SCN5A mutations in 442 neonates and children: genotype-phenotype correlation and identification of higher-risk subgroups.

Aims To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve their risk stratification. Methods and results A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between 1990 and 2015. All patients ≤16 years of age diagnosed with a genetically confirmed SCN5A mutation were included in the analysis. There was no restriction made based on their clinical diagnosis. A total of 442 children {55.7% boys, 40.3% probands, median age: 8.0 [interquartile range (IQR) 9.5] years} from 350 families were included; 67.9% were asymptomatic at diagnosis. Four main phenotypes were identified: isolated progressive cardiac conduction disorders (25.6%), overlap phenotype (15.6%), isolated long QT syndrome type 3 (10.6%), and isolated Brugada syndrome type 1 (1.8%); 44.3% had a negative electrocardiogram phenotype. During a median follow-up of 5.9 (IQR 5.9) years, 272 cardiac events (CEs) occurred in 139 (31.5%) patients. Patients whose mutation localized in the C-terminus had a lower risk. Compound genotype, both gain- and loss-of-function SCN5A mutation, age ≤1 year at diagnosis in probands and age ≤1 year at diagnosis in non-probands were independent predictors of CE. Conclusion In this large paediatric cohort of SCN5A mutation-positive subjects, cardiac conduction disorders were the most prevalent phenotype; CEs occurred in about one-third of genotype-positive children, and several independent risk factors were identified, including age ≤1 year at diagnosis, compound mutation, and mutation with both gain- and loss-of-function

Long QT syndrome: from genetic basis to treatment

The congenital long QT syndrome (LQTS) is a monogenic disorder, not as rare as it was originally estimated to be, mainly caused by mutations in genes encoding for ion channels. Molecular screening in this disease is part of the diagnostic process and this has already been recognized by current guidelines since 2006. However, very recently, two consensus documents have been published, with the recommendations for the use of genetic testing in the clinical evaluation of genetically transmitted arrhythmogenic diseases. Therefore, we devoted a specific section of the present review to the discussion of these two documents in relation to LQTS. The clinical presentation of the disease is typically characterized by a prolongation of the QT interval on the electrocardiogram (ECG) and by the occurrence of syncope or cardiac arrest, mainly precipitated by sympathetic activation. While the diagnosis of typical cases it is quite easy, borderline cases can be quite challenging and therefore the availability of diagnostic criteria is very useful to support the diagnostic process. Very recently, the LQTS diagnostic criteria have been updated and they are presented in the current review. Finally, the clinical management of LQTS patients is presented together with a schematic flow-chart and recent data coming from the LQTS-ICD European registry are illustrated. The last part of the review is dedicated at future perspectives and latest results on modifier genes and stem cells are presented

Congenital long QT syndrome.

Abstract 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 β-blockers, unless there are valid contraindications. If the patient has one more syncope despite a full dose β-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.</p

Condizioni cliniche associate ad anomalie dell&#39;intervallo QT: Implicazioni cliniche.

Impressive progress has been made in the last 40 years in the understanding of the role of QT interval and its genetic basis in sudden cardiac death risk. The present review will provide a first practical part on QT measurement and its correction for heart rate. Subsequently, the long QT syndrome and short QT syndrome will be described, as the two main arrhythmogenic congenital heart diseases characterized by abnormal QT length. Furthermore, we will discuss about prolonged QT in the pathogenesis of sudden infant death syndrome and the preventive role of neonatal ECG screening. The prognostic role of QT interval will be presented also in the context of myocardial infarction and hypertrophic cardiomyopathy. The last part of the review is devoted to future perspectives and latest results on modifier genes

Condizioni cliniche associate ad anomalie dell'intervallo QT: Implicazioni cliniche [Clinical conditions associated with abnormal QT interval: clinical implications].

Impressive progress has been made in the last 40 years in the understanding of the role of QT interval and its genetic basis in sudden cardiac death risk. The present review will provide a first practical part on QT measurement and its correction for heart rate. Subsequently, the long QT syndrome and short QT syndrome will be described, as the two main arrhythmogenic congenital heart diseases characterized by abnormal QT length. Furthermore, we will discuss about prolonged QT in the pathogenesis of sudden infant death syndrome and the preventive role of neonatal ECG screening. The prognostic role of QT interval will be presented also in the context of myocardial infarction and hypertrophic cardiomyopathy. The last part of the review is devoted to future perspectives and latest results on modifier gene

[The preparation and characterization of steroid antisera (author's transl)]

The steroids, as compounds of low molecular weight, are not immunogenic; however, certain small molecules (haptens) when covalently linked to proteins become antigenic i.e., they provoke the production of unique antibody. If a steroid were covalently copuled to a protein, an artifical antigen would be produced capable of eliciting the formation of antibody with specificity not only for the protein carrier but also for the particular haptenic steroid. The results would be an in vivo production of a tailor made binding sites for any steroid that can be attached as a hapten to a protein by covalent bonds and thus become antigenic. This procedure allow the preparation of steroid specific antisera suitable for clinical use in radioimmunoassay, methods. The Authors report the techniques of preparation of steroid-derivative antigens of Androstenedion, Testosteron, and Progesteron. The three derivative steroid antigens have shown a good antigenic property by eliciting the formation of specifical antisera in 5 out of 6 rabbits used for the immunization. After 10 weeks from the beginning of immunization antisera useful in radioimmunoassay at the diluition 1/300; 1/1600; 1/2000 respectively for Progesteron, Testosteron and Androstenedion were obtained. The standard curves show a good sensitivity suitable for clinical use