CASQ2:NM_001232.4:c.420+2T>C classified as pathogenic, and a 9.2 kb structural variation that spans exon 2 of the KCNQ1 gene, which is likely to cause Jervell-Lange-Nielssen syndrome. In addition, we also identified a loss-of-function variation and 16 structural variations of unknown significance (VUS). Further studies are required to elucidate the role of these identified VUS in gene regulation and decipher the underlying genetic and molecular mechanisms of these disorders. Our present study serves as a pilot for understanding the utility of WGS over clinical exomes in diagnosing cardiac channelopathy disorders.

Asunto(s)

Canalopatías , Secuenciación del Exoma , Linaje , Secuenciación Completa del Genoma , Humanos , Canalopatías/genética , Canalopatías/diagnóstico , Femenino , Masculino , Canal de Potasio KCNQ1/genética , Canales de Calcio Tipo L/genética , Adulto , Estudios Retrospectivos , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/diagnóstico , Niño , Mutación , Exoma/genética , Predisposición Genética a la Enfermedad

RESUMEN

Inherited cardiovascular diseases are rare diseases that are difficult to diagnose by non-expert professionals. Genetic analyses play a key role in the diagnosis of these diseases, in which the identification of a pathogenic genetic variant is often a diagnostic criterion. Therefore, genetic variant classification and routine reinterpretation as data become available represent one of the main challenges associated with genetic analyses. Using the genetic variants identified in an inherited cardiovascular diseases unit during a 10-year period, the objectives of this study were: 1) to evaluate the impact of genetic variant reinterpretation, 2) to compare the reclassification rates between different cohorts of cardiac channelopathies and cardiomyopathies, and 3) to establish the most appropriate periodicity for genetic variant reinterpretation. All the evaluated cohorts (full cohort of inherited cardiovascular diseases, cardiomyopathies, cardiac channelopathies, hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, Brugada syndrome, long QT syndrome and catecholaminergic polymorphic ventricular tachycardia) showed reclassification rates above 25%, showing even higher reclassification rates when there is definitive evidence of the association between the gene and the disease in the cardiac channelopathies. Evaluation of genetic variant reclassification rates based on the year of the initial classification showed that the most appropriate frequency for the reinterpretation would be 2 years, with the possibility of a more frequent reinterpretation if deemed convenient. To keep genetic variant classifications up to date, genetic counsellors play a critical role in the reinterpretation process, providing clinical evidence that genetic diagnostic laboratories often do not have at their disposal and communicating changes in classification and the potential implications of these reclassifications to patients and relatives.

Asunto(s)

Enfermedades Cardiovasculares , Humanos , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/diagnóstico , Canalopatías/genética , Canalopatías/diagnóstico , Pruebas Genéticas/métodos , Variación Genética , Cardiomiopatías/genética , Cardiomiopatías/diagnóstico , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/diagnóstico , Síndrome de Brugada/genética , Síndrome de Brugada/diagnóstico

RESUMEN

The limited literature and increasing interest in studies on cardiac electrophysiology, explicitly focusing on cardiac ion channelopathies and sudden cardiac death in diverse populations, has prompted a comprehensive examination of existing research. Our review specifically targets Hispanic/Latino and Indigenous populations, which are often underrepresented in healthcare studies. This review encompasses investigations into genetic variants, epidemiology, etiologies, and clinical risk factors associated with arrhythmias in these demographic groups. The review explores the Hispanic paradox, a phenomenon linking healthcare outcomes to socioeconomic factors within Hispanic communities in the United States. Furthermore, it discusses studies exemplifying this observation in the context of arrhythmias and ion channelopathies in Hispanic populations. Current research also sheds light on disparities in overall healthcare quality in Indigenous populations. The available yet limited literature underscores the pressing need for more extensive and comprehensive research on cardiac ion channelopathies in Hispanic/Latino and Indigenous populations. Specifically, additional studies are essential to fully characterize pathogenic genetic variants, identify population-specific risk factors, and address health disparities to enhance the detection, prevention, and management of arrhythmias and sudden cardiac death in these demographic groups.

