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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(3): 289-294, 2020 Mar 10.
Artigo em Chinês | MEDLINE | ID: mdl-32128746

RESUMO

Long Q-T syndrome (LQTS) is an ion channel disease of the heart featuring single gene inheritance. It is characterized by prolonged QT interval, abnormal T wave, torsade de points (TdP) on electrocardiogram, with recurrent syncope, convulsion and even sudden death. Although the overall prevalence of LQTS is not high, the disease has attracted attention of cardiologists for its high incidence of sudden cardiac death. The compilation of this guideline has referred to the consensus of basic and clinical research, guidelines of other countries, and summarized the clinical manifestations, molecular basis, diagnostic criteria, treatment and prognosis, and genetic counseling of LQTS, with an aim to standardize its clinical diagnosis and treatment.


Assuntos
Canalopatias/diagnóstico , Canalopatias/terapia , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/terapia , Guias de Prática Clínica como Assunto , Morte Súbita Cardíaca , Eletrocardiografia , Humanos , Canais Iônicos , Prognóstico
2.
Med Clin North Am ; 103(5): 809-820, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31378327

RESUMO

With recent advances in genetic diagnostics, many inherited diseases, which can cause life-threatening arrhythmias, are being better characterized. Many of these diseases are caused by genetic disorders that affect the function of the ion channels that regulate the action potential or the function of important cardiac muscle regulatory proteins. This article summarizes the diseases that we have learned about, such as the long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. The article examines the diagnosis, genetic screening of patients and their relatives, management, and referral to a specialist for further therapy.


Assuntos
Arritmias Cardíacas/congênito , Canalopatias/diagnóstico , Morte Súbita Cardíaca/etiologia , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiologia , Canalopatias/complicações , Humanos , Prognóstico , Avaliação de Sintomas
3.
Seizure ; 67: 11-14, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30849713

RESUMO

PURPOSE: Ryanodine receptor 2 (RYR2) mutation is well-established in the aetiology of an inherited cardiac disorder known as catecholaminergic polymorphic ventricular tachycardia (CPVT). The RYR2 receptor is expressed in cardiomyocytes, and also in the hippocampus. The RYR2 mutation has not been reported as a potential cause of adult-onset genetic generalised epilepsy (GGE). METHOD: Case report. RESULTS: A 32-year-old right-handed female presented with three unprovoked generalised seizures over twelve years. Electroencephalogram showed epileptiform activity which coincided with normal electrocardiogram recording. Her brother survived a cardiac arrest in his 20's and was diagnosed with CPVT and found to be heterozygous for a novel mutation in the RYR2 gene at chromosome 1q43, c.229 G > A p.(Ala77Thr). The patient inherited the same missense variant, predicted to be damaging by numerous in silico analytic tools. This mutation affects the N-terminal domain of the RYR2 receptor which plays a role in channel activation. However, the patient had repeatedly normal cardiac investigations including normal exercise stress tests. CONCLUSION: We propose that the RYR2 mutation is a potentially novel neurocardiac calcium channelopathy that may manifest with either CPVT or GGE depending on selective involvement of RYR2 receptors expressed in the heart or in the brain. RYR2 mutant mice have demonstrated spontaneous EEG-positive seizures independent of cardiac arrhythmia. Whole exome sequencing analyses have identified RYR2 as a candidate gene in GGE. This case is a reminder for careful assessment of episodes of transient loss of consciousness in an individual with CPVT, so as to not mistake possible neurogenic seizure for cardiogenic syncope, carrying obvious implications for treatment.


Assuntos
Canalopatias/diagnóstico , Canalopatias/genética , Epilepsia Generalizada/diagnóstico , Epilepsia Generalizada/genética , Mutação , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Adulto , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Diagnóstico Diferencial , Feminino , Humanos
4.
Heart Lung Circ ; 28(1): 22-30, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30389366

