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Riccio AM, Gurvitch DL. Does the Diagnosis of Intraoperative Malignant Hyperthermia Require Case Termination? A Case Report. A A Pract 2025; 19:e01900. [PMID: 39791600 DOI: 10.1213/xaa.0000000000001900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
Malignant hyperthermia (MH) is a rare genetic disorder triggered by inhalational anesthetics or depolarizing neuromuscular blocking agents that carries significant mortality if not promptly treated. The following case presents a healthy 39-year-old man who developed MH several hours into an anesthetic exposure. Rapid intraoperative stabilization tactics that paralleled intensive care unit (ICU) level care allowed for continuation of operative management as opposed to case termination given the patient was at high risk for permanent nerve palsy if the case were to be aborted during dissection.
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Affiliation(s)
- Alessandra M Riccio
- From the Department of Anesthesiology, New York Presbyterian Hospital, Weill Cornell Medical Center, New York, NY
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2
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Zhou W, Zhao P, Gao J, Zhang Y. A novel CACNA1S gene variant in a child with hypokalemic periodic paralysis: a case report and literature review. BMC Pediatr 2023; 23:500. [PMID: 37784084 PMCID: PMC10544472 DOI: 10.1186/s12887-023-04326-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 09/24/2023] [Indexed: 10/04/2023] Open
Abstract
BACKGROUND The CACNA1S gene encodes the alpha 1 S-subunit of the voltage-gated calcium channel, which is primarily expressed in the skeletal muscle cells. Pathogenic variants of CACNA1S can cause hypokalemic periodic paralysis (HypoPP), malignant hyperthermia susceptibility, and congenital myopathy. We aimed to study the clinical and molecular features of a male child with a CACNA1S variant and depict the molecular sub-regional characteristics of different phenotypes associated with CACNA1S variants. CASE PRESENTATION We presented a case of HypoPP with recurrent muscle weakness and hypokalemia. Genetic analyses of the family members revealed that the proband had a novel c.497 C > A (p.Ala166Asp) variant of CACNA1S, which was inherited from his father. The diagnosis of HypoPP was established in the proband as he met the consensus diagnostic criteria. The patient and his parents were informed to avoid the classical triggers of HypoPP. The attacks of the patient are prevented by lifestyle changes and nutritional counseling. We also showed the molecular sub-regional location of the variants of CACNA1S which was associated with different phenotypes. CONCLUSIONS Our results identified a new variant of CACNA1S and expanded the spectrum of variants associated with HypoPP. Early genetic diagnosis can help avoid diagnostic delays, perform genetic counseling, provide proper treatment, and reduce morbidity and mortality.
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Affiliation(s)
- Wen Zhou
- Department of Pediatrics, People's Hospital of Jinping Miao, Yao and Dai Autonomous County, Honghe Prefecture, Yunnan Province, China
| | - Peilin Zhao
- Department of Pediatrics, People's Hospital of Jinping Miao, Yao and Dai Autonomous County, Honghe Prefecture, Yunnan Province, China
| | - Jian Gao
- Department of Pediatrics, People's Hospital of Jinping Miao, Yao and Dai Autonomous County, Honghe Prefecture, Yunnan Province, China
| | - Yunjian Zhang
- Department of Neurology, National Children's Medical Center, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102, China.
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3
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Zhu Y, Hamill RM, Mullen AM, Kelly AL, Gagaoua M. Molecular mechanisms contributing to the development of beef sensory texture and flavour traits and related biomarkers: Insights from early post-mortem muscle using label-free proteomics. J Proteomics 2023; 286:104953. [PMID: 37390894 DOI: 10.1016/j.jprot.2023.104953] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/12/2023] [Accepted: 06/14/2023] [Indexed: 07/02/2023]
Abstract
Beef sensory quality comprises a suite of traits, each of which manifests its ultimate phenotype through interaction of muscle physiology with environment, both in vivo and post-mortem. Understanding variability in meat quality remains a persistent challenge, but omics studies to uncover biological connections between natural variability in proteome and phenotype could provide validation for exploratory studies and offer new insights. Multivariate analysis of proteome and meat quality data from Longissimus thoracis et lumborum muscle samples taken early post-mortem from 34 Limousin-sired bulls was conducted. Using for the first-time label-free shotgun proteomics combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), 85 proteins were found to be related with tenderness, chewiness, stringiness and flavour sensory traits. The putative biomarkers were classified in five interconnected biological pathways; i) muscle contraction, ii) energy metabolism, iii) heat shock proteins, iv) oxidative stress, v) regulation of cellular processes and binding. Among the proteins, PHKA1 and STBD1 correlated with all four traits, as did the GO biological process 'generation of precursor metabolites and energy'. Optimal regression models explained a high level (58-71%) of phenotypic variability with proteomic data for each quality trait. The results of this study propose several regression equations and biomarkers to explain the variability of multiple beef eating quality traits. Thanks to annotation and network analyses, they further suggest protein interactions and mechanisms underpinning the physiological processes regulating these key quality traits. SIGNIFICANCE: The proteomic profiles of animals with divergent quality profiles have been compared in numerous studies; however, a wide range of phenotypic variation is required to better understand the mechanisms underpinning the complex biological pathways correlated with beef quality and protein interactions. We used multivariate regression analyses and bioinformatics to analyse shotgun proteomics data to decipher the molecular signatures involved in beef texture and flavour variations with a focus on multiple quality traits. We developed multiple regression equations to explain beef texture and flavour. Additionally, potential candidate biomarkers correlated with multiple beef quality traits are suggested, which could have utility as indicators of beef overall sensory quality. This study explained the biological process responsible for determining key quality traits such as tenderness, chewiness, stringiness, and flavour in beef, which will provide support for future beef proteomics studies.
