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RYR1-Related Rhabdomyolysis: A Spectrum of Hypermetabolic States Due to Ryanodine Receptor Dysfunction.
Kruijt, N, den Bersselaar, LV, Snoeck, M, Kramers, K, Riazi, S, Bongers, C, Treves, S, Jungbluth, H, Voermans, N
Current pharmaceutical design. 2022;(1):2-14
Abstract
Variants in the ryanodine receptor-1 gene (RYR1) have been associated with a wide range of neuromuscular conditions, including various congenital myopathies and malignant hyperthermia (MH). More recently, a number of RYR1 variants, mostly MH-associated, have been demonstrated to contribute to rhabdomyolysis events not directly related to anesthesia in otherwise healthy individuals. This review focuses on RYR1-related rhabdomyolysis in the context of several clinical presentations (i.e., exertional rhabdomyolysis, exertional heat illnesses and MH), and conditions involving a similar hypermetabolic state, in which RYR1 variants may be present (i.e., neuroleptic malignant syndrome and serotonin syndrome). The variety of triggers that can evoke rhabdomyolysis, on their own or in combination, as well as the number of potentially associated complications, illustrates that this is a condition relevant to several medical disciplines. External triggers include but are not limited to strenuous physical exercise, especially if unaccustomed or performed under challenging environmental conditions (e.g., high ambient temperature or humidity), alcohol/illicit drugs, prescription medication (in particular statins, other anti-lipid agents, antipsychotics and antidepressants) infection, or heat. Amongst all patients presenting with rhabdomyolysis, genetic susceptibility is present in a proportion, with RYR1 being one of the most common genetic causes. Clinical clues for a genetic susceptibility include recurrent rhabdomyolysis, creatine kinase (CK) levels above 50 times the upper limit of normal, hyperCKemia lasting for 8 weeks or longer, drug/medication doses insufficient to explain the rhabdomyolysis event, and positive family history. For the treatment or prevention of RYR1-related rhabdomyolysis, the RYR1 antagonist dantrolene can be administered, both in the acute phase or prophylactically in patients with a history of muscle cramps and/or recurrent rhabdomyolysis events. Aside from dantrolene, several other drugs are being investigated for their potential therapeutic use in RYR1-related disorders. These findings offer further therapeutic perspectives for humans, suggesting an important area for future research.
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Pediatric Catecholaminergic Polymorphic Ventricular Tachycardia: A Translational Perspective for the Clinician-Scientist.
Kallas, D, Lamba, A, Roston, TM, Arslanova, A, Franciosi, S, Tibbits, GF, Sanatani, S
International journal of molecular sciences. 2021;(17)
Abstract
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and potentially lethal inherited arrhythmia disease characterized by exercise or emotion-induced bidirectional or polymorphic ventricular tachyarrhythmias. The median age of disease onset is reported to be approximately 10 years of age. The majority of CPVT patients have pathogenic variants in the gene encoding the cardiac ryanodine receptor, or calsequestrin 2. These lead to mishandling of calcium in cardiomyocytes resulting in after-depolarizations, and ventricular arrhythmias. Disease severity is particularly pronounced in younger individuals who usually present with cardiac arrest and arrhythmic syncope. Risk stratification is imprecise and long-term prognosis on therapy is unknown despite decades of research focused on pediatric CPVT populations. The purpose of this review is to summarize contemporary data on pediatric CPVT, highlight knowledge gaps and present future research directions for the clinician-scientist to address.
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Catecholaminergic Polymorphic Ventricular Tachycardia.
Kim, CW, Aronow, WS, Dutta, T, Frenkel, D, Frishman, WH
Cardiology in review. 2020;(6):325-331
Abstract
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare congenital arrhythmogenic disorder induced by physical or emotional stress. It mainly affects children and younger adults and is characterized by rapid polymorphic and bidirectional ventricular tachycardia. Symptoms can include dizziness, palpitations, and presyncope, which may progress to syncope, hypotonia, convulsive movements, and sudden cardiac death. CPVT is the result of perturbations in Ca ion handling in the sarcoplasmic reticulum of cardiac myocytes. Mutations in the cardiac ryanodine receptor gene and the calsequestrin isoform 2 gene are most commonly seen in familial CPVT patients. Under catecholaminergic stimulation, either mutation can result in an excess Ca load during diastole resulting in delayed after depolarization and subsequent arrhythmogenesis. The current first-line treatment for CPVT is β-blocker therapy. Other therapeutic interventions that can be used in conjunction with β-blockers include moderate exercise training, flecainide, left cardiac sympathetic denervation, and implantable cardioverter-defibrillators. Several potential therapeutic interventions, including verapamil, dantrolene, JTV519, and gene therapy, are also discussed.