Asunto(s)

Arritmias Cardíacas , Canalopatías , Muerte Súbita Cardíaca , Predisposición Genética a la Enfermedad , Hispánicos o Latinos , Humanos , Muerte Súbita Cardíaca/etnología , Muerte Súbita Cardíaca/etiología , Canalopatías/genética , Canalopatías/etnología , Canalopatías/mortalidad , Canalopatías/diagnóstico , Arritmias Cardíacas/etnología , Arritmias Cardíacas/fisiopatología , Arritmias Cardíacas/genética , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/mortalidad , Factores de Riesgo , Medición de Riesgo , Disparidades en el Estado de Salud , Masculino , Disparidades en Atención de Salud/etnología , Femenino , Estados Unidos/epidemiología , Fenotipo , Pronóstico , Adulto , Factores Raciales , Potenciales de Acción , Persona de Mediana Edad

RESUMEN

OBJECTIVES: This study aimed to determine the usefulness of electrophysiological exercise tests. The significance of slightly abnormal exercise tests was also examined. METHODS: We identified all the patients who had undergone exercise testing between February 2007 to June 2022 in Tampere University Hospital, Finland. Their medical records after diagnostic workup and exercise test reports were reviewed. A binary logistic regression was performed to evaluate the association between positive test result in short exercise test, long exercise test, or short exercise test with cooling and genetically confirmed skeletal muscle channelopathy or myotonic disorder. RESULTS: We identified 256 patients. 27 patients were diagnosed with nondystrophic myotonia, periodic paralysis, myotonic dystrophy type 1, myotonic dystrophy type 2, or other specified myopathy. 14 patients were suspected to have a skeletal muscle channelopathy, but pathogenic variants could not be identified. The remaining 215 patients were diagnosed with other conditions than skeletal muscle channelopathy or myotonic disorder. The combined sensitivity of exercise tests was 59.3% and specificity 99.1%. Abnormal exercise test result was associated with increased risk of skeletal muscle channelopathy or myotonic disorder (OR 164.3, 95% CI 28.3-954.6, p < 0.001). CONCLUSIONS: Electrophysiological exercise test is not optimal to exclude skeletal muscle channelopathy. It may be useful if a skeletal muscle channelopathy is suspected and genetic testing is negative or indeterminate and further evidence is required. Slightly abnormal exercise test results are possible in various conditions and result from different aetiologies. There is a demand for neurophysiological studies with higher sensitivity to detect skeletal muscle channelopathies.

Asunto(s)

Canalopatías , Trastornos Miotónicos , Distrofia Miotónica , Humanos , Prueba de Esfuerzo , Estudios Retrospectivos , Canalopatías/diagnóstico , Canalopatías/genética , Músculo Esquelético , Trastornos Miotónicos/diagnóstico , Trastornos Miotónicos/genética

RESUMEN

INTRODUCTION: Skeletal muscle channelopathies (SMCs) are a heterogenous group of disorders, caused by mutations in skeletal ion channels leading to abnormal muscle excitability, resulting in either delayed muscle relaxation (myotonia) which characterizes non-dystrophic myotonias (NDMs), or membrane transient inactivation, causing episodic weakness, typical of periodic paralyses (PPs). AREAS COVERED: SMCs include myotonia congenita, paramyotonia congenita, and sodium-channel myotonia among NDMs, and hyper-normokalemic, hypokalemic, or late-onset periodic paralyses among PPs. When suspecting an SMC, a structured diagnostic approach is required. Detailed personal and family history and clinical examination are essential, while neurophysiological tests should confirm myotonia and rule out alternative diagnosis. Moreover, specific electrodiagnostic studies are important to further define the phenotype of de novo cases and drive molecular analyses together with clinical data. Definite diagnosis is achieved through genetic testing, either with Sanger sequencing or multigene next-generation sequencing panel. In still unsolved patients, more advanced techniques, as exome-variant sequencing or whole-genome sequencing, may be considered in expert centers. EXPERT OPINION: The diagnostic approach to SMC is still mainly based on clinical data; moreover, definite diagnosis is sometimes complicated by the difficulty to establish a proper genotype-phenotype correlation. Lastly, further studies are needed to allow the genetic characterization of unsolved patients.