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Affiliation(s)
- Yao Zhu
- Food Quality and Sensory Science Department, Teagasc Ashtown Food Research Centre, Ashtown, D15KN3K Dublin 15, Ireland; School of Food and Nutritional Sciences, University College Cork, Cork T12 K8AF, Ireland
| | - Ruth M Hamill
- Food Quality and Sensory Science Department, Teagasc Ashtown Food Research Centre, Ashtown, D15KN3K Dublin 15, Ireland.
| | - Anne Maria Mullen
- Food Quality and Sensory Science Department, Teagasc Ashtown Food Research Centre, Ashtown, D15KN3K Dublin 15, Ireland
| | - Alan L Kelly
- School of Food and Nutritional Sciences, University College Cork, Cork T12 K8AF, Ireland
| | - Mohammed Gagaoua
- Food Quality and Sensory Science Department, Teagasc Ashtown Food Research Centre, Ashtown, D15KN3K Dublin 15, Ireland; PEGASE, INRAE, Institut Agro, 35590 Saint-Gilles, France.
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4
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Feng W, Lopez JR, Antrobus S, Zheng J, Uryash A, Dong Y, Beqollari D, Bannister RA, Hopkins PM, Beam KG, Allen PD, Pessah IN. Putative malignant hyperthermia mutation Ca V1.1-R174W is insufficient to trigger a fulminant response to halothane or confer heat stress intolerance. J Biol Chem 2023; 299:104992. [PMID: 37392848 PMCID: PMC10413282 DOI: 10.1016/j.jbc.2023.104992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 06/16/2023] [Accepted: 06/20/2023] [Indexed: 07/03/2023] Open
Abstract
Malignant hyperthermia susceptibility (MHS) is an autosomal dominant pharmacogenetic disorder that manifests as a hypermetabolic state when carriers are exposed to halogenated volatile anesthetics or depolarizing muscle relaxants. In animals, heat stress intolerance is also observed. MHS is linked to over 40 variants in RYR1 that are classified as pathogenic for diagnostic purposes. More recently, a few rare variants linked to the MHS phenotype have been reported in CACNA1S, which encodes the voltage-activated Ca2+ channel CaV1.1 that conformationally couples to RyR1 in skeletal muscle. Here, we describe a knock-in mouse line that expresses one of these putative variants, CaV1.1-R174W. Heterozygous (HET) and homozygous (HOM) CaV1.1-R174W mice survive to adulthood without overt phenotype but fail to trigger with fulminant malignant hyperthermia when exposed to halothane or moderate heat stress. All three genotypes (WT, HET, and HOM) express similar levels of CaV1.1 by quantitative PCR, Western blot, [3H]PN200-110 receptor binding and immobilization-resistant charge movement densities in flexor digitorum brevis fibers. Although HOM fibers have negligible CaV1.1 current amplitudes, HET fibers have similar amplitudes to WT, suggesting a preferential accumulation of the CaV1.1-WT protein at triad junctions in HET animals. Never-the-less both HET and HOM have slightly elevated resting free Ca2+ and Na+ measured with double barreled microelectrode in vastus lateralis that is disproportional to upregulation of transient receptor potential canonical (TRPC) 3 and TRPC6 in skeletal muscle. CaV1.1-R174W and upregulation of TRPC3/6 alone are insufficient to trigger fulminant malignant hyperthermia response to halothane and/or heat stress in HET and HOM mice.
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Affiliation(s)
- Wei Feng
- Department of Molecular Biosciences, University of California Davis, Davis, California, USA
| | - Jose R Lopez
- Department of Molecular Biosciences, University of California Davis, Davis, California, USA; Department of Research, Mount Sinai Medical Center, Miami Beach, Florida, USA
| | - Shane Antrobus
- Department of Molecular Biosciences, University of California Davis, Davis, California, USA
| | - Jing Zheng
- Department of Molecular Biosciences, University of California Davis, Davis, California, USA
| | - Arkady Uryash
- Department of Research, Mount Sinai Medical Center, Miami Beach, Florida, USA
| | - Yao Dong
- Department of Molecular Biosciences, University of California Davis, Davis, California, USA
| | - Donald Beqollari
- Department of Medicine-Cardiology Division, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Roger A Bannister
- Department of Medicine-Cardiology Division, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Philip M Hopkins
- Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
| | - Kurt G Beam
- Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Paul D Allen
- Department of Molecular Biosciences, University of California Davis, Davis, California, USA; Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
| | - Isaac N Pessah
- Department of Molecular Biosciences, University of California Davis, Davis, California, USA.
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5
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Scarpa JR, Elemento O. Multi-omic molecular profiling and network biology for precision anaesthesiology: a narrative review. Br J Anaesth 2023:S0007-0912(23)00125-3. [PMID: 37055274 DOI: 10.1016/j.bja.2023.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 02/21/2023] [Accepted: 03/04/2023] [Indexed: 04/15/2023] Open
Abstract
Technological advancement, data democratisation, and decreasing costs have led to a revolution in molecular biology in which the entire set of DNA, RNA, proteins, and various other molecules - the 'multi-omic' profile - can be measured in humans. Sequencing 1 million bases of human DNA now costs US$0.01, and emerging technologies soon promise to reduce the cost of sequencing the whole genome to US$100. These trends have made it feasible to sample the multi-omic profile of millions of people, much of which is publicly available for medical research. Can anaesthesiologists use these data to improve patient care? This narrative review brings together a rapidly growing literature in multi-omic profiling across numerous fields that points to the future of precision anaesthesiology. Here, we discuss how DNA, RNA, proteins, and other molecules interact in molecular networks that can be used for preoperative risk stratification, intraoperative optimisation, and postoperative monitoring. This literature provides evidence for four fundamental insights: (1) Clinically similar patients have different molecular profiles and, as a consequence, different outcomes. (2) Vast, publicly available, and rapidly growing molecular datasets have been generated in chronic disease patients and can be repurposed to estimate perioperative risk. (3) Multi-omic networks are altered in the perioperative period and influence postoperative outcomes. (4) Multi-omic networks can serve as empirical, molecular measurements of a successful postoperative course. With this burgeoning universe of molecular data, the anaesthesiologist-of-the-future will tailor their clinical management to an individual's multi-omic profile to optimise postoperative outcomes and long-term health.