RESUMO

Forty per cent (40%) of sudden unexpected natural deaths in people under 35 years of age are associated with a negative autopsy, and the cardiac ion channelopathies are the prime suspects in such cases. Long QT syndrome (LQTS), Brugada syndrome (BrS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) are the most commonly identified with genetic testing. The cellular action potential driving the heart cycle is shaped by a specific series of depolarising and repolarising ion currents mediated by ion channels. Alterations in any of these currents, and in the availability of intracellular free calcium, leaves the myocardium vulnerable to polymorphic ventricular tachycardia or ventricular fibrillation. Each channelopathy has its own electrocardiogram (ECG) signature, typical mode of presentation, and most commonly related gene. Long QT type 1 (gene, KCNQ1) and CPVT (gene, RyR2) typically present with cardiac events (ie syncope or cardiac arrest) during or immediately after exercise in young males; long QT type 2 (gene, KCNH2) after startle or during the night in adult females-particularly early post-partum, and long QT type 3 and Brugada syndrome (gene, SCN5A) during the night in young adult males. They are commonly misdiagnosed as seizure disorders. Fever-triggered cardiac events should also raise the suspicion of BrS. This review summarises genetics, cellular mechanisms, risk stratification and treatments. Beta blockers are the mainstay of treatment for long QT syndrome and CPVT, and flecainide is remarkably effective in CPVT. Brugada syndrome is genetically a more complex disease than the others, and risk stratification and management is more difficult.


Assuntos
Canalopatias , Morte Súbita Cardíaca/etiologia , Testes Genéticos/métodos , Canalopatias/complicações , Canalopatias/diagnóstico , Canalopatias/genética , Humanos
5.
J Cardiovasc Med (Hagerstown) ; 19(11): 633-642, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30222664

RESUMO

: Cardiomyopathies and channelopathies are heterogeneous disorders that increase the risk of sudden cardiac death (SCD). Implantable cardioverter-defibrillator (ICD) therapy is safe and effective for preventing SCD in patients at risk for malignant ventricular arrhythmias. Because of the poor positive predictive value of current risk stratification tools, the majority of patients implanted with an ICD will never receive a life-saving therapy but will be exposed to the risk of complications such as device infection, lead failure and inappropriate therapy. Subcutaneous ICD (S-ICD) now constitutes a valuable alternative to conventional transvenous ICD in patients with cardiomyopathies and channelopathies as it provides protection from SCD while avoiding the risks of intravascular lead infection or failure. This may be particularly advantageous for young patients with a very long life expectancy. On the other hand, S-ICD cannot deliver antitachycardia pacing or antibradycardia pacing. The purpose of this article is to review the available evidence and the future perspectives of S-ICD therapy in patients with cardiomyopathies or channelopathies.


Assuntos
Cardiomiopatias/terapia , Canalopatias/terapia , Morte Súbita Cardíaca/prevenção & controle , Desfibriladores Implantáveis , Cardioversão Elétrica/instrumentação , Cardiomiopatias/diagnóstico , Cardiomiopatias/mortalidade , Cardiomiopatias/fisiopatologia , Canalopatias/diagnóstico , Canalopatias/mortalidade , Canalopatias/fisiopatologia , Tomada de Decisão Clínica , Cardioversão Elétrica/efeitos adversos , Cardioversão Elétrica/mortalidade , Humanos , Seleção de Pacientes , Valor Preditivo dos Testes , Desenho de Prótese , Medição de Risco , Fatores de Risco , Resultado do Tratamento
6.
Arch. med. deporte ; 35(186): 246-253, jul.-ago. 2018. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-177467

RESUMO

La seguridad de la actividad física y deportiva en pacientes con cardiopatías familiares aún no está bien establecida. Las recomendaciones sobre el ejercicio físico en estos pacientes suele ser bastante restrictiva sin que haya clara evidencia para ello, a pesar de que el deporte haya demostrado importantes beneficios cardiovasculares. La participación en deportes en los adultos con cardiopatías familiares se considera un territorio relativamente poco conocido y muchos clínicos se encuentran con dificultades en el asesoramiento a sus pacientes. El desarrollo de la medicina actual ha supuesto una mejoría significativa en el estudio de las cardiopatías familiares, así como en su diagnóstico precoz y tratamiento. Asimismo, los estudios genéticos han supuestos un pilar fundamental en el seguimiento de estas cardiopatías, guiando de manera más adecuada la actitud terapéutica que debemos seguir. Hasta hace poco tiempo, los pacientes que presentan dichas cardiopatías han sido descalificados de manera frecuente de los deportes competitivos y en muchas ocasiones, se recomienda el cese completo de la actividad física, incluido el deporte tipo recreacional. Sin embargo, las recomendaciones actuales son menos restrictivas, insistiendo en individualizar los diferentes casos en función del tipo de patología, del tipo de actividad física realizada, si éstos presentan la enfermedad o son únicamente portadores de mutaciones genéticas causales, etc. Las investigaciones actuales se centran fundamentalmente en la seguridad de la actividad física en pacientes con cardiopatías familiares, y el temor a que la práctica de actividad física a nivel competitivo pueda aumentar significativamente el riesgo de eventos adversos, especialmente de eventos arrítmicos y muerte súbita. En esta revisión, analizamos numerosos estudios y las guías de práctica clínica, con el fin de establecer las recomendaciones de actividad física, así como sus restricciones en función de los diferentes tipos de cardiopatías familiares


