Clinical and Genetic Characteristics of Long QT Syndrome Argelia Medeiros-Domingo,A,C Pedro Iturralde-Torres,B and Michael J
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Document downloaded from http://www.revespcardiol.org, day 09/04/2016. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. REVIEW ARTICLE Clinical and Genetic Characteristics of Long QT Syndrome Argelia Medeiros-Domingo,a,c Pedro Iturralde-Torres,b and Michael J. Ackermanc aUnidad de Biología Molecular y Medicina Genómica, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de Mexico, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico bInstituto Nacional de Cardiología Ignacio Chávez, Mexico cDepartment of Medicine/Department of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, MN, USA Long QT syndrome (LQTS) is an arrhythmogenic ion Clínica y genética en el síndrome de QT largo channel disorder characterized by severely abnormal ventricular repolarization, which results in QT internal El síndrome de QT largo (SQTL) es una canalopatía prolongation. The condition is associated with sudden arritmogénica caracterizada por una grave alteración en cardiac death due to malignant ventricular arrhythmias in la repolarización ventricular, traducida electrocardiográfi- form of torsade de pointes. Eleven years after the camente por una prolongación del intervalo QT. Predis- identification of the principle cardiac channels involved in pone a muerte súbita por arritmias ventriculares malignas the condition, hundreds of mutations in, to date, 10 genes del tipo de torsade de pointes. A 11 años de la identifica- have been associated with the syndrome. Genetic ción de los principales canales afectados en esta enfer- investigations carried out up until the present have shown medad, se han descrito cientos de mutaciones distribui- that, although the severe form of the disease is sporadic, das en hasta ahora 10 genes relacionados con el there are a number of common polymorphisms in genes síndrome. El escrutinio genético realizado desde enton- associated with the condition that may confer susceptibility ces ha mostrado que, si bien la forma grave de la enfer- to the development of torsade de pointes in some medad es esporádica, hay polimorfismos comunes en los individuals, particularly when specific drugs are being genes relacionados con la enfermedad que pueden gene- administered. Moreover, some polymorphisms have been rar susceptibilidad individual al desarrollo de torsade de shown to have regulatory properties that either enhance pointes, en particular con el uso de determinados fárma- or counteract a particular mutation’s impact. Understanding cos; más aún, se han identificado polimorfismos con cua- of the molecular processes underlying the syndrome has lidades reguladoras que pueden exacerbar o silenciar la enabled treatment to be optimized and has led to better gravedad de una mutación. El entendimiento de los pro- survival among sufferers, thereby demonstrating a key cesos moleculares de la enfermedad ha permitido opti- correspondence between genotype, phenotype, and mizar el tratamiento y mejorar la supervivencia de los therapy. Despite these developments, a quarter of patients afectados, generando así una importante correlación ge- do not have mutations in the genes identified to date. notipo-fenotipo-tratamiento. A pesar de los avances, una Consequently, LQTS continues to be an area of active cuarta parte de los casos no tiene mutaciones en los ge- research. This article contains a summary of the main nes descritos hasta el momento, por lo que el SQTL con- clinical and genetic developments concerning the syndrome tinúa siendo motivo de investigación. El presente artículo that have taken place during the last decade. representa el análisis de los principales conceptos clíni- cos y genéticos desarrollados en los últimos años sobre Key words: Long QT syndrome. Arrhythmias. Sudden esta singular enfermedad. death. Cardiac arrest. Syncope. Gene mutation. Torsade de pointes. Palabras clave: Síndrome de QT largo. Arritmias. Muerte súbita. Parada cardiaca. Síncope. Mutación genética. Torsade de pointes. SEE EDITORIAL ON PAGES 675-82 INTRODUCTION Dr. Medeiros receives economic support from CONACyT Long QT syndrome (LQTS) is characterized by severely and FUNSALUD. altered ventricular repolarization, resulting in prolongation Correspondence: of the QT interval on electrocardiogram (ECG). The Dra. A. Medeiros-Domingo. Unidad de Biología Molecular. Instituto Nacional de Ciencias Médicas condition predisposes patients to malignant ventricular y Nutrición Salvador Zubirán. arrhythmia (torsade de pointes) and sudden death. The Vasco de Quiroga, 15. Tlalpan 14000. Mexico DF. Mexico. clinical and electrocardiographic description of long QT E-mail: [email protected] syndrome was reported in 1957 by Anton Jervell and Rev Esp Cardiol. 