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Affiliation(s)
- Joseph R Scarpa
- Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA.
| | - Olivier Elemento
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
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6
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Campiglio M, Dyrda A, Tuinte WE, Török E. Ca V1.1 Calcium Channel Signaling Complexes in Excitation-Contraction Coupling: Insights from Channelopathies. Handb Exp Pharmacol 2023; 279:3-39. [PMID: 36592225 DOI: 10.1007/164_2022_627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
In skeletal muscle, excitation-contraction (EC) coupling relies on the mechanical coupling between two ion channels: the L-type voltage-gated calcium channel (CaV1.1), located in the sarcolemma and functioning as the voltage sensor of EC coupling, and the ryanodine receptor 1 (RyR1), located on the sarcoplasmic reticulum serving as the calcium release channel. To this day, the molecular mechanism by which these two ion channels are linked remains elusive. However, recently, skeletal muscle EC coupling could be reconstituted in heterologous cells, revealing that only four proteins are essential for this process: CaV1.1, RyR1, and the cytosolic proteins CaVβ1a and STAC3. Due to the crucial role of these proteins in skeletal muscle EC coupling, any mutation that affects any one of these proteins can have devastating consequences, resulting in congenital myopathies and other pathologies.Here, we summarize the current knowledge concerning these four essential proteins and discuss the pathophysiology of the CaV1.1, RyR1, and STAC3-related skeletal muscle diseases with an emphasis on the molecular mechanisms. Being part of the same signalosome, mutations in different proteins often result in congenital myopathies with similar symptoms or even in the same disease.
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Affiliation(s)
- Marta Campiglio
- Institute of Physiology, Medical University Innsbruck, Innsbruck, Austria.
| | - Agnieszka Dyrda
- Institute of Physiology, Medical University Innsbruck, Innsbruck, Austria
| | - Wietske E Tuinte
- Institute of Physiology, Medical University Innsbruck, Innsbruck, Austria
| | - Enikő Török
- Institute of Physiology, Medical University Innsbruck, Innsbruck, Austria
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Murayama T, Kurebayashi N, Numaga-Tomita T, Kobayashi T, Okazaki S, Yamashiro K, Nakada T, Mori S, Ishida R, Kagechika H, Yamada M, Sakurai T. A reconstituted depolarization-induced Ca2+ release platform for validation of skeletal muscle disease mutations and drug discovery. J Gen Physiol 2022; 154:213630. [PMID: 36318155 PMCID: PMC9629852 DOI: 10.1085/jgp.202213230] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 09/06/2022] [Accepted: 10/03/2022] [Indexed: 11/06/2022] Open
Abstract
In skeletal muscle excitation-contraction (E-C) coupling, depolarization of the plasma membrane triggers Ca2+ release from the sarcoplasmic reticulum (SR), referred to as depolarization-induced Ca2+ release (DICR). DICR occurs through the type 1 ryanodine receptor (RyR1), which physically interacts with the dihydropyridine receptor Cav1.1 subunit in specific machinery formed with additional essential components including β1a, Stac3 adaptor protein, and junctophilins. Exome sequencing has accelerated the discovery of many novel mutations in genes encoding DICR machinery in various skeletal muscle diseases. However, functional validation is time-consuming because it must be performed in a skeletal muscle environment. In this study, we established a platform of the reconstituted DICR in HEK293 cells. The essential components were effectively transduced into HEK293 cells expressing RyR1 using baculovirus vectors, and Ca2+ release was quantitatively measured with R-CEPIA1er, a fluorescent ER Ca2+ indicator, without contaminant of extracellular Ca2+ influx. In these cells, [K+]-dependent Ca2+ release was triggered by chemical depolarization with the aid of inward rectifying potassium channel, indicating a successful reconstitution of DICR. Using the platform, we evaluated several Cav1.1 mutations that are implicated in malignant hyperthermia and myopathy. We also tested several RyR1 inhibitors; whereas dantrolene and Cpd1 inhibited DICR, procaine had no effect. Furthermore, twitch potentiators such as perchlorate and thiocyanate shifted the voltage dependence of DICR to more negative potentials without affecting Ca2+-induced Ca2+ release. These results well reproduced the findings with the muscle fibers and the cultured myotubes. Since the procedure is simple and reproducible, the reconstituted DICR platform will be highly useful for the validation of mutations and drug discovery for skeletal muscle diseases.
