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1.
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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Relevance of pathogenicity prediction tools in human RYR1 variants of unknown significance.
Hoppe, K, Jurkat-Rott, K, Kranepuhl, S, Wearing, S, Heiderich, S, Merlak, S, Klingler, W
Scientific reports. 2021;(1):3445
Abstract
Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle metabolism characterized by generalized muscle rigidity, increased body temperature, rhabdomyolysis, hyperkalemia and severe metabolic acidosis. The underlying mechanism of MH involves excessive Ca2+ release from myotubes via the ryanodine receptor type 1 (RYR1) and the voltage-dependent L-type calcium channel (CACNA1S). As more than 300 variants of unknown significance have been detected to date, we examined whether freely available pathogenicity prediction tools are able to detect relevant MH causing variants. In this diagnostic accuracy study, blood samples from 235 individuals with a history of a clinical malignant hyperthermia or their close relatives were genetically screened for RYR1 variants of all 106 RYR1 exons and additionally for known variants of CACNA1S. In vitro contracture tests were conducted on muscle biopsies obtained from all individuals, independently of whether a pathogenic variant, a variant of unknown significance or no variant was detected. Comparisons were made to three established bioinformatic pathogenicity detection tools to identify the clinical impact of the variants of unknown significance. All detected genetic variants were tested for pathogenicity by three in silico approaches and compared to the in vitro contracture test. Sensitivity and specificity of exon screening of all individuals listed in our MH database was analyzed. Exon screening identified 97 (41%) of the 235 individuals as carriers of pathogenic variants. Variants of unknown significance were detected in 21 individuals. Variants of unknown significance were subdivided into 19 malignant-hyperthermia-susceptible individuals and 2 non-malignant-hyperthermia-susceptible individuals. All pathogenic variants as well as the malignant-hyperthermia-suspectible variants were correctly identified by the bioinformatic prediction tools. Sensitivity of in silico approaches ranged between 0.71 and 0.98 (Polyphen 0.94 [CI 95% 0.75; 0.99]; Sift 0.98 [CI 95% 0.81; 0.99]; MutationTaster 0.92 [CI 95% 0.75; 0.99]). Specificity differed depending on the used tool (Polphen 0.98 [CI 95% 0.32; 0.99]; Sift 0.98 [CI 95% 0.32; 0.99]; MutationTaster 0.00 [CI 95% 0.00; 0.60]). All pathogenic variants and variants of unknown significance were scored as probably damaging in individuals, demonstrating a high sensitivity. Specificity was very low in one of the three tested programs. However, due to potential genotype-phenotype discordance, bioinformatic prediction tools are currently of limited value in diagnosing pathogenicity of MH-susceptible variants.
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4.
Understanding Symptoms in RYR1-Related Myopathies: A Mixed-Methods Analysis Based on Participants' Experience.
Capella-Peris, C, Cosgrove, MM, Chrismer, IC, Razaqyar, MS, Elliott, JS, Kuo, A, Emile-Backer, M, Meilleur, KG
The patient. 2020;(4):423-434
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Abstract
BACKGROUND In rare diseases such as ryanodine receptor 1-related myopathies (RYR1-RM), health-related quality of life (HRQoL) measures are critically important so clinicians and researchers can better understand what symptoms are most important to participants, with the ultimate goal of finding tangible solutions for them. OBJECTIVES The main objective of this study was to characterize symptoms in individuals with RYR1-RM to inform future research. A secondary objective of this study was to analyze positive and negative sentiments regarding symptoms and treatment effects post N-acetylcysteine (NAC) administration in individuals with RYR1-RM. METHODS The study used a mixed-methods design applying methodological triangulation. Qualitative data were collected via semi-structured interviews at three visits to characterize symptoms in individuals with RYR1-RM and to analyze treatment effects. Qualitative data were then transformed into quantitative results to measure the frequency with which each symptom was mentioned by participants. RESULTS A total of 12 symptoms were identified as areas of interest to participants with RYR1-RM, highlighting fatigue and weakness as key symptoms. Data transformation categorized more than 1000 citations, reporting a greater number of positive comments for postintervention interviews than for baseline and preintervention visits and that NAC group participants stated more positive comments regarding treatment effect than did the placebo group. CONCLUSIONS We present a comprehensive characterization of symptoms in RYR1-RM and how those symptoms influence HRQoL. Furthermore, the introduction of mixed methods may be a valuable way to better understand patient-centered data in rare diseases to support affected individuals in coping with their symptoms.
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5.
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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6.
Identification of a Novel Homozygous Multi-Exon Duplication in RYR2 Among Children With Exertion-Related Unexplained Sudden Deaths in the Amish Community.