2007;60(7):739-52 739 Document downloaded from http://www.revespcardiol.org, day 09/04/2016. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. Medeiros-Domingo A et al. Clinical and Genetic of Long QT Syndrome patients who have the mutation and manifest the ABBREVIATIONS phenotype, ranges from 25% to 90%.9 Less frequently, AV: atrioventricular there may be variations in the expressivity of the disease, AID: automatic implantable defibrillator with several phenotypes resulting from the same ECG: electrocardiogram mutation. Molecular genetic studies developed over the QTc: heart rate-corrected QT last 11 years have yielded important genotype-phenotype ATS: Andersen-Tawil syndrome correlations, which have helped to guide the treatment LQTS: long QT syndrome approach. In addition, interesting observations have been made on individual susceptibility to developing arrhythmia in studies investigating the frequent nonsynonymous polymorphisms in this population, an aspect that has aroused considerable interest, particularly Fred Lange Nielsen,1 who published their studies on a in the area of pharmacogenomics. family of nonconsanguineous parents with 6 children. Four of the children had congenital deafness and syncopal CLASSIFICATION OF LONG QT SYNDROME episodes, and 3 presented sudden death. ECG study of these patients showed an unusually long QT interval. General Concepts Both parents were asymptomatic, had a normal ECG, and presented no hearing problems. In 1964, Romano The LQTS classification used in the past was based on and Ward independently reported a cardiac syndrome the homozygous or heterozygous presentation of the characterized by recurrent syncope, a family history of disease, which gives rise to Jervell-Lange-Nielsen sudden death, and prolongation of the QT interval without syndrome (with deafness) and Romano-Ward syndrome neuronal deafness.2 Later genetic studies showed that the (without deafness), respectively. The present classification syndrome described by Jervell and Lange Nielsen, which emphasizes the genetic findings, as is illustrated in Table 1. is accompanied by congenital neuronal deafness, The 3 main genes associated with the disease were corresponds to homozygous mutations, with a severe described in 1995-1996. These genes, which code for phenotype and high risk of sudden death. The condition pore-forming units of the potassium channels IKs and IKr, known as Romano-Ward syndrome generally corresponds and the sodium channel Nav1.5, account for nearly 65% to heterozygous mutations, patients do not display hearing of the cases. Although in subsequent years seven additional alterations, and the severity of the disease varies genes have been included in the list, they account for considerably. Almost half a century later, in 1995,3,4 the only 5% of the cases. principal genes associated with LQTS were described Ion channels are transmembrane proteins that transport and the disease was recognized as a cardiac ion channel ions through the cell membrane. The channels implicated disorder. It was the first cardiac channelopathy to be in LQTS are selective or specialized in transporting a described and is perhaps the most extensively investigated single ion and are voltage-dependent, ie, their activation arrhythmogenic ion channel disorder to date. The clinical occurs at a specific intracellular voltage, which varies picture varies greatly: the patient can be asymptomatic, according to the channel subtype. The electrical and or show recurrent syncope, seizures, or sudden death as contractile phenomena that occur in the cardiomyocyte the first manifestation of the disease. Initially, LQTS was are controlled by these structures. Ion channels form considered a rare syndrome and, in effect, the severe macromolecular complexes consisting of a main unit that presentation of the disease is sporadic. Nonetheless, the forms the channel pore and auxiliary proteins that regulate incidence of related mutations is estimated at 1/3000- it (Figure 1). The channel dysfunction seen in LQTS can 5000 cases,5 32% of asymptomatic carriers can have a occur at these two sites: the main protein or the regulating heart rate-corrected QT interval (QTc) within normal proteins (Table 1). Involvement of the pore-forming unit, limits, the disease is transmitted to 50% of their known as alpha, generates the three most common subtypes descendants, they are more susceptible to develop of LQTS: LQTS1 (affecting the IKs potassium channel), arrhythmia when compared to the general population, LQTS2 (affecting the IKr potassium channel), and LQTS3 and up to 20% can become symptomatic.6 (affecting the sodium channel). Because these are the Long QT syndrome displays great