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Affiliation(s)
- Takashi Murayama
- Department of Pharmacology, Juntendo University School of Medicine, Tokyo, Japan
| | - Nagomi Kurebayashi
- Department of Pharmacology, Juntendo University School of Medicine, Tokyo, Japan
| | - Takuro Numaga-Tomita
- Department of Molecular Pharmacology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takuya Kobayashi
- Department of Pharmacology, Juntendo University School of Medicine, Tokyo, Japan
| | - Satoru Okazaki
- Department of Pharmacology, Juntendo University School of Medicine, Tokyo, Japan
| | - Kyosuke Yamashiro
- Department of Pharmacology, Juntendo University School of Medicine, Tokyo, Japan
| | - Tsutomu Nakada
- Department of Molecular Pharmacology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Shuichi Mori
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ryosuke Ishida
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroyuki Kagechika
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mitsuhiko Yamada
- Department of Molecular Pharmacology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takashi Sakurai
- Department of Pharmacology, Juntendo University School of Medicine, Tokyo, Japan
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Malignant Hyperthermia in PICU—From Diagnosis to Treatment in the Light of Up-to-Date Knowledge. CHILDREN 2022; 9:children9111692. [DOI: 10.3390/children9111692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 10/04/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022]
Abstract
Malignant Hyperthermia (MH) is a rare, hereditary, life-threatening disease triggered by volatile anesthetics and succinylcholine. Rarely, MH can occur after non-pharmacological triggers too. MH was detected more often in children and young adults, which makes this topic very important for every pediatric specialist, both anesthesiologists and intensivists. MH crisis is a life-threatening severe hypermetabolic whole-body reaction. Triggers of MH are used in pediatric intensive care unit (PICU) as well, volatile anesthetics in difficult sedation, status asthmaticus or epilepticus, and succinylcholine still sometimes in airway management. Recrudescence or delayed onset of MH crisis hours after anesthesia was previously described. MH can also be a cause of rhabdomyolysis and hyperpyrexia in the PICU. In addition, patients with neuromuscular diseases are often admitted to PICU and they might be at risk for MH. The most typical symptoms of MH are hypercapnia, tachycardia, hyperthermia, and muscle rigidity. Thinking of the MH as the possible cause of deterioration of a patient’s clinical condition is the key to early diagnosis and treatment. The sooner the correct treatment is commenced, the better patient´s outcome. This narrative review article aims to summarize current knowledge and guidelines about recognition, treatment, and further management of MH in PICU.
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Chi X, Xu Y, Liao H, Chen T, Li Q, Fu Q. Perioperative management of malignant hyperthermia during general anesthesia: A report of two cases. Clin Case Rep 2022; 10:e6426. [PMID: 36245440 PMCID: PMC9552991 DOI: 10.1002/ccr3.6426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 08/18/2022] [Accepted: 09/20/2022] [Indexed: 11/12/2022] Open
Abstract
Malignant hyperthermia (MH) is a lethal complication associated with general anesthesia characterized by sudden onset, rapid progression, and high mortality. We present two seemingly typical cases of intraoperative MH development, with details on perioperative assessment and rescue. Postoperative genetic test showed mutations in the ryanodine receptor type 1 gene.
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Affiliation(s)
- Xiaowei Chi
- Department of Anesthesiology, Third People's Hospital of ChengduSouthwest Jiaotong UniversityChengduChina
| | - Yi Xu
- Department of AnesthesiologyThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Hongbing Liao
- Department of Anesthesiology, Third People's Hospital of ChengduSouthwest Jiaotong UniversityChengduChina
| | - Tao Chen
- Department of Anesthesiology, Third People's Hospital of ChengduSouthwest Jiaotong UniversityChengduChina
| | - Qiang Li
- Department of Anesthesiology, Third People's Hospital of ChengduSouthwest Jiaotong UniversityChengduChina
| | - Qiang Fu
- Department of Anesthesiology, Third People's Hospital of ChengduSouthwest Jiaotong UniversityChengduChina
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10
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Benítez-Alonso EO, López-Hernández JC, Galnares-Olalde JA, Alcalá RE, Vargas-Cañas ES. Short-Communication: Variable Expression of Clinical Symptoms and an Unexpected Finding of Vacuolar Myopathy Related to a Pathogenic Variant in the CACNA1S Gene in a Previous Case Report. Cureus 2022; 14:e23760. [PMID: 35509735 PMCID: PMC9060183 DOI: 10.7759/cureus.23760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/01/2022] [Indexed: 11/05/2022] Open
Abstract
Several clinical phenotypes have been described related to the CACNA1S gene (calcium channel voltage-dependent L-type alpha-1S subunit), such as autosomal dominant hypokalemic periodic paralysis 1 and autosomal dominant malignant hyperthermia susceptibility and are associated with autosomal dominant and recessive congenital myopathy. Recently, an interesting case of a 58-year-old male patient was published describing an unusual clinical presentation of hypokalemic periodic paralysis where a late-onset limb-girdle myopathy had developed 41 years after paralysis occurred when the patient was 11 years old. Muscle biopsy results were consistent with myopathic changes and revealed the presence of vacuoles, without inflammatory reaction. Later, molecular analysis revealed a pathogenic variant c.3716G>A (p.Arg1239His) in exon 30 of the CACNA1S gene. This technical report provides an extension of the molecular findings and evaluates the clinical and histopathological relationship previously published regarding this case.
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Mutations associated with hypokalemic periodic paralysis: from hotspot regions to complete analysis of CACNA1S and SCN4A genes. Neurogenetics 2021; 23:19-25. [PMID: 34608571 DOI: 10.1007/s10048-021-00673-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 09/26/2021] [Indexed: 01/10/2023]
Abstract
Familial periodic paralyses (PPs) are inherited disorders of skeletal muscle characterized by recurrent episodes of flaccid muscle weakness. PPs are classified as hypokalemic (HypoPP), normokalemic (NormoPP), or hyperkalemic (HyperPP) according to the potassium level during the paralytic attacks. HypoPP is an autosomal dominant disease caused by mutations in the CACNA1S gene, encoding for Cav1.1 channel (HypoPP-1), or SCN4A gene, encoding for Nav1.4 channel (HypoPP-2). In the present study, we included 60 patients with a clinical diagnosis of HypoPP. Fifty-one (85%) patients were tested using the direct sequencing (Sanger method) of all reported HypoPP mutations in CACNA1S and SCN4A genes; the remaining 9 (15%) patients were analyzed through a next-generation sequencing (NGS) panel, including the whole CACNA1S and SCN4A genes, plus other genes rarely associated to PPs. Fifty patients resulted mutated: 38 (76%) cases showed p.R528H and p.R1239G/H CACNA1S mutations and 12 (24%) displayed p.R669H, p.R672C/H, p.R1132G/Q, and p.R1135H SCN4A mutations. Forty-one mutated cases were identified among the 51 patients managed with Sanger sequencing, while all the 9 cases directly analyzed with the NGS panel showed mutations in the hotspot regions of SCN4A and CACNA1S. Ten out of the 51 patients unresolved through the Sanger sequencing were further analyzed with the NGS panel, without the detection of any mutation. Hence, our data suggest that in HypoPP patients, the extension of genetic analysis from the hotspot regions using the Sanger method to the NGS sequencing of the entire CACNA1S and SCN4A genes does not lead to the identification of new pathological mutations.