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On a Magical Mystery Tour with 8-Bromo-Cyclic ADP-Ribose: From All-or-None Block to Nanojunctions and the Cell-Wide Web.
Evans, AM
Molecules (Basel, Switzerland). 2020;(20)
Abstract
A plethora of cellular functions are controlled by calcium signals, that are greatly coordinated by calcium release from intracellular stores, the principal component of which is the sarco/endooplasmic reticulum (S/ER). In 1997 it was generally accepted that activation of various G protein-coupled receptors facilitated inositol-1,4,5-trisphosphate (IP3) production, activation of IP3 receptors and thus calcium release from S/ER. Adding to this, it was evident that S/ER resident ryanodine receptors (RyRs) could support two opposing cellular functions by delivering either highly localised calcium signals, such as calcium sparks, or by carrying propagating, global calcium waves. Coincidentally, it was reported that RyRs in mammalian cardiac myocytes might be regulated by a novel calcium mobilising messenger, cyclic adenosine diphosphate-ribose (cADPR), that had recently been discovered by HC Lee in sea urchin eggs. A reputedly selective and competitive cADPR antagonist, 8-bromo-cADPR, had been developed and was made available to us. We used 8-bromo-cADPR to further explore our observation that S/ER calcium release via RyRs could mediate two opposing functions, namely pulmonary artery dilation and constriction, in a manner seemingly independent of IP3Rs or calcium influx pathways. Importantly, the work of others had shown that, unlike skeletal and cardiac muscles, smooth muscles might express all three RyR subtypes. If this were the case in our experimental system and cADPR played a role, then 8-bromo-cADPR would surely block one of the opposing RyR-dependent functions identified, or the other, but certainly not both. The latter seemingly implausible scenario was confirmed. How could this be, do cells hold multiple, segregated SR stores that incorporate different RyR subtypes in receipt of spatially segregated signals carried by cADPR? The pharmacological profile of 8-bromo-cADPR action supported not only this, but also indicated that intracellular calcium signals were delivered across intracellular junctions formed by the S/ER. Not just one, at least two. This article retraces the steps along this journey, from the curious pharmacological profile of 8-bromo-cADPR to the discovery of the cell-wide web, a diverse network of cytoplasmic nanocourses demarcated by S/ER nanojunctions, which direct site-specific calcium flux and may thus coordinate the full panoply of cellular processes.
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5.
Overlapping Mechanisms of Exertional Heat Stroke and Malignant Hyperthermia: Evidence vs. Conjecture.
Laitano, O, Murray, KO, Leon, LR
Sports medicine (Auckland, N.Z.). 2020;(9):1581-1592
Abstract
Exertional heat stroke (EHS) and malignant hyperthermia (MH) are life-threatening conditions, triggered by different environmental stimuli that share several clinical symptoms and pathophysiological features. EHS manifests during physical activity normally, but not always, in hot and humid environments. MH manifests during exposure to haloalkane anesthetics or succinylcholine, which leads to a rapid, unregulated release of calcium (Ca2+) within the skeletal muscles inducing a positive-feedback loop within the excitation-contraction coupling mechanism that culminates in heat stroke-like symptoms, if not rapidly recognized and treated. Rare cases of awake MH, independent of anesthesia exposure, occur during exercise and heat stress. It has been suggested that EHS and MH are mediated by similar mechanisms, including mutations in Ca2+ regulatory channels within the skeletal muscle. Rapid cooling, which is the most effective treatment for EHS, is ineffective as an MH treatment; rather, a ryanodine receptor antagonist drug, dantrolene sodium (DS), is administered to the victim to prevent further muscle contractions and hyperthermia. Whether DS can be an effective treatment for EHS victims remains uncertain. In the last decade, multiple reports have suggested a number of mechanistic links between EHS and MH. Here, we discuss aspects related to the pathophysiology, incidence, diagnosis and treatment. Furthermore, we present evidence regarding potential overlapping mechanisms between EHS and MH and explore current knowledge to establish what is supported by evidence or a lack thereof (i.e. conjecture).
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Identification of a novel exon3 deletion of RYR2 in a family with catecholaminergic polymorphic ventricular tachycardia.