Asunto(s)

Canalopatías , Miotonía , Trastornos Miotónicos , Parálisis Periódicas Familiares , Humanos , Miotonía/diagnóstico , Miotonía/genética , Canalopatías/diagnóstico , Canalopatías/genética , Músculo Esquelético , Trastornos Miotónicos/genética , Mutación , Parálisis

RESUMEN

Sudden cardiac death is a sudden, unexpected death developed by one of the many different causes of cardiac arrest that occur within 1 hour of the onset of new symptoms. Sudden unexplained death (SUD) comprises a normal heart at postmortem examination and negative toxicological analysis. SUD often arises from cardiac genetic disease, particularly channelopathies. Channelopathies, or inherited arrhythmia syndromes, are a group of disorders characterized by an increased risk of sudden cardiac death, abnormal cardiac electrical function, and, typically, a structurally normal heart. They share an underlying genetic etiology where disease-causing genetic variants may lead to the absence or dysfunction of proteins involved in the generation and propagation of the cardiac action potential. Our study aimed to evaluate the importance of next-generation sequencing in the postmortem investigations of SUD cases. In this study, 5 forensic SUD cases were investigated for inherited cardiac disorders. We screened a total of 68 cardiac genes for the sibling of case 1, as well as case 2, and 51 genes for cases 3, 4, and 5. Of the 12 variants identified, 2 likely pathogenic variants (16.7%) were the TMEM43 _ c.1000+2T>C splice site mutation and the SCN5A _ p.W703X nonsense mutation. The remaining 10 variants of uncertain significance were detected in the TRPM4 , RANGRF , A KAP9 , KCND3 , KCNE1 , DSG2 , CASQ1 , and SNTA1 genes. Irrespective of genetic testing, all SUD families require detailed clinical testing to identify relatives who may be at risk. Molecular autopsy and detailed premorbid clinical and family histories can survive family members of SUD cases.

Asunto(s)

Canalopatías , Humanos , Autopsia , Canalopatías/diagnóstico , Canalopatías/genética , Canalopatías/complicaciones , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/patología , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Arritmias Cardíacas/complicaciones , Mutación

RESUMEN

In the early nineties, few years before the birth of Europace, the clinical and scientific world of familial arrhythmogenic conditions was revolutionized by the identification of the first disease-causing genes. The explosion of genetic studies over a 15-year period led to the discovery of major disease-causing genes in practically all channelopathies and cardiomyopathies, bringing insight into the pathophysiological mechanisms of these conditions. The birth of next generation sequencing allowed a further step forward and other significant genes, as CALM1-3 in channelopathies and FLN C and TTN in cardiomyopathies were identified. Genotype-phenotype studies allowed the implementation of the genetic results in diagnosis, risk stratification, and therapeutic management with a different level of evidence in different arrhythmogenic conditions. The influence of common genetic variants, i.e. SNPs, on disease manifestation was proved in mid-twenties, and in the last 10 years with the advent of genome-wide association studies performed in familial arrhythmogenic diseases, the concept of polygenic risk score has been consolidated. Now, we are at the start of another amazing phase, i.e. the initiation of first gene therapy clinical trials.

Asunto(s)

Cardiomiopatías , Canalopatías , Humanos , Canalopatías/diagnóstico , Canalopatías/genética , Canalopatías/terapia , Estudio de Asociación del Genoma Completo , Cardiomiopatías/diagnóstico , Cardiomiopatías/genética , Cardiomiopatías/terapia , Cognición , Secuenciación de Nucleótidos de Alto Rendimiento