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12
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Abstract
We sought to review the effects of statins on the ryanodine receptor (RyR) and on RyR-associated diseases, with an emphasis on catecholaminergic polymorphic ventricular tachycardia (CPVT). Statins can affect skeletal muscle and produce statin-associated muscle symptoms (SAMS) but have no adverse effects on cardiac muscle. These contrasting effects may be due to differences in how statins affect the skeletal (RyR1) and cardiac (RyR2) RyR. We searched PubMed to identify English language articles reporting the pathophysiology of the RyR, the effect of statins on RyR function, and on RyR-associated genetic diseases. We selected 150 articles for abstract review, 96 of which provided sufficient information to be included and were reviewed in detail. Fifteen articles highlighted the interaction of statins with the RyR. Nine identified the interaction of statins with RyR1, six addressed the interaction of statins with RyR2, 13 suggested that statins reduce ventricular arrhythmias (VA), and seven suggested that statins increase the risk of malignant hyperthermia (MH). In general, statins increase RyR1 and decrease RyR2 activity. We identified no articles examining the effect of statins on CPVT, a condition often caused by defects in RyR2. Statins appear to increase the risk of MH and decrease the risk of ventricular arrhythmia. The effect of statins on CPVT has not been directly examined, but statins' reduction in RyR2 function and their apparent reduction in VA suggest that they may be beneficial in this condition.
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Affiliation(s)
- Mohsin Haseeb
- Division of Cardiology, Loyola University Medical Center, Maywood, Illinois
| | - Paul D Thompson
- Division of Cardiology, Hartford Hospital, Hartford, Connecticut
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13
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Beebe D, Puram VV, Gajic S, Thyagarajan B, Belani KG. Genetics of Malignant Hyperthermia: A Brief Update. J Anaesthesiol Clin Pharmacol 2021; 36:552-555. [PMID: 33840940 PMCID: PMC8022069 DOI: 10.4103/joacp.joacp_360_19] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 01/02/2020] [Accepted: 02/24/2020] [Indexed: 11/25/2022] Open
Abstract
Malignant hyperthermia susceptibility (MHS) and the associated condition malignant hyperthermia (MH) are rare but well-known disorders in the field of anesthesiology. MHS is usually determined by a history of a family member developing a positive episode during general anesthesia and then confirmed by an invasive caffeine halothane contracture test (CHCT). More recently, within the context of MH as a pharmacogenetic disorder, the question of whether or not MHS can be principally genetically determined is of high importance as knowledge of detailed pathogenesis may prevent against its largely invariable lethality if untreated. Thus, in this brief report, genetic terms, as well as updates in the genetics of MHS, will be reviewed in order to better understand both the condition and the current research.
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Affiliation(s)
- David Beebe
- Department of Anesthesiology, University of Minnesota, Minneapolis, MN, USA
| | - Vikram V Puram
- University of Minnesota Medical School, Minneapolis, MN, USA
| | - Srdjan Gajic
- Department of Anesthesiology, University of Minnesota, Minneapolis, MN, USA
| | - Bharat Thyagarajan
- Department of Lab Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
| | - Kumar G Belani
- Department of Anesthesiology, University of Minnesota, Minneapolis, MN, USA
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Han N, Oh JM, Kim IW. Combination of Genome-Wide Polymorphisms and Copy Number Variations of Pharmacogenes in Koreans. J Pers Med 2021; 11:33. [PMID: 33430289 PMCID: PMC7825650 DOI: 10.3390/jpm11010033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/16/2020] [Accepted: 01/04/2021] [Indexed: 12/12/2022] Open
Abstract
For predicting phenotypes and executing precision medicine, combination analysis of single nucleotide variants (SNVs) genotyping with copy number variations (CNVs) is required. The aim of this study was to discover SNVs or common copy CNVs and examine the combined frequencies of SNVs and CNVs in pharmacogenes using the Korean genome and epidemiology study (KoGES), a consortium project. The genotypes (N = 72,299) and CNV data (N = 1000) were provided by the Korean National Institute of Health, Korea Centers for Disease Control and Prevention. The allele frequencies of SNVs, CNVs, and combined SNVs with CNVs were calculated and haplotype analysis was performed. CYP2D6 rs1065852 (c.100C>T, p.P34S) was the most common variant allele (48.23%). A total of 8454 haplotype blocks in 18 pharmacogenes were estimated. DMD ranked the highest in frequency for gene gain (64.52%), while TPMT ranked the highest in frequency for gene loss (51.80%). Copy number gain of CYP4F2 was observed in 22 subjects; 13 of those subjects were carriers with CYP4F2*3 gain. In the case of TPMT, approximately one-half of the participants (N = 308) had loss of the TPMT*1*1 diplotype. The frequencies of SNVs and CNVs in pharmacogenes were determined using the Korean cohort-based genome-wide association study.
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Affiliation(s)
| | | | - In-Wha Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea; (N.H.); (J.M.O.)