The safety of physical activity and sports in patients with inherited heart disease is not well established. The recommendations on physical exercise in these patients are usually quite restrictive without clear evidence for this, despite the fact that sport has shown important cardiovascular benefits. Participation in sports in adults with inherited heart disease is considered a relatively little known territory and many clinicians find it difficult to advise their patients. The development of current medicine has meant a significant improvement in the study of inherited heart diseases, as well as in their early diagnosis and treatment. In addition, genetic studies have assumed a fundamental aspect in the follow-up of these heart diseases, guiding more appropriately the therapeutic attitude that we must follow. Until recently, patients with such heart disease have been frequently disqualified from competitive sports, and in many cases, complete cessation of physical activity, including recreational sport, is recommended. However, current recommendations are less restrictive, insisting on individualizing the different cases depending on the type of pathology, the type of physical activity performed, whether they present the disease or are only carriers of causal genetic mutations, etc. Current research focuses primarily on the safety of physical activity in patients with inherited heart disease and the fear that the practice of competitive physical activity can significantly increase the risk of adverse events, especially arrhythmic events and sudden death. In this review, we analyzed numerous studies and clinical practice guidelines, in order to establish the recommendations of physical activity, as well as their restrictions depending on the different types of inherited heart disease


Assuntos
Humanos , Exercício Físico , Cardiopatias/epidemiologia , Cardiopatias/prevenção & controle , Canalopatias/epidemiologia , Esportes/fisiologia , Canalopatias/diagnóstico , Canalopatias/terapia
7.
Rev Port Cardiol ; 37(2): 179-199, 2018 Feb.
Artigo em Inglês, Português | MEDLINE | ID: mdl-29525288

RESUMO

INTRODUCTION AND OBJECTIVES: The importance of sodium channels for the normal electrical activity of the heart is emphasized by the fact that mutations (inherited or de novo) in genes that encode for these channels or their associated proteins cause arrhythmogenic syndromes such as the Brugada syndrome and the long QT syndrome (LQTS). The aim of this study is to conduct a review of the literature on the mutations in the sodium channel complex responsible for heart disease and the implications of a close relationship between genetics and the clinical aspects of the main cardiac channelopathies, namely at the level of diagnosis, risk stratification, prognosis, screening of family members and treatment. METHODS: The online Pubmed® database was used to search for articles published in this field in indexed journals. The MeSH database was used to define the following query: "Mutation [Mesh] AND Sodium Channels [Mesh] AND Heart Diseases [Mesh]", and articles published in the last 15 years, written in English or Portuguese and referring to research in human beings were included. CONCLUSIONS: In the past few years, significant advances have been made to clarify the genetic and molecular basis of these syndromes. A greater understanding of the underlying pathophysiological mechanisms showed the importance of the relationship between genotype and phenotype and led to progress in the clinical approach to these patients. However, it is still necessary to improve diagnostic capacity, optimize risk stratification, and develop new specific treatments according to the genotype-phenotype binomial.


Assuntos
Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Canalopatias/genética , Canalopatias/metabolismo , Mutação , Canais de Sódio/genética , Algoritmos , Cardiomiopatias/diagnóstico , Canalopatias/diagnóstico , Humanos , Canais de Sódio/fisiologia
8.
AACN Adv Crit Care ; 29(1): 43-57, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29496713

RESUMO

The discovery of the human genome has ushered in a new era of molecular testing, advancing our knowledge and ability to identify cardiac channelopathies. Genetic variations can affect the opening and closing of the potassium, sodium, and calcium channels, resulting in arrhythmias and sudden death. Cardiac arrhythmias caused by disorders of ion channels are known as cardiac channelopathies. Nurses are important members of many interdisciplinary teams and must have a general understanding of the pathophysiology of the most commonly encountered cardiac channelopathies, electrocardiogram characteristics, approaches to treatment, and care for patients and their families. This article provides an overview of cardiac channelopathies that nurses might encounter in an array of clinical and research settings, focusing on the clinically relevant features of long QT syndrome, short QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and arrhythmogenic right ventricular dysplasia/cardiomyopathy.