RESUMEN

The field of pediatric skeletal muscle channelopathies has seen major new advances in terms of a wider understanding of clinical presentations and new phenotypes. Skeletal muscle channelopathies cause significant disability and even death in some of the newly described phenotypes. Despite this, there are virtually no data on the epidemiology and longitudinal natural history of these conditions or randomized controlled trial evidence of efficacy or tolerability of any treatment in children, and thus best practice care recommendations do not exist. Clinical history, and to a lesser extent examination, is key to eliciting symptoms and signs that indicate a differential diagnosis of muscle channelopathy. Normal routine investigations should not deter one from the diagnosis. Specialist neurophysiologic investigations have an additional role, but their availability should not delay genetic testing. New phenotypes are increasingly likely to be identified by next-generation sequencing panels. Many treatments or interventions for symptomatic patients are available, with anecdotal data to support their benefit, but we lack trial data on efficacy, safety, or superiority. This lack of trial data in turn can lead to hesitancy in prescribing among doctors or in accepting medication by parents. Holistic management addressing work, education, activity, and additional symptoms of pain and fatigue provides significant benefit. Preventable morbidity and sometimes mortality occurs if the diagnosis and therefore treatment is delayed. Advances in genetic sequencing technology and greater access to testing may help to refine recently identified phenotypes, including histology, as more cases are described. Randomized controlled treatment trials are required to inform best practice care recommendations. A holistic approach to management is essential and should not be overlooked. Good quality data on prevalence, health burden, and optimal treatment are urgently needed.

Asunto(s)

Canalopatías , Niño , Humanos , Canalopatías/diagnóstico , Canalopatías/genética , Canalopatías/terapia , Músculo Esquelético/patología , Pruebas Genéticas , Ensayos Clínicos Controlados Aleatorios como Asunto

RESUMEN

In general, asymptomatic patients with channelopathies are at increased risk of sudden cardiac death (SCD), due to pathogenic variants in genes encoding ion channels that result in pathological ion currents. Channelopathies include long-QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and short-QT syndrome (SQTS). In addition to the patient's clinical presentation, history and clinical tests, the main diagnostic tools are electrocardiography and genetic testing to identify known gene mutations. Early and correct diagnosis as well as further risk stratification of affected individuals and their relatives are paramount for prognosis. The recent availability of risk score calculators for LQTS and BrS allows SCD risk to be accurately estimated. The extent to which these improve patient selection for treatment with an implantable cardioverter-defibrillator (ICD) system is currently unknown. In most cases, initiation of basic therapy in asymptomatic patients in the form of avoidance of triggers, which are usually medication or stressful situations, is sufficient and contributes to risk reduction. In addition, there are other risk-reducing prophylactic measures, such as permanent medication with nonselective ß­ blockers (for LQTS and CPVT) or mexiletine for LQTS3. Patients and their family members should be referred to specialized outpatient clinics for individual risk stratification in the sense of primary prophylaxis.

Asunto(s)

Síndrome de Brugada , Canalopatías , Síndrome de QT Prolongado , Taquicardia Ventricular , Humanos , Canalopatías/diagnóstico , Canalopatías/genética , Canalopatías/prevención & control , Arritmias Cardíacas/diagnóstico , Muerte Súbita Cardíaca/prevención & control , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/prevención & control , Taquicardia Ventricular/diagnóstico , Antagonistas Adrenérgicos beta , Medición de Riesgo

RESUMEN

PURPOSE OF REVIEW: This article describes the clinical features, diagnosis, pathophysiology, and management of nondystrophic myotonia and periodic paralysis. RECENT FINDINGS: An increasing awareness exists about the genotype-phenotype overlap in skeletal muscle channelopathies, and thus genetic testing is needed to make a definitive diagnosis. Electrodiagnostic testing in channelopathies is highly specialized with significant overlap in various mutation subtypes. Randomized clinical trials have now been conducted in these disorders with expanded treatment options for patients with muscle channelopathies. SUMMARY: Skeletal muscle channelopathies are rare heterogeneous conditions characterized by lifelong symptoms that require a comprehensive management plan that includes pharmacologic and nonpharmacologic interventions. The significant variability in biophysical features of various mutations, coupled with the difficulties of performing clinical trials in rare diseases, makes it challenging to design and implement treatment trials for muscle channelopathies.