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15
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Packiasabapathy S, Rangasamy V, Horn N, Hendrickson M, Renschler J, Sadhasivam S. Personalized pediatric anesthesia and pain management: problem-based review. Pharmacogenomics 2020; 21:55-73. [PMID: 31849281 DOI: 10.2217/pgs-2019-0108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Pharmacogenetics, the genetic influence on the interpersonal variability in drug response, has enabled tailored pharmacotherapy and emerging 'personalized medicine.' Although oncology spearheaded the clinical implementation of personalized medicine, other specialties are rapidly catching up. In anesthesia, classical examples of genetically mediated idiosyncratic reactions have been long known (e.g., malignant hyperthermia and prolonged apnea after succinylcholine). The last two decades have witnessed an expanding body of pharmacogenetic evidence in anesthesia. This review highlights some of the prominent pharmacogenetic associations studied in anesthesia and pain management, with special focus on pediatric anesthesia.
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Affiliation(s)
- Senthil Packiasabapathy
- Department of Anesthesia, Indiana University School of Medicine, Riley Hospital for Children at Indiana University Health, Indianapolis, IN 46202, USA
| | - Valluvan Rangasamy
- Department of Anesthesia, Indiana University School of Medicine, Riley Hospital for Children at Indiana University Health, Indianapolis, IN 46202, USA
| | - Nicole Horn
- Department of Anesthesia, Indiana University School of Medicine, Riley Hospital for Children at Indiana University Health, Indianapolis, IN 46202, USA
| | - Michele Hendrickson
- Department of Anesthesia, Indiana University School of Medicine, Riley Hospital for Children at Indiana University Health, Indianapolis, IN 46202, USA
| | - Janelle Renschler
- Department of Anesthesia, Indiana University School of Medicine, Riley Hospital for Children at Indiana University Health, Indianapolis, IN 46202, USA
| | - Senthilkumar Sadhasivam
- Department of Anesthesia, Indiana University School of Medicine, Riley Hospital for Children at Indiana University Health, Indianapolis, IN 46202, USA
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Yeh HM, Liao MH, Chu CL, Lin YH, Sun WZ, Lai LP, Chen PL. Next-generation sequencing and bioinformatics to identify genetic causes of malignant hyperthermia. J Formos Med Assoc 2020; 120:883-892. [PMID: 32919876 DOI: 10.1016/j.jfma.2020.08.028] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 06/02/2020] [Accepted: 08/18/2020] [Indexed: 10/23/2022] Open
Abstract
BACKGROUND/PURPOSE Malignant hyperthermia (MH) is a life-threatening pharmacogenetic disease with only two known causative genes, RYR1 and CACNA1S. Both are huge genes containing numerous exons, and they reportedly only account for 50-70% of known MH patients. Next-generation sequencing (NGS) technology and bioinformatics could help delineate the genetic diagnosis of MH and several MH-like clinical presentations. METHODS We established a capture-based targeted NGS sequencing framework to examine the whole genomic regions of RYR1, CACNA1S and the 16.6 Kb mitochondrial genome, as well as 12 other genes related to excitation-contraction coupling and/or skeletal muscle calcium homeostasis. We applied bioinformatics analyses to the variants identified in this study and also to the 48 documented RYR1 pathogenic variants. RESULTS The causative variants were identified in seven of the eight (87.5%) MH families, but in none of the 10 individuals classified as either normal controls (N = 2) or patients displaying MH-like clinical features later found to be caused by other etiologies (N = 8). We showed that RYR1 c.1565A>G (p.Tyr522Cys)(rs118192162) could be a genetic hot spot in the Taiwanese population. Bioinformatics analyses demonstrated low population frequencies and predicted damaging effects from all known pathogenic RYR1 variants. We estimated that more than one in 1149 individuals worldwide carry MH pathogenic variants at RYR1. CONCLUSION NGS and bioinformatics are sensitive and specific tools to examine RYR1 and CACNA1S for the genetic diagnosis of MH. Pathogenic variants in RYR1 can be found in the majority of MH patients in Taiwan.
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Affiliation(s)
- Huei-Ming Yeh
- Department of Anesthesiology National Taiwan University Hospital, Taipei, Taiwan
| | - Min-Hua Liao
- Scientist, Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Lin Chu
- Department of Anesthesiology, National Taiwan University Hospital, Yun-Lin Branch, Yunlin, Taiwan
| | - Yin-Hung Lin
- Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Wei-Zen Sun
- Department of Anesthesiology National Taiwan University Hospital, Taipei, Taiwan
| | - Ling-Ping Lai
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Lung Chen
- Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
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17
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Bautista-Medina MA, Gallardo-Blanco HL, Martinez-Garza LE, Cerda-Flores RM, Lavalle-Gonzalez FJ, Villarreal-Perez JZ. Association study in Mexican patients with thyrotoxic hypokalemic periodic paralysis. Biomed Rep 2020; 13:24. [PMID: 32765863 PMCID: PMC7403830 DOI: 10.3892/br.2020.1331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 03/26/2020] [Indexed: 11/29/2022] Open
Abstract
Hypokalemic periodic paralysis type 1 (OMIM; HOKPP1) and type 2 (OMIM; HOKPP2) are diseases of the muscle characterized by episodes of painless muscle weakness, and is associated with low potassium blood levels. Hyperthyroidism has been associated with thyrotoxic periodic paralysis (TTPP) (OMIM; TTPP1 and TTPP2), and genetic susceptibility has been implicated. In the present study, the clinical and epidemiological characteristics of patients with TTPP are described, together with their association with genetic variants reported previously in other populations. A prospective and a retrospective search of the medical records of patients who attended the emergency department at the Hospital Universitario ‘Dr. Jose E. Gonzalez’ in Monterrey, Nuevo León, Mexico, and were diagnosed with TTPP was performed. A total of 16 gene variants in the genes MUC1, CACNA1S, KCNE3 and SCN4A, and nine ancestry informative markers (AIMs), were analysed by Multiplex TaqMan™ Open Array assay, and a genetic association study was performed. A total of 11 patients were recruited, comprising nine males and two females (age range, 19-52 years) and 64 control subjects. Only two cases (18%) had a previous diagnosis of hyperthyroidism; the rest were diagnosed subsequently with Graves' disease. Based on the analysis, two DNA variants were found to potentially confer an increased risk for TTPP: S1PR1 rs3737576 [odds ratio (OR), 4.38; 95% confidence interval (CI), 1.08-17.76] and AIM rs2330442 (OR, 4.50; 95% CI, 1.21-16.69), and one variant was suggested to be possibly associated with TTPP, namely MUC1 rs4072037 (OR, 3.08; 95% CI, 0.841-1.38). However, there were no statistically significant associations between any of the 24 DNA variants and TTPP in a population from northeast Mexico.