Assuntos
Arritmias Cardíacas/genética , Arritmias Cardíacas/enfermagem , Canalopatias/genética , Canalopatias/enfermagem , Morte Súbita Cardíaca/prevenção & controle , Genômica/métodos , Medicina de Precisão/métodos , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/fisiopatologia , Canalopatias/diagnóstico , Canalopatias/fisiopatologia , Gerenciamento Clínico , Humanos
9.
Hong Kong Med J ; 24(4): 340-349, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29497013

RESUMO

INTRODUCTION: Hereditary channelopathies and cardiomyopathies are potentially lethal and are clinically and genetically heterogeneous, involving at least 90 genes. Genetic testing can provide an accurate diagnosis, guide treatment, and enable cascade screening. The genetic basis among the Hong Kong Chinese population is largely unknown. We aimed to report on 28 unrelated patients with positive genetic findings detected from January 2006 to December 2015. METHODS: Sanger sequencing was performed for 28 unrelated patients with a clinical diagnosis of channelopathies or cardiomyopathies, testing for the following genes: KCNQ1,KCNH2,KCNE1,KCNE2, and SCN5A, for long QT syndrome; SCN5A for Brugada syndrome; RYR2 for catecholaminergic polymorphic ventricular tachycardia; MYH7 and MYBPC3 for hypertrophic cardiomyopathy; LMNA for dilated cardiomyopathy; and PKP2 and DSP for arrhythmogenic right ventricular dysplasia/cardiomyopathy. RESULTS: There were 17 males and 11 females; their mean age at diagnosis was 39 years (range, 1-80 years). The major clinical presentations included syncope, palpitations, and abnormal electrocardiography findings. A family history was present in 13 (46%) patients. There were 26 different heterozygous mutations detected, of which six were novel-two in SCN5A (NM_198056.2:c.429del and c.2024-11T>A), two in MYBPC3 (NM_000256.3:c.906-22G>A and c.2105_2106del), and two in LMNA (NM_170707.3:c.73C>A and c.1209_1213dup). CONCLUSIONS: We have characterised the genetic heterogeneity in channelopathies and cardiomyopathies among Hong Kong Chinese patients in a 10-year case series. Correct interpretation of genetic findings is difficult and requires expertise and experience. Caution regarding issues of non-penetrance, variable expressivity, phenotype-genotype correlation, susceptibility risk, and digenic inheritance is necessary for genetic counselling and cascade screening.


Assuntos
Cardiomiopatias/diagnóstico , Cardiomiopatias/genética , Canalopatias/diagnóstico , Canalopatias/genética , Testes Genéticos/estatística & dados numéricos , Adolescente , Adulto , Idoso de 80 Anos ou mais , Criança , Eletrocardiografia , Feminino , Heterozigoto , Hong Kong , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Adulto Jovem
10.
Int J Mol Sci ; 19(3)2018 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-29495624

RESUMO

Long QT syndrome, short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia are inherited primary electrical disorders that predispose to sudden cardiac death in the absence of structural heart disease. Also known as cardiac channelopathies, primary electrical disorders respond to mutations in genes encoding cardiac ion channels and/or their regulatory proteins, which result in modifications in the cardiac action potential or in the intracellular calcium handling that lead to electrical instability and life-threatening ventricular arrhythmias. These disorders may have low penetrance and expressivity, making clinical diagnosis often challenging. However, because sudden cardiac death might be the first presenting symptom of the disease, early diagnosis becomes essential. Genetic testing might be helpful in this regard, providing a definite diagnosis in some patients. Yet important limitations still exist, with a significant proportion of patients remaining with no causative mutation identifiable after genetic testing. This review aims to provide the latest knowledge on the genetic basis of cardiac channelopathies and discuss the role of the affected proteins in the pathophysiology of each one of these diseases.