Dharmawan, T, Nakajima, T, Ohno, S, Iizuka, T, Tamura, S, Kaneko, Y, Horie, M, Kurabayashi, M
Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc. 2019;(3):e12623
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Abstract
BACKGROUND RYR2, encoding cardiac ryanodine receptor, is the major responsible gene for catecholaminergic polymorphic ventricular tachycardia (CPVT). Meanwhile, KCNJ2, encoding inward-rectifier potassium channel (IK1 ), can be the responsible gene for atypical CPVT. We recently encountered a family with CPVT and sought to identify a responsible gene variant. METHODS A targeted panel sequencing (TPS) was employed in the proband. Copy number variation (CNV) in RYR2 was identified by focusing on read numbers in the TPS and long-range PCR. Cascade screening was conducted by a Sanger method and long-range PCR. KCNJ2 wild-type (WT) or an identified variant was expressed in COS-1 cells, and whole-cell currents (IK1 ) were recorded using patch-clamp techniques. RESULTS A 40-year-old female experienced cardiopulmonary arrest while cycling. Her ECG showed sinus bradycardia with prominent U-waves (≥0.2 mV). She had left ventricular hypertrabeculation at apex. Exercise induced frequent polymorphic ventricular arrhythmias. Her sister died suddenly at age 35 while bouldering. Her father and paternal aunt, with prominent U-waves, received permanent pacemaker due to sinus node dysfunction. The initial TPS and cascade screening identified a KCNJ2 E118D variant in all three symptomatic patients. However, after focusing on read numbers, we identified a novel exon3 deletion of RYR2 (RYR2-exon3 deletion) in all of them. Functional analysis revealed that KCNJ2 E118D generated IK1 indistinguishable from KCNJ2 WT, even in the presence of catecholaminergic stimulation. CONCLUSIONS Focusing on the read numbers in the TPS enabled us to identify a novel CNV, RYR2-exon3 deletion, which was associated with phenotypic features of this family.
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Severe congenital RYR1-associated myopathy complicated with atrial tachycardia and sinus node dysfunction: a case report.
Hayakawa, I, Abe, Y, Ono, H, Kubota, M
Italian journal of pediatrics. 2019;(1):165
Abstract
BACKGROUND Cardiac arrhythmias are sometimes encountered in patients with hereditary myopathies and muscular dystrophies. Description of arrhythmias in myopathies and muscular dystrophies is very important, because arrhythmias have a strong impact on the outcomes for these patients and are potentially treatable. CASE PRESENTATION A girl with severe congenital RYR1-related myopathy exhibited atrial tachycardia and sinus node dysfunction during infancy. She was born after uncomplicated caesarian delivery. She showed no breathing, complete ophthalmoplegia, complete bulbar paralysis, complete facial muscle paralysis, and extreme floppiness. At 5 months old, she developed persistent tachycardia around 200-210 beats per minutes. Holter monitoring revealed ectopic atrial tachycardia during tachyarrhythmia and occasional sinus pauses with junctional escape beats. Propranolol effectively alleviated tachyarrhythmia but was discontinued due to increased frequency and duration of the sinus pauses that led to bradyarrhythmia. There was no evidence of structural heart diseases or heart failure. The arrhythmia gradually resolved spontaneously and at 11 months old, she showed complete sinus rhythm. CONCLUSIONS Although supraventricular arrhythmia is sometimes encountered in congenital myopathies, this is the first report of cardiac arrhythmia requiring drug intervention in RYR1-associated myopathy.
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Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for the Use of Potent Volatile Anesthetic Agents and Succinylcholine in the Context of RYR1 or CACNA1S Genotypes.
Gonsalves, SG, Dirksen, RT, Sangkuhl, K, Pulk, R, Alvarellos, M, Vo, T, Hikino, K, Roden, D, Klein, TE, Poler, SM, et al
Clinical pharmacology and therapeutics. 2019;(6):1338-1344
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Abstract
The identification in a patient of 1 of the 50 variants in the RYR1 or CACNA1S genes reviewed here should lead to a presumption of malignant hyperthermia susceptibility (MHS). MHS can lead to life-threatening reactions to potent volatile anesthetic agents or succinylcholine. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of these agents in patients with these RYR1 or CACNA1S variants (updates at https://cpicpgx.org/guidelines and www.pharmgkb.org).
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Malignant Hyperthermia in the Post-Genomics Era: New Perspectives on an Old Concept.
Riazi, S, Kraeva, N, Hopkins, PM
Anesthesiology. 2018;(1):168-180
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Abstract
This article reviews advancements in the genetics of malignant hyperthermia, new technologies and approaches for its diagnosis, and the existing limitations of genetic testing for malignant hyperthermia. It also reviews the various RYR1-related disorders and phenotypes, such as myopathies, exertional rhabdomyolysis, and bleeding disorders, and examines the connection between these disorders and malignant hyperthermia.
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Prominent myalgia-an important clue in the diagnosis of a muscle disorder.
Jain, P, Sehgal, V
World journal of pediatrics : WJP. 2017;(3):282