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Affiliation(s)
- Mario Arturo Bautista-Medina
- Endocrinology Department, University Hospital José Eleuterio González, Autonomous University of Nuevo León, Monterrey, Nuevo León 64460, Mexico
| | - Hugo Leonid Gallardo-Blanco
- Department of Genetics, University Hospital José Eleuterio González, Autonomous University of Nuevo León, Monterrey, Nuevo León 64460, Mexico
| | - Laura Elia Martinez-Garza
- Department of Genetics, University Hospital José Eleuterio González, Autonomous University of Nuevo León, Monterrey, Nuevo León 64460, Mexico
| | | | - Fernando Javier Lavalle-Gonzalez
- Endocrinology Department, University Hospital José Eleuterio González, Autonomous University of Nuevo León, Monterrey, Nuevo León 64460, Mexico
| | - Jesus Zacarias Villarreal-Perez
- Endocrinology Department, University Hospital José Eleuterio González, Autonomous University of Nuevo León, Monterrey, Nuevo León 64460, Mexico
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Cote DR, Fuentes E, Elsayes AH, Ross JJ, Quraishi SA. A "crush" course on rhabdomyolysis: risk stratification and clinical management update for the perioperative clinician. J Anesth 2020; 34:585-598. [PMID: 32424487 DOI: 10.1007/s00540-020-02792-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Accepted: 05/09/2020] [Indexed: 12/14/2022]
Abstract
Rhabdomyolysis, the release of myoglobin and other cellular breakdown products from necrotic muscle tissue, is seen in patients with crush injuries, drug overdose, malignant hyperthermia, muscular dystrophy, and with increasing frequency in obese patients undergoing routine procedures. For the perioperative clinician, managing the resultant shock, hyperkalemia, acidosis, and myoglobinuric acute kidney injury can present a significant challenge. Prompt recognition, hydration, and correction of metabolic disturbances may reduce or eliminate the need for long-term renal replacement therapy. This article reviews the pathophysiology and discusses key issues in the perioperative diagnosis, risk stratification, and management of rhabdomyolysis.
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Affiliation(s)
- Devan R Cote
- Department of Anesthesiology, Critical Care and Pain Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA
| | - Eva Fuentes
- Department of Surgery, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA
| | - Ali H Elsayes
- Department of Anesthesiology and Perioperative Medicine, Tufts Medical Center, Tufts University School of Medicine, 800 Washington Street, Boston, MA, 02111, USA
| | - Jonathan J Ross
- Department of Anesthesiology, Baystate Medical Center, Tufts University School of Medicine, Springfield, MA, USA
| | - Sadeq A Quraishi
- Department of Anesthesiology and Perioperative Medicine, Tufts Medical Center, Tufts University School of Medicine, 800 Washington Street, Boston, MA, 02111, USA.
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Tammineni ER, Kraeva N, Figueroa L, Manno C, Ibarra CA, Klip A, Riazi S, Rios E. Intracellular calcium leak lowers glucose storage in human muscle, promoting hyperglycemia and diabetes. eLife 2020; 9:e53999. [PMID: 32364497 PMCID: PMC7282812 DOI: 10.7554/elife.53999] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 05/04/2020] [Indexed: 12/18/2022] Open
Abstract
Most glucose is processed in muscle, for energy or glycogen stores. Malignant Hyperthermia Susceptibility (MHS) exemplifies muscle conditions that increase [Ca2+]cytosol. 42% of MHS patients have hyperglycemia. We show that phosphorylated glycogen phosphorylase (GPa), glycogen synthase (GSa) - respectively activated and inactivated by phosphorylation - and their Ca2+-dependent kinase (PhK), are elevated in microsomal extracts from MHS patients' muscle. Glycogen and glucose transporter GLUT4 are decreased. [Ca2+]cytosol, increased to MHS levels, promoted GP phosphorylation. Imaging at ~100 nm resolution located GPa at sarcoplasmic reticulum (SR) junctional cisternae, and apo-GP at Z disk. MHS muscle therefore has a wide-ranging alteration in glucose metabolism: high [Ca2+]cytosol activates PhK, which inhibits GS, activates GP and moves it toward the SR, favoring glycogenolysis. The alterations probably cause these patients' hyperglycemia. For basic studies, MHS emerges as a variable stressor, which forces glucose pathways from the normal to the diseased range, thereby exposing novel metabolic links.