Tester, DJ, Bombei, HM, Fitzgerald, KK, Giudicessi, JR, Pitel, BA, Thorland, EC, Russell, BG, Hamrick, SK, Kim, CSJ, Haglund-Turnquist, CM, et al
JAMA cardiology. 2020;(3):13-18
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Abstract
IMPORTANCE The exome molecular autopsy may elucidate a pathogenic substrate for sudden unexplained death. OBJECTIVE To investigate the underlying cause of multiple sudden deaths in young individuals and sudden cardiac arrests that occurred in 2 large Amish families. DESIGN, SETTING, AND PARTICIPANTS Two large extended Amish families with multiple sudden deaths in young individuals and sudden cardiac arrests were included in the study. A recessive inheritance pattern was suggested based on an extended family history of sudden deaths in young individuals and sudden cardiac arrests, despite unaffected parents. A family with exercise-associated sudden deaths in young individuals occurring in 4 siblings was referred for postmortem genetic testing using an exome molecular autopsy. Copy number variant (CNV) analysis was performed on exome data using PatternCNV. Chromosomal microarray validated the CNV identified. The nucleotide break points of the CNV were determined by mate-pair sequencing. Samples were collected for this study between November 2004 and June 2019. MAIN OUTCOMES AND MEASURES The identification of an underlying genetic cause for sudden deaths in young individuals and sudden cardiac arrests consistent with the recessive inheritance pattern observed in the families. RESULTS A homozygous duplication, involving approximately 26 000 base pairs of intergenic sequence, RYR2's 5'UTR/promoter region, and exons 1 through 4 of RYR2, was identified in all 4 siblings of a family. Multiple distantly related relatives experiencing exertion-related sudden cardiac arrest also had the identical RYR2 homozygous duplication. A second, unrelated family with multiple exertion-related sudden deaths and sudden cardiac arrests in young individuals, with the same homozygous duplication, was identified. Several living, homozygous duplication-positive symptomatic patients from both families had nondiagnostic cardiologic testing, with only occasional ventricular ectopy occurring during exercise stress tests. CONCLUSIONS AND RELEVANCE In this analysis, we identified a novel, highly penetrant, homozygous multiexon duplication in RYR2 among Amish youths with exertion-related sudden death and sudden cardiac arrest but without an overt phenotype that is distinct from RYR2-mediated catecholaminergic polymorphic ventricular tachycardia. Considering that no cardiac tests reliably identify at-risk individuals and given the high rate of consanguinity in Amish families, identification of unaffected heterozygous carriers may provide potentially lifesaving premarital counseling and reproductive planning.
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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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Recruiting RyRs to Open in a Ca2+ Release Unit: Single-RyR Gating Properties Make RyR Group Dynamics.
Gillespie, D
Biophysical journal. 2020;(1):232-242
Abstract
In cardiac myocytes, clusters of type-2 ryanodine receptors (RyR2s) release Ca2+ from the sarcoplasmic reticulum (SR) via a positive feedback mechanism in which fluxed Ca2+ activates nearby RyRs. Although the general principles of this are understood, less is known about how single-RyR gating properties define the RyR group dynamics in an array of many channels. Here, we examine this using simulations with three models of RyR gating that have identical open probabilities: the commonly used two-state Markov gating model, one that utilizes multiple exponentials to fit single-channel open time (OT) and closed time (CT) distributions, and an extension of this multiexponential model that also includes experimentally measured correlations between single-channel OTs and CTs. The simulations of RyR clusters that utilize the multiexponential gating model produce infrequent Ca2+ release events with relatively few open RyRs. Ca2+ release events become even smaller when OT/CT correlations are included. This occurs because the correlations produce a small but consistent bias against recruiting more RyRs to open during the middle of a Ca2+ release event, between the initiation and termination phases (which are unaltered compared to the uncorrelated simulations). In comparison, the two-state model produces frequent, large, and long Ca2+ release events because it had a recruitment bias in favor of opening more RyRs. This difference stems from the two-state model's single-RyR OT and CT distributions being qualitatively different from the experimental ones. Thus, the details of single-RyR gating can profoundly affect SR Ca2+ release even if open probability and mean OTs and CTs are identical. We also show that Ca2+ release events can terminate spontaneously without any reduction in SR [Ca2+], luminal regulation, Ca2+-dependent inactivation, or physical coupling between RyRs when Ca2+ flux is below a threshold value. This supports and extends the pernicious attrition/induction decay hypothesis that SR Ca2+ release events terminate below a threshold Ca2+ flux.
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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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Reliability and Validity of Self-Report Questionnaires as Indicators of Fatigue in RYR1-Related Disorders.
Kuo, A, Todd, JJ, Witherspoon, JW, Lawal, TA, Elliott, J, Chrismer, IC, Shelton, MO, Razaqyar, MS, Jain, MS, Vasavada, R, et al
Journal of neuromuscular diseases. 2019;(1):133-141
Abstract
BACKGROUND RYR1-related disorders (RYR1-RD), are a spectrum of genetic neuromuscular disorders. Affected individuals frequently experience fatigue yet appropriate tools to assess RYR1-RD-associated fatigue remain underdeveloped. OBJECTIVE This study assessed the reliability and validity of two self-report questionnaires, the multidimensional fatigue inventory (MFI-20) and adult/pediatric functional assessment of chronic illness-fatigue (FACIT-F/Peds-FACIT-F) as potential fatigue measures in RYR1-RD affected individuals. METHODS Participants (n = 37) were enrolled in an RYR1-RD combined natural history study and clinical trial. At baseline, participants completed fatigue questionnaires, six-minute walk test (6MWT), cardiopulmonary exercise test (CPET) and saliva collection for fatigue biomarker index (FBI) quantification. RESULTS All questionnaires exhibited good test-retest reliability (n = 18, ICC > 0.80). MFI-20 (n = 37), and FACIT-F (n = 28) also showed good internal consistency (Cronbach's α> 0.80). All MFI-20 subscales, except mental fatigue, and FACIT-F demonstrated evidence of criterion validity when correlated against percent predicted 6MWT distance (MFI-20 n = 37; r = -0.34 to -0.47, all p < 0.05, mental fatigue, r = -0.16, p = 0.35; FACIT-F n = 28, r = 0.41, p = 0.03). This was not the case for percent predicted VO2 peak (all p > 0.05). FBI correlated with MFI-20 general fatigue dimension only (r = -0.35, p = 0.03). Comparison of standardized questionnaire scores revealed that RYR1-RD affected individuals experience significantly greater fatigue than the general population. CONCLUSIONS MFI-20 and FACIT-F are valid and reliable tools for assessing RYR1-RD-associated fatigue, a symptom centrally implicated in this rare disorder.