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Investigation of Sudden Cardiac Death
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
Potassium channels play a role in the repolarization of the cardiac action potential, and anomalies in the rate of cardiac repolarization can lead to SCD. Notably, KCNH2 which encodes the Kv11.1 channel that regulates the rapid component of the delayed rectifier potassium current; and KCNQ1 which encodes the Kv7.1 channel that regulates the slow delayed rectifier current are important targets. Several KCNH2 and KCNQ1 mutations are present in LQTS. Many of the hundreds of mutations are unique to a family or very rare. Approximately 5% of families have two mutations, and these tend to be more severely affected. Two mutations on opposite chromosomes in either the LQT1 or LQT5 gene causes a severe autosomal recessive form of LQTS usually with associated sensorineural deafness, low gastric-acid secretion and iron deficiency anaemia (Jervell and Lange-Nielsen syndrome). However, 25% of families with LQTS do not yet have a recognized mutation.
Sudden unexpected death in epilepsy
Published in Helen Whitwell, Christopher Milroy, Daniel du Plessis, Forensic Neuropathology, 2021
Christopher Milroy, Daniel du Plessis
There is an increasing realisation that genetic disorders may underlie epilepsy (Tu et al. 2011; Coll et al. 2016; Devinsky et al. 2016). Several genes linked to cardiac channelopathies are also associated with epilepsy. The two entities may overlap (Bagnall et al. 2016). Mutations in the SCN5A and KCNH2 genes have been associated with both long QT syndrome and epilepsy (Klassen et al. 2014). The KCNQ1 gene has been reported in a family with both epilepsy and long QT syndrome (Tiron et al. 2015).
Cardiovascular medicine
Published in Shibley Rahman, Avinash Sharma, A Complete MRCP(UK) Parts 1 and 2 Written Examination Revision Guide, 2018
Shibley Rahman, Avinash Sharma
Jervell-Lange-Nielsen syndrome includes deafness as well, and is due to mutations in the KCNE1 and KCNQ1 genes. The KCNE1 and KCNQ1 genes provide instructions for making proteins that work together to form a channel across cell membranes. These channels transport positively charged potassium atoms (ions) out of cells. The movement of potassium ions through these channels is critical for maintaining the normal functions of inner ear structures and cardiac muscle.
Histopathology of the Conduction System in Long QT Syndrome
Published in Fetal and Pediatric Pathology, 2022
Alexandra Rogers, Rachel Taylor, Janet Poulik, Bahig M. Shehata
Jervell and Lange-Nielsen Syndrome (JLNS) is an uncommon form of LQT1 commonly thought to be inherited in an autosomal recessive pattern. JLNS is caused by mutations in the KCNQ1 and, less commonly, the KCNE1 genes which code for the α subunit and regulatory proteins of the IKs channel, respectively [6]. Clinically, the disease manifests with uni- or bilateral sensorineural deafness, cardiac arrhythmias, syncope, severe QT prolongation, and sudden death with a reported mortality rate greater than 50% in untreated children [6,7]. Symptoms appear to be dose dependent, with homozygous or compound heterozygotes experiencing the most severe phenotypic expression [7]. Heterozygous carriers may experience mild symptoms including slight QT prolongation, but most are asymptomatic. Patients harboring KCNQ1 mutations tend to have more severe phenotypes than those with KCNE1 defects [6]. Common treatments for JLNS include β-blocker therapy, left cardiac sympathetic denervation (LCSD), and in the most severe cases, surgical insertion of an implantable cardioverter-defibrillator device (ICD) [7].
Precision medicine in cardiac electrophysiology: where we are and where we need to go
Published in Expert Review of Precision Medicine and Drug Development, 2020
Ashish Correa, Syed Waqas Haider, Wilbert S. Aronow
Understanding the genetic basis of LQTS has helped advance our understanding of the pathophysiologic underpinnings of various clinical presentations of this condition. For instance, while LQT1, 2 and 3 are all characterized by a prolonged QT interval on the surface EKG, each of these conditions is associated with a different trigger that can bring about a cardiac event, and these relate to the underlying ion channel disorder. In LQT1, loss-of-function mutations of KCNQ1 result in decreased IKs current, that is normally responsible for limiting the QT interval in situations where the heart rate rises. It follows that there is an increased risk of R-on-T arrhythmic events, and thus ventricular tachycardia/fibrillation, during situations of increased heart rate. Predictably, studies have shown that in LQT1, cardiac events occur during exercise (particularly swimming) and stress [43]. In LQT2, sudden auditory stimuli or sudden arousal from sleep can trigger cardiac events [21]. Patients with LQT3 rarely have cardiac events during exercise, as they have preserved IKs currents permitting appropriate shortening of the QT interval with increases in heart rate. Rather, these patients tend to experience cardiac events during sleep or while at rest [21]. Our understanding of this genotype–phenotype relationship and our ability to diagnose a specific genotype in a given patient will enable us to develop management strategies tailored to that individual patient that will more precisely target the underlying disorder. This will be explored in the next section.
Induced pluripotent stem cell derived cardiac models: effects of Thymosin β4
Published in Expert Opinion on Biological Therapy, 2018
Tilman Ziegler, Rabea Hinkel, Christian Kupatt
In one example of iPSC-based disease modeling, Moretti et al. reprogrammed primary fibroblasts from two family members suffering from long-QT syndrome type 1 carrying a missense mutation in the KCNQ1 gene and subsequently differentiated those cells into cardiac myocytes [7]. The long-QT syndrome, to a high percentage caused by mutations in the KCNQ1 gene, is characterized by an increase in the slow outward potassium current, leading to an increase in the cardiomyocyte action potential resulting in a propensity to develop ventricular tachycardia and sudden cardiac death [58]. Measuring action potentials unveiled a prolonged action potential in all three cardiac cell types (atrial, nodal, ventricular) which was the result of an aberrant cellular localization of the KCNQ1 protein in long-QT syndrome patients. Furthermore, patient-derived iPSC-CMs demonstrated an increased vulnerability to catecholamine-induced tachyarrhythmia and an attenuation of this vulnerability via beta blockade.