Asunto(s)

Canalopatías , Miotonía , Trastornos Miotónicos , Parálisis Periódicas Familiares , Humanos , Canalopatías/diagnóstico , Canalopatías/genética , Canalopatías/terapia , Músculo Esquelético , Miotonía/diagnóstico , Miotonía/genética , Miotonía/terapia , Trastornos Miotónicos/diagnóstico , Trastornos Miotónicos/genética , Mutación/genética

RESUMEN

Pediatric sudden cardiac death (SCD) is the sudden unexpected death of a child or adolescent due to a presumed cardiac etiology. Heritable causes of pediatric SCD are predominantly cardiomyopathies and cardiac ion channelopathies. This review illustrates recent advances in determining the genetic cause of established and emerging channelopathies and cardiomyopathies, and how broader genomic sequencing is uncovering complex interactions between genetic architecture and disease manifestation. We discuss innovative models and experimental platforms for resolving the variant of uncertain significance as both the variants and genes associated with disease continue to evolve. Finally, we highlight the growing problem of incidentally identified variants in cardiovascular disease-causing genes and review innovative methods to determining whether these variants may ultimately result in penetrant disease. Overall, we seek to illustrate both the promise and inherent challenges in bridging the traditional role for genetics in diagnosing cardiomyopathies and channelopathies to one of true risk-predictive precision medicine.

Asunto(s)

Cardiomiopatías , Canalopatías , Adolescente , Cardiomiopatías/diagnóstico , Cardiomiopatías/genética , Canalopatías/complicaciones , Canalopatías/diagnóstico , Canalopatías/genética , Niño , Muerte Súbita Cardíaca/etiología , Técnicas y Procedimientos Diagnósticos/efectos adversos , Pruebas Genéticas , Genómica , Humanos , Medicina de Precisión

RESUMEN

BACKGROUND: Accurately determining variant pathogenicity is critical in the diagnosis of cardiac channelopathies; however, it remains unknown how variant pathogenicity status changes over time. Our aim is to use a comprehensive analysis of ClinVar to understand the mutability of variant evaluation in channelopathy-associated genes to inform clinical decision-making around variant calling. METHODS: We identified 10 genes (RYR2, CASQ2, KCNQ1, KCNH2, SCN5A, CACNA1C, CALM1, CALM2, CALM3, TRDN) strongly associated with cardiac channelopathies, as well as 3 comparison gene sets (disputed long QT syndrome, sudden unexpected death in epilepsy, and all ClinVar). We comprehensively analyzed variant pathogenicity calls over time using the ClinVar database with Rstudio. Analyses focused on the frequency and directionality of clinically meaningful changes in disease association, defined as a change from one of the following three categories to another: likely benign/benign, conflicting evidence of pathogenicity/variant of uncertain significance, and likely pathogenic/pathogenic. RESULTS: In total, among channelopathy-associated genes, there were 9975 variants in ClinVar and 8.4% had a clinically meaningful change in disease association at least once over the past 10 years, as opposed to 4.9% of all ClinVar variants. The 3 channelopathy-associated genes with the most variants undergoing a clinically significant change were KCNQ1 (20.9%), SCN5A (11.2%), and KCNH2 (10.1%). Ten of the 12 included genes had variant evaluations that trended toward diagnostic uncertainty over time. Specifically, channelopathy-associated gene variants with either pathogenic/likely pathogenic or benign/likely benign assignments were 5.6× and 2×, respectively, as likely to be reevaluated to conflicting/variant of uncertain significance compared to the converse. CONCLUSIONS: Over the past 10 years, 8.4% of variants in channelopathy-associated genes have changed pathogenicity status with a decline in overall diagnostic certainty. Ongoing clinical and genetic variant follow-up is needed to account for presence of clinically meaningful change in variant pathogenicity assignment over time.

Asunto(s)

Canalopatías , Arritmias Cardíacas/genética , Canalopatías/diagnóstico , Canalopatías/genética , Canal de Potasio ERG1/genética , Humanos , Canal de Potasio KCNQ1/genética , Canal de Sodio Activado por Voltaje NAV1.5/genética , Incertidumbre , Virulencia

RESUMEN

The understanding and prevalence of cardiac channelopathies has grown over time. Many patients are asymptomatic but are at risk for malignant arrhythmias during high-acuity medical admissions. Long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia are discussed with specific consideration given for the role these medical conditions play during an intensive care unit admission-for either cardiac or noncardiac reasons.

Asunto(s)

Canalopatías , Taquicardia Ventricular , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/terapia , Canalopatías/diagnóstico , Canalopatías/genética , Canalopatías/terapia , Muerte Súbita Cardíaca , Humanos , Unidades de Cuidados Intensivos , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/terapia

RESUMEN

The results of molecular genetic testing may affect recommended treatment or therapeutic decisions and risk assessment, may help with identification of family members at risk. Here, we report a case of a young patient with a paradoxical combination of two inherited arrhythmic syndromes and demonstrate the role of genetic testing as one of the basis of personalized approach in diagnosis, treatment and prevention complications of inherited channelopathies complications. Integration of genetic testing results into clinical practice is a successful example of the concept of personalized medicine.

