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Investigation of Sudden Cardiac Death
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
The ion channelopathies result from mutations in genes encoding channels or related proteins, altering their properties. A mutation may make a channel non-functional, underactive, overactive or leaky. SCN5A, encodes the alpha subunit of the voltage-gated sodium channel Nav1.5. Nav1.5 regulates the influx of sodium ion, and thus the initiation and propagation of action potentials of the heart. Failure of the channel to close results in LQT type 3, and failure to open causes BrS. The same mutation may cause either within the same family.
Electrophysiological Recording of a Gain-of-Function Polycystin-2 Channel with a Two-Electrode Voltage Clamp
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Courtney Ng, Zhifei Wang, Bin Li, Yong Yu
Genetic studies have revealed that the linker region between S4 and S5 (S4-S5 linker) and the first half of S5 helix is a hot spot for GOF mutations of many TRP channels.23 Mutations at this region have been linked to over activity-induced channelopathies in human beings. For example, N855S in TRPA1 causes familial episodic pain syndrome,24 G573S in TRPV3 causes Olmsted syndrome,25 multiple mutations in this region of TRPV4 cause various skeletal dysplasias and motor/sensory neuropathies,26,27 and multiple mutations of TRPML1 have been found to be the underlying cause of mucolipidosis type IV.28 Some other GOF mutations of TRP channels have been generated by doing mutagenesis screens, which also fall into this region.29 These GOF mutations paved the way for scientists to study the function and regulation of these channels, especially for those that are difficult to be activated extrinsically or intrinsically.
Death from natural causes
Published in Jason Payne-James, Richard Jones, Simpson's Forensic Medicine, 2019
Jason Payne-James, Richard Jones
The channelopathies are a group of disorders representing a proportion of sudden deaths, presumed to be of cardiac origin. SCD following ventricular tachyarrhythmias constitutes an important clinical cause of mortality; 4 per cent of cases may involve ion channel-mediated cellular excitation in structurally normal hearts. Changes in these mechanisms may disturb action potential conduction, depolarisation/repolarisation gradients, or Ca2+ homeostasis with potential arrhythmogenic consequences. Defects in genes encoding myocyte contractile units have been characterised and these affect the function of sodium, potassium and calcium channels. Patients may present with symptoms of palpitations or haemodynamic compromise, including dizziness, seizure or syncope, particularly following exertion. In all inherited cardiac death syndromes, first-degree relatives should be referred to a cardiologist and should undergo testing appropriate for the condition.
Mechanisms behind diffuse idiopathic peripheral neuropathy in humans – a systematic review
Published in Scandinavian Journal of Gastroenterology, 2023
Hanna Tufvesson, Viktor Hamrefors, Bodil Ohlsson
Most of our knowledge about channelopathies in humans are derived from genetic studies on rare, often inherited diseases. The properties of the various ion channels, such as VGSCs and VGKCs, have been extensively studied in animal models, but its complex nature with inflammation, enhanced transcription, and increased phosphorylation by various effector kinases of the intracellular N-terminal of the VGSC are difficult to study in humans [40,52]. Indirect evidence points in the same direction as in animals. Elevated levels of NaV channel mRNA, as well as MAP kinases, have been detected in blind nerve endings of resected painful human neuromas [33,52,76], with increased ectopic impulse generation. Nevertheless, channelopathy is seldom or never considered in clinical praxis in patients with GI dysmotility. This entity may be under-diagnosed, due to rare genetic examinations. Genetic testing should be considered, both in sporadic and hereditary cases of severe idiopathic peripheral neuropathy.
Improving genetic diagnostics of skeletal muscle channelopathies
Published in Expert Review of Molecular Diagnostics, 2020
Vinojini Vivekanandam, Roope Männikkö, Emma Matthews, Michael G. Hanna
Mutations in genes that are not ion channels or that are not expressed in skeletal muscle can present with symptoms associated with skeletal muscle channelopathies. SLC2A1 is implicated in Glucose Transporter Deficiency Syndrome [24]. While this is not a skeletal muscle channelopathy, the episodic symptoms predominantly affect the lower limbs and are often triggered by movement or exercise, which can cause diagnostic confusion with periodic paralysis. Glucose Transport Deficiency syndromes are highly treatable and should not be missed. CACNA1A encodes calcium channel Cav2.1 with neuronal expression. It is implicated in Familial Hemiplegic Migraine and Episodic Ataxia type 2 [25]. These conditions can also have overlapping symptoms or cause diagnostic confusion with presentations of skeletal muscle channelopathies including paresis, and share common triggers. Expansion from a four gene to a seven-gene panel has improved diagnostic rates of previously undiagnosed rare causes of channelopathies and allows parallel diagnosis of channelopathy mimics.
Current controversies in pre-participation cardiovascular screening for young competitive athletes
Published in Expert Review of Cardiovascular Therapy, 2020
Bradley J. Petek, Aaron L. Baggish
There are numerous reported causes of SCD in young competitive athletes (Table 1). Historically, the most frequent cause of SCD among competitive athletes below the age of 35 was thought to be hypertrophic cardiomyopathy (HCM). However, recent studies have provided conflicting results [19,20,23–25]. Harmon et al. assessed the incidence and causes of SCD in NCAA athletes from 2003 to 2013 and found that unexplained autopsy-negative sudden death accounted for 25% of cases followed by congenital anomalous coronary arteries (11%), myocarditis (9%), and coronary atherosclerosis (9%) [19]. HCM was only diagnosed in 8% of autopsies. These data suggest that primary channelopathies or other electrical disturbances in the absence of structural heart disease may be more common than previously reported. In contrast, Maron et al. performed another recent study assessing the incidence and causes of SCD in NCAA athletes from 2002 to 2011 which attributed 21/47 (45%) confirmed cardiovascular-related deaths to be due to HCM [20]. Interestingly, the incidence of HCM may also be less than previously reported as many athletes with LVH on autopsy in the past have been thought to have HCM, but now idiopathic LVH appears to be a distinct entity from HCM [26]. While explanations for this inconsistency are of academic interest, the clinical imperative is to remember that HCM is an important cause of SCD, but perhaps more common etiologies exist in parallel.