Assuntos
Canalopatias/etiologia , Canalopatias/metabolismo , Morte Súbita Cardíaca/etiologia , Canais Iônicos/genética , Canais Iônicos/metabolismo , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Síndrome de Brugada/etiologia , Síndrome de Brugada/metabolismo , Síndrome de Brugada/fisiopatologia , Eletrofisiologia Cardíaca , Canalopatias/complicações , Canalopatias/diagnóstico , Predisposição Genética para Doença , Humanos , Síndrome do QT Longo/etiologia , Síndrome do QT Longo/metabolismo , Síndrome do QT Longo/fisiopatologia , Fenótipo , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatologia
11.
Acta Clin Belg ; 73(1): 1-6, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29088983

RESUMO

OBJECTIVES: Non-dystrophic myotonia, periodic paralysis and, to a certain extent, myotonic dystrophies are rare hereditary skeletal muscle channelopathies, charactarized by myotonia or episodic muscle weakness. This review highlights the diagnostic challenges and treatment options. RESULTS: Some of these rare skeletal muscle disorders are associated with a broad range of systemic and nonspecific muscle symptoms. Consequently, patients are often referred to the internist before seeing a neurologist. This article provides clinical clues to better diagnose an tackle these unique disorders. CONCLUSION: A increased knowledge will reduce the diagnostic delay, improve monitoring and treatment, and might even prevent potentially life-threatening conditions as seen in DM.


Assuntos
Canalopatias/diagnóstico , Transtornos Miotônicos/diagnóstico , Paralisias Periódicas Familiares/diagnóstico , Canalopatias/terapia , Humanos , Medicina Interna , Transtornos Miotônicos/terapia , Paralisias Periódicas Familiares/terapia
12.
Neuropharmacology ; 132: 98-107, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28476643

RESUMO

With the rapid evolution of understanding of neurological channelopathies comes a need for sensitive tools to evaluate patients in clinical practice. Neurological channelopathies with a single-gene basis can manifest as seizures, headache, ataxia, vertigo, confusion, weakness and neuropathic pain and it is likely that other genetic factors contribute to the phenotype of many of these disorders. Ion channel dysfunction can result in abnormal cell membrane excitability but utilisation of advanced neurophysiology techniques has lagged behind developments in clinical, genetic and imaging evaluation of channelopathies. However, momentum in the application of in vivo axonal excitability testing sees these tests emerging as valuable tools, with the capacity to provide sensitive and specific insights into the mechanism of disease. While single-channel function cannot be directly measured in vivo, evaluation of subjects with single-gene channelopathies has provided insights into the effects of mutation-related alterations of membrane excitability, as well as compensatory adaptive changes. By showing how ion channel dysfunction can affect axonal excitability in vivo, studies of the excitability of peripheral nerve axons complement in vitro analysis of single channel activity. The interpretation of results is enhanced by mathematical modelling of axonal function and insights provided by in vitro work. This article is part of the Special Issue entitled 'Channelopathies.'


Assuntos
Canalopatias/fisiopatologia , Nervos Periféricos/fisiopatologia , Animais , Canalopatias/diagnóstico , Humanos
13.
J Pediatr Rehabil Med ; 11(2): 133-137, 2018 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-28655139

RESUMO

BACKGROUND: There is evidence that channelopathies are the cause of many different neurological diseases. The epileptic perinatal encephalopathy due to mutation in the KCNQ2 gene is a rare disease involving severe tetraparesis and cerebral visual impairment. Diseases of this kind are associated with severe disability that involves multiple systems and requires accurate genetic diagnosis and early multidisciplinary care once clinical stability is reached. CASE REPORT: We describe a case of a baby girl with KCNQ2 encephalopathy who came to our observation for rehabilitation at age 2 years and 6 months. CLINICAL REHABILITATION IMPACT: We stress the importance of a correct clinical, pharmacological and visual diagnosis. Correct diagnosis made it possible to involve the baby girl and her care-giver in an early process of visual rehabilitation lasting 6 months, the effects of which proved to persist at follow-up after more than a year, making it possible to start a useful inter-professional rehabilitation plan.