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The results of genetic testing may help to clarify the diagnosis, help the doctor to choose treatment and patient management tactics. We report a case of a young patient with the relatively rare arrythmia. We are highlighting the role of genetic testing as a basis of personalized approach of arrhythmia patient.

Asunto(s)

Síndrome de Brugada , Canalopatías , Síndrome de QT Prolongado , Síndrome de Brugada/complicaciones , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/genética , Canalopatías/diagnóstico , Canalopatías/genética , Canalopatías/terapia , Familia , Pruebas Genéticas , Humanos , Síndrome de QT Prolongado/complicaciones , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/terapia

RESUMEN

BACKGROUND: International guidelines recommend work-up of relatives to autopsy negative sudden cardiac death victims, denoted as sudden unexplained death (SUD) and nonautopsied possible sudden cardiac death (pSCD) victims. This study assesses and compare baseline characteristics and clinical outcome at initial evaluation and during follow-up of relatives to SUD and pSCD victims. METHODS: We retrospectively included data from systematic screening and routine follow-up of first-degree relatives to SUD and pSCD victims referred to our Unit for Inherited Cardiac Diseases, Copenhagen, 2005-2018. Victims with an antemortem known inherited cardiac disease were excluded. RESULTS: We included 371 first-degree relatives from 187 families (120 SUD, 67 pSCD): 276 SUD relatives (age 33 ± 18 years, 54% men) and 95 pSCD relatives (age 40 ± 15 years, 51% men). The diagnostic yields of inherited cardiac diseases in SUD and pSCD families were 16% and 13%, respectively (p = .8). The diagnoses in SUD families were mainly channelopathies (68%), whereas pSCD families were equally diagnosed with cardiomyopathies, channelopathies, and premature ischemic heart disease. Ninety-three percent of diagnosed families were diagnosed at initial evaluation and 7% during follow-up (5.4 ± 3.3 years). During follow-up 34% of relatives with a diagnosed inherited cardiac disease had an arrhythmic event, compared to 5% of relatives without established diagnosis (p < .0001). CONCLUSIONS: Channelopathies dominated in SUD families whereas a broader spectrum of inherited diseases was diagnosed in pSCD families. Most affected relatives were diagnosed at initial evaluation. The event rate was low in relatives without an established diagnosis. Long-term clinical follow-up may not be warranted in all relatives with normal baseline-findings.

Asunto(s)

Canalopatías , Cardiopatías , Adolescente , Adulto , Autopsia , Canalopatías/diagnóstico , Canalopatías/genética , Muerte Súbita Cardíaca/epidemiología , Femenino , Pruebas Genéticas , Cardiopatías/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto Joven

RESUMEN

Among the inherited ion channelopathies associated with potentially life-threatening ventricular arrhythmia syndromes in nominally structurally normal hearts are the J wave syndromes, which include the Brugada (BrS) and early repolarization (ERS) syndromes. These ion channelopathies are responsible for sudden cardiac death (SCD), most often in young adults in the third and fourth decade of life. Our principal goal in this review is to briefly outline the clinical characteristics, as well as the molecular, ionic, cellular, and genetic mechanisms underlying these primary electrical diseases that have challenged the cardiology community over the past two decades. In addition, we discuss our recently developed whole-heart experimental model of BrS, providing compelling evidence in support of the repolarization hypothesis for the BrS phenotype as well as novel findings demonstrating that voltage-gated sodium and transient outward current channels can modulate each other's function via trafficking and gating mechanisms with implications for improved understanding of the genetics of both cardiac and neuronal syndromes.

Asunto(s)

Síndrome de Brugada , Canalopatías , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Arritmias Cardíacas/terapia , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/genética , Síndrome de Brugada/terapia , Canalopatías/diagnóstico , Canalopatías/genética , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/prevención & control , Electrocardiografía , Humanos