Congenital long QT syndrome

Orphanet Journal of Rare Diseases Congenital long QT syndrome Lia Crotti 0 1 2 Giuseppe Celano 1 2 Federica Dagradi 1 2 P t r J S hw rtz 0 1 2 3 4 5 0 Molecular Cardiology Laboratory, IRCCS Fondazione Policlinico S. Matteo , Pavia , Italy 1 Department of Cardiology, IRCCS Fondazione Policlinico S. Matteo , Pavia , Italy 2 Section of Cardiology, Department of Lung, Blood and Heart, University of Pavia , Pavia , Italy 3 Cardiovascular Genetics Laboratory, Hatter Institute for Cardiovascular Research, Department of Medicine, University of Cape Town , South Africa 4 Department of Medicine, University of Stellenbosch , South Africa 5 Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico , Milan , Italy Congenital long QT syndrome (LQTS) is a hereditary cardiac disease characterized by a prolongation of the QT interval at basal ECG and by a high risk of life-threatening arrhythmias. Disease prevalence is estimated at close to 1 in 2,500 live births. The two cardinal manifestations of LQTS are syncopal episodes, that may lead to cardiac arrest and sudden cardiac death, and electrocardiographic abnormalities, including prolongation of the QT interval and T wave abnormalities. The genetic basis of the disease was identified in the mid-nineties and all the LQTS genes identified so far encode cardiac ion channel subunits or proteins involved in modulating ionic currents. Mutations in these genes (KCNQ1, KCNH2, KCNE1, KCNE2, CACNA1c, CAV3, SCN5A, SCN4B) cause the disease by prolonging the duration of the action potential. The most prevalent LQTS variant (LQT1) is caused by mutations in the KCNQ1 gene, with approximately half of the genotyped patients carrying KCNQ1 mutations. Given the characteristic features of LQTS, the typical cases present no diagnostic difficulties for physicians aware of the disease. However, borderline cases are more complex and require the evaluation of various electrocardiographic, clinical, and familial findings, as proposed in specific diagnostic criteria. Additionally, molecular screening is now part of the diagnostic process. Treatment should always begin with -blockers, unless there are valid contraindications. If the patient has one more syncope despite a full dose -blockade, left cardiac sympathetic denervation (LCSD) should be performed without hesitation and implantable cardioverter defibrillator (ICD) therapy should be considered with the final decision being based on the individual patient characteristics (age, sex, clinical history, genetic subgroup including mutation-specific features in some cases, presence of ECG signs - including 24-hour Holter recordings - indicating high electrical instability). The prognosis of the disease is usually good in patients that are correctly diagnosed and treated. However, there are a few exceptions: patients with Timothy syndrome, patients with Jervell Lange-Nielsen syndrome carrying KCNQ1 mutations and LQT3 patients with 2:1 atrio-ventricular block and very early occurrence of cardiac arrhythmias. - Background The congenital long QT syndrome (LQTS) is a relatively uncommon but important clinical disorder. Since 1975 [1] it includes under the unifying name of "Long QT syndrome" two hereditary variants. One is associated with deafness [2,3] and one is not [4,5]; they are referred to as the Jervell and Lange-Nielsen syndrome (J-LN) and as the Romano-Ward syndrome (R-W), respectively. Long-QT syndrome has been subdivided into types based on the gene in which causative mutations occur. The most prevalent forms are LQT1 and LQT2 (due to mutations in potassium channels), and LQT3 (due to a sodium channel mutation). The clinical manifestations of the disease are rather dramatic as they involve syncopal episodes, which often result in cardiac arrest and sudden death and usually occur in conditions of either physical or emotional stress in otherwise healthy young individuals, mostly children and teenagers. The high lethality among symptomatic and untreated patients in the presence of very effective therapies makes unacceptable the existence of symptomatic and undiagnosed patients. The genetic findings of the last 15 years have made of LQTS a unique paradigm for genetically mediated sudden cardiac death that allows to correlate genotype and phenotype, and provides a direct bridge between molecular biology and clinical cardiology. Epidemiology Initially considered as a very rare condition, already in 1975 [1] we suggested that LQTS "could be more unrecognized than rare". When coming, however, to actual numbers everything seemed to go and the prevalence was assumed to be anywhere between 1/5,000 [6] to 1/20,000 [7], with most investigators settling for 1/10,000 [8]. Importantly, none of these estimates was based on actual data. The first data-driven indication of the prevalence of LQTS is coming from the largest prospective study of neonatal electrocardiography ever performed [9]. An electrocardiogam (ECG) was recorded in 44,596 infants at 34 weeks of age. Among them, 1.4% had a corrected QT (QTc) interval between 440 and 469 ms and 0.7/1,000 had a QTc 470 ms, regarded as markedly prolonged by the European Task Force on Neonatal Electrocardiography [10]. In the latter group (n = 31), more than 90% of infants underwent molecular screening and LQTS diseasecausing mutations were found in 13 of 28 (46%) [9]. As almost 50% of the infants with QTc 470 ms (0.7/1,000) are affected by LQTS, and as at least some (number being currently defined by extensive molecular screening) of the infants with QTc between 440 and 469 ms are also likely to be affected, it follows that the prevalence of LQTS must be close to 1/2,500 at least. This is probably a bit of an underestimate because we have postulated first [11] and demonstrated later [12,13] that there is a significant number of silent mutation carriers (QTc < 440 ms) that actually ranges between 10% and 36% according to genotype. For the first time the prevalence of a cardiac disease of genetic origin has been quantified on the basis of actual data. Cardiac events and their relation to genotype The syncopal episodes are due to Torsade-de-Pointes (TdP), a polymorphic ventricular tachycardia with a characteristic twist of the QRS complex around the isoelectric baseline, often degenerating into ventricular fibrillation. TdP or ventricular fibrillation can initiate without changes in heart rate and without specific sequences such as "short-long-short" interval, even though long pauses in LQTS patients increase the probability of TdP [14]. While it had been known for quite sometime that although most patients would develop their symptoms under stress, it was also known that in a minority of cases these life-threatening cardiac events could occur at rest. The reason(s) for these different patterns remained obscure until molecular biology allowed to distinguish between different genotypes. As predicted by their impairment on the IKs current (essential for QT sho (...truncated)