Assuntos
Canalopatias/complicações , Epilepsia/etiologia , Canal de Potássio KCNQ2/genética , Mutação/genética , Transtornos da Visão/diagnóstico , Transtornos da Visão/reabilitação , Canalopatias/diagnóstico , Pré-Escolar , Feminino , Humanos , Transtornos da Visão/etiologia
14.
Rev Esp Cardiol (Engl Ed) ; 70(11): 983-990, 2017 Nov.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-28928069

RESUMO

Sudden cardiac death is the most common medical cause of death during the practice of sports. Several structural and electrical cardiac conditions are associated with sudden cardiac death in athletes, most of them showing abnormal findings on resting electrocardiogram (ECG). However, because of the similarity between some ECG findings associated with physiological adaptations to exercise training and those of certain cardiac conditions, ECG interpretation in athletes is often challenging. Other factors related to ECG findings are race, age, sex, sports discipline, training intensity, and athletic background. Specific training and experience in ECG interpretation in athletes are therefore necessary. Since 2005, when the first recommendations of the European Society of Cardiology were published, growing scientific evidence has increased the specificity of ECG standards, thus lowering the false-positive rate while maintaining sensitivity. New international consensus guidelines have recently been published on ECG interpretation in athletes, which are the result of consensus among a group of experts in cardiology and sports medicine who gathered for the first time in February 2015 in Seattle, in the United States. The document is an important milestone because, in addition to updating the standards for ECG interpretation, it includes recommendations on appropriate assessment of athletes with abnormal ECG findings. The present article reports and discusses the most novel and relevant aspects of the new standards. Nevertheless, a complete reading of the original consensus document is highly recommended.


Assuntos
Arritmias Cardíacas/diagnóstico , Morte Súbita Cardíaca/prevenção & controle , Medicina Esportiva/métodos , Atletas , Cardiomegalia Induzida por Exercícios/fisiologia , Cardiomiopatias/diagnóstico , Canalopatias/diagnóstico , Consenso , Diagnóstico Precoce , Eletrocardiografia , Feminino , Previsões , Humanos , Masculino , Padrões de Referência , Esportes/fisiologia , Medicina Esportiva/tendências
15.
J Pediatr ; 188: 181-185.e6, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28662944

RESUMO

OBJECTIVE: To ascertain the presenting symptoms of children with skeletal muscle channelopathies to promote early diagnosis and treatment. STUDY DESIGN: Retrospective case review of 38 children with a skeletal muscle channelopathy attending the specialist pediatric neuromuscular service at Great Ormond Street Hospital over a 15-year period. RESULTS: Gait disorder and leg cramps are a frequent presentation of myotonic disorders (19 of 29). Strabismus or extraocular myotonia (9 of 19) and respiratory and/or bulbar symptoms (11 of 19) are common among those with sodium channelopathy. Neonatal hypotonia was observed in periodic paralysis. Scoliosis and/or contractures were demonstrated in 6 of 38 children. School attendance or ability to engage fully in all activities was often limited (25 of 38). CONCLUSIONS: Children with skeletal muscle channelopathies frequently display symptoms that are uncommon in adult disease. Any child presenting with abnormal gait, leg cramps, or strabismus, especially if intermittent, should prompt examination for myotonia. Those with sodium channel disease should be monitored for respiratory or bulbar complications. Neonatal hypotonia can herald periodic paralysis. Early diagnosis is essential for children to reach their full educational potential.


Assuntos
Canalopatias/complicações , Transtornos Miotônicos/diagnóstico , Canais de Sódio/genética , Absenteísmo , Adolescente , Obstrução das Vias Respiratórias , Canalopatias/diagnóstico , Criança , Pré-Escolar , Contratura/etiologia , Diplopia/etiologia , Feminino , Transtornos Neurológicos da Marcha , Humanos , Lactente , Recém-Nascido , Masculino , Cãibra Muscular/etiologia , Hipotonia Muscular/etiologia , Transtornos Miotônicos/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Sons Respiratórios/etiologia , Estudos Retrospectivos , Escoliose/etiologia , Estrabismo/etiologia
16.
Sci Rep ; 7(1): 4583, 2017 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-28676720

RESUMO

Channelopathy mutations prove informative on disease causing mechanisms and channel gating dynamics. We have identified a novel heterozygous mutation in the KCNA1 gene of a young proband displaying typical signs and symptoms of Episodic Ataxia type 1 (EA1). This mutation is in the S4 helix of the voltage-sensing domain and results in the substitution of the highly conserved phenylalanine 303 by valine (p.F303V). The contributions of F303 towards K+ channel voltage gating are unclear and here have been assessed biophysically and by performing structural analysis using rat Kv1.2 coordinates. We observed significant positive shifts of voltage-dependence, changes in the activation, deactivation and slow inactivation kinetics, reduced window currents, and decreased current amplitudes of both Kv1.1 and Kv1.1/1.2 channels. Structural analysis revealed altered interactions between F303V and L339 and I335 of the S5 helix of a neighboring subunit. The substitution of an aromatic phenylalanine with an aliphatic valine within the voltage-sensor destabilizes the open state of the channel. Thus, F303 fine-tunes the Kv1.1 gating properties and contributes to the interactions between the S4 segment and neighboring alpha helices. The resulting channel's loss of function validates the clinical relevance of the mutation for EA1 pathogenesis.


Assuntos
Ataxia/genética , Ataxia/metabolismo , Canalopatias/genética , Canalopatias/metabolismo , Ativação do Canal Iônico/genética , Canal de Potássio Kv1.1/genética , Canal de Potássio Kv1.1/metabolismo , Mutação , Alelos , Sequência de Aminoácidos , Ataxia/diagnóstico , Canalopatias/diagnóstico , Sequência Conservada , Feminino , Genótipo , Humanos , Canal de Potássio Kv1.1/química , Masculino , Modelos Moleculares , Linhagem , Fenilalanina/genética , Conformação Proteica , Avaliação de Sintomas
17.
Rev Esp Cardiol (Engl Ed) ; 70(10): 808-816, 2017 Oct.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-28566242

RESUMO

INTRODUCTION AND OBJECTIVES: Nonischemic sudden cardiac death (SCD) is predominantly caused by cardiomyopathies and channelopathies. There are many diagnostic tests, including some complex techniques. Our aim was to analyze the diagnostic yield of a systematic diagnostic protocol in a specialized unit. METHODS: The study included 56 families with at least 1 index case of SCD (resuscitated or not). Survivors were studied with electrocardiogram, advanced cardiac imaging, exercise testing, familial study, genetic testing and, in some cases, pharmacological testing. Families with deceased probands were studied using the postmortem findings, familial evaluation, and molecular autopsy with next-generation sequencing (NGS). RESULTS: A positive diagnosis was obtained in 80.4% of the cases, with no differences between survivors and nonsurvivors (P=.53). Cardiac channelopathies were more prevalent among survivors than nonsurvivors (66.6% vs 40%, P=.03). Among the 30 deceased probands, the definitive diagnosis was given by autopsy in 7. A diagnosis of cardiomyopathy tended to be associated with a higher event rate in the family. Genetic testing with NGS was performed in 42 index cases, with a positive result in 28 (66.6%), with no differences between survivors and nonsurvivors (P=.21). CONCLUSIONS: There is a strong likelihood of reaching a diagnosis in SCD after a rigorous protocol, with a more prevalent diagnosis of channelopathy among survivors and a worse familial prognosis in cardiomyopathies. Genetic testing with NGS is useful and its value is increasing with respect to the Sanger method.


Assuntos
Arritmias Cardíacas/diagnóstico , Cardiomiopatias/diagnóstico , Canalopatias/diagnóstico , Morte Súbita Cardíaca/etiologia , Família , Testes Genéticos , Adolescente , Adulto , Arritmias Cardíacas/complicações , Arritmias Cardíacas/genética , Displasia Arritmogênica Ventricular Direita/complicações , Displasia Arritmogênica Ventricular Direita/diagnóstico , Displasia Arritmogênica Ventricular Direita/genética , Síndrome de Brugada/complicações , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/genética , Cardiomiopatias/complicações , Cardiomiopatias/genética , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/genética , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/genética , Canalopatias/complicações , Canalopatias/genética , Criança , Eletrocardiografia , Teste de Esforço , Feminino , Predisposição Genética para Doença , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Síndrome do QT Longo/complicações , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos , Análise de Sequência de DNA , Taquicardia Ventricular/complicações , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/genética , Adulto Jovem
18.
Nat Rev Cardiol ; 14(9): 521-535, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28470179

RESUMO

Cardiac arrhythmias confer a considerable burden of morbidity and mortality in industrialized countries. Although coronary artery disease and heart failure are the prevalent causes of cardiac arrest, in 5-15% of patients, structural abnormalities at autopsy are absent. In a proportion of these patients, mutations in genes encoding cardiac ion channels are documented (inherited channelopathies), but, to date, the molecular autopsy is negative in nearly 70% of patients. Emerging evidence indicates that autoimmunity is involved in the pathogenesis of cardiac arrhythmias. In particular, several arrhythmogenic autoantibodies targeting specific calcium, potassium, or sodium channels in the heart have been identified. Experimental and clinical studies demonstrate that these autoantibodies can promote conduction disturbances and life-threatening tachyarrhythmias by inducing substantial electrophysiological changes. In this Review, we propose the term 'autoimmune cardiac channelopathies' to define this novel pathogenic mechanism of cardiac arrhythmias, which could be more frequent and clinically relevant than previously appreciated. Indeed, pathogenic autoantibodies against ion channels are detectable not only in patients with manifest autoimmune disease, but also in apparently healthy individuals, which suggests a causal role in some cases of unexplained arrhythmias and cardiac arrest. Considering this possibility and performing specific testing in patients with 'idiopathic' rhythm disturbances could create novel treatment opportunities.


Assuntos
Arritmias Cardíacas/etiologia , Doenças Autoimunes/complicações , Canalopatias/complicações , Adulto , Anticorpos Anti-Idiotípicos/imunologia , Arritmias Cardíacas/imunologia , Arritmias Cardíacas/terapia , Autoanticorpos/metabolismo , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/terapia , Canais de Cálcio/imunologia , Canalopatias/diagnóstico , Canalopatias/terapia , Criança , Humanos , Canais Iônicos/imunologia , Miócitos Cardíacos/imunologia , Canais de Potássio/imunologia , Canais de Sódio/imunologia
19.
Int J Cardiol ; 237: 45-48, 2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-28532586

RESUMO

Sudden cardiac death (SCD) has a strong familial component; however, our understanding of its genetic basis varies significantly according to the underlying causes. When coronary artery disease is involved, the predisposing genetic background is complex and despite some interesting findings it remains largely unknown. Quite different is the case of monogenic structural and non-structural heart diseases, in which a number of disease-causing genes have been established and are being used in clinical practice. As SCD can be the first clinical manifestation of inherited syndromes, in order to ascertain the cause of death, it is extremely important to include molecular autopsy among the standard post-mortem examinations. Indeed, molecular screening of the major disease-causing genes in the deceased person is often the only way to achieve a post-mortem diagnosis in channelopathies, which may prove crucial for the identification and management of at risk family members. Overall, these data, together with the inclusion in current guidelines of molecular screening for diagnosis and/or risk stratification of specific inherited cardiac diseases, exemplify how research on the genetic basis of SCD may be deeply translational, while the transition of genetic testing from the research to the diagnostic setting is already improving every-day clinical practice.


Assuntos
Cardiomiopatias/genética , Canalopatias/genética , Morte Súbita Cardíaca/prevenção & controle , Predisposição Genética para Doença/genética , Testes Genéticos/tendências , Fibrilação Ventricular/genética , Cardiomiopatias/diagnóstico , Cardiomiopatias/prevenção & controle , Canalopatias/diagnóstico , Canalopatias/prevenção & controle , Humanos , Fibrilação Ventricular/diagnóstico , Fibrilação Ventricular/prevenção & controle
20.
Int J Cardiol ; 237: 53-55, 2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-28343764

RESUMO

The cardiac channelopathies are a group of diseases with (disease-) specific electrocardiographic (ECG) characteristics and a disease-specific risk of sudden cardiac death (SCD). This group includes the Long QT Syndromes (LQTS), Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), Brugada Syndrome (BrS), Short QT Syndromes (SQTS), and Early Repolarization Syndrome (ERS). In the past 2 decades the genetic basis for these disease entities has largely been unraveled and that, together with the identification of the genetic basis of the cardiomyopathies, has paved the way for the complete new field of Cardiogenetics. By virtue of the identification of the genetic underpinning of a given disease, presymptomatic carriers of the genetic aberrancy can be identified and timely treatment can be installed. In addition, it has become clear that the pathophysiological substrate of some diseases previously considered to be one disease is not identical, and this has led to gene-specific treatment in some and complete new treatment, based on the newly developed insight, in others. Finally, the genetic information proved to be important in the prediction of risk on lethal ventricular arrhythmias of affected individuals and that is the topic of this brief review.


Assuntos
Canalopatias/diagnóstico , Canalopatias/genética , Morte Súbita Cardíaca/prevenção & controle , Testes Genéticos/tendências , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Arritmias Cardíacas/mortalidade , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/genética , Síndrome de Brugada/mortalidade , Canalopatias/mortalidade , Testes Genéticos/métodos , Humanos , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/genética , Síndrome do QT Longo/mortalidade , Medição de Risco/métodos , Medição de Risco/tendências
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