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Affiliation(s)
- Eshwar R Tammineni
- Department of Physiology and Biophysics, Rush University Medical CenterChicagoUnited States
| | - Natalia Kraeva
- Malignant Hyperthermia Investigation Unit (MHIU) of the University Health Network (Canada)TorontoCanada
- Department of Anaesthesia & Pain Management, Toronto General Hospital, UHN, University of TorontoTorontoCanada
| | - Lourdes Figueroa
- Department of Physiology and Biophysics, Rush University Medical CenterChicagoUnited States
| | - Carlo Manno
- Department of Physiology and Biophysics, Rush University Medical CenterChicagoUnited States
| | - Carlos A Ibarra
- Malignant Hyperthermia Investigation Unit (MHIU) of the University Health Network (Canada)TorontoCanada
- Department of Anaesthesia & Pain Management, Toronto General Hospital, UHN, University of TorontoTorontoCanada
| | - Amira Klip
- Cell Biology Program, The Hospital for Sick ChildrenTorontoCanada
| | - Sheila Riazi
- Malignant Hyperthermia Investigation Unit (MHIU) of the University Health Network (Canada)TorontoCanada
- Department of Anaesthesia & Pain Management, Toronto General Hospital, UHN, University of TorontoTorontoCanada
| | - Eduardo Rios
- Department of Physiology and Biophysics, Rush University Medical CenterChicagoUnited States
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20
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Flucher BE. Skeletal muscle Ca V1.1 channelopathies. Pflugers Arch 2020; 472:739-754. [PMID: 32222817 PMCID: PMC7351834 DOI: 10.1007/s00424-020-02368-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 03/06/2020] [Accepted: 03/17/2020] [Indexed: 12/15/2022]
Abstract
CaV1.1 is specifically expressed in skeletal muscle where it functions as voltage sensor of skeletal muscle excitation-contraction (EC) coupling independently of its functions as L-type calcium channel. Consequently, all known CaV1.1-related diseases are muscle diseases and the molecular and cellular disease mechanisms relate to the dual functions of CaV1.1 in this tissue. To date, four types of muscle diseases are known that can be linked to mutations in the CACNA1S gene or to splicing defects. These are hypo- and normokalemic periodic paralysis, malignant hyperthermia susceptibility, CaV1.1-related myopathies, and myotonic dystrophy type 1. In addition, the CaV1.1 function in EC coupling is perturbed in Native American myopathy, arising from mutations in the CaV1.1-associated protein STAC3. Here, we first address general considerations concerning the possible roles of CaV1.1 in disease and then discuss the state of the art regarding the pathophysiology of the CaV1.1-related skeletal muscle diseases with an emphasis on molecular disease mechanisms.
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Affiliation(s)
- Bernhard E Flucher
- Department of Physiology and Medical Biophysics, Medical University Innsbruck, Schöpfstraße 41, A6020, Innsbruck, Austria.
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21
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Gardner L, Miller DM, Daly C, Gupta PK, House C, Roiz de Sa D, Shaw MA, Hopkins PM. Investigating the genetic susceptibility to exertional heat illness. J Med Genet 2020; 57:531-541. [DOI: 10.1136/jmedgenet-2019-106461] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 11/25/2019] [Accepted: 12/21/2019] [Indexed: 12/16/2022]
Abstract
BackgroundWe aimed to identify rare (minor allele frequency ≤1%), potentially pathogenic non-synonymous variants in a well-characterised cohort with a clinical history of exertional heat illness (EHI) or exertional rhabdomyolysis (ER). The genetic link between malignant hyperthermia (MH) and EHI was investigated due to their phenotypic overlap.MethodsThe coding regions of 38 genes relating to skeletal muscle calcium homeostasis or exercise intolerance were sequenced in 64 patients (mostly military personnel) with a history of EHI, or ER and who were phenotyped using skeletal muscle in vitro contracture tests. We assessed the pathogenicity of variants using prevalence data, in silico analysis, phenotype and segregation evidence and by review of the literature.ResultsWe found 51 non-polymorphic, potentially pathogenic variants in 20 genes in 38 patients. Our data indicate that RYR1 p.T3711M (previously shown to be likely pathogenic for MH susceptibility) and RYR1 p.I3253T are likely pathogenic for EHI. PYGM p.A193S was found in 3 patients with EHI, which is significantly greater than the control prevalence (p=0.000025). We report the second case of EHI in which a missense variant at CACNA1S p.R498 has been found. Combinations of rare variants in the same or different genes are implicated in EHI.ConclusionWe confirm a role of RYR1 in the heritability of EHI as well as ER but highlight the likely genetic heterogeneity of these complex conditions. We propose defects, or combinations of defects, in skeletal muscle calcium homeostasis, oxidative metabolism and membrane excitability are associated with EHI.
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22
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Schiemann AH, Roesl C, Pollock N, Langton E, Bulger T, Stowell KM. Identification and Functional Analysis of RYR1 Variants in a Family with a Suspected Myopathy and Associated Malignant Hyperthermia. J Neuromuscul Dis 2020; 7:51-60. [PMID: 31903994 DOI: 10.3233/jnd-190430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND The ryanodine receptor 1 (RyR1) is a major skeletal muscle calcium release channel located in the sarcoplasmic reticulum and involved in excitation-contraction coupling. Variants in the gene encoding RyR1 have been linked to a range of neuromuscular disorders including myopathies and malignant hyperthermia (MH). OBJECTIVE We have identified three RYR1 variants (c.1983 G>A, p.Trp661*; c.7025A>G, p.Asn2342Ser and c.2447 C>T, p.Pro816Leu) in a family with a suspected myopathy and associated malignant hyperthermia susceptibility. We used calcium release assays to functionally characterise these variants in a recombinant system. METHODS Site-directed mutagenesis was used to introduce each variant separately into the human RYR1 cDNA. HEK293-T cells were transfected with the recombinant constructs and calcium release assays were carried out using 4-chloro-m-cresol (4-CmC) as the RyR1 agonist to investigate the functional consequences of each variant. RESULTS RYR1 c.1983 G>A, p.Trp661* resulted in a non-functional channel, c.7025A>G, p.Asn2342Ser in a hypersensitive channel and c.2447 C>T, p.Pro816Leu in a hypersensitive channel at higher concentrations of 4-CmC. CONCLUSIONS The p.Trp661* RYR1 variant should be considered as a risk factor for myopathies. The p.Asn2342Ser RYR1 variant, when expressed as a compound heterozygote with a nonsense mutation on the second allele, is likely to result in MH-susceptibility. The role of the p.Pro816Leu variant in MH remains unclear.
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Affiliation(s)
- Anja H Schiemann
- School of Fundamental Sciences, Massey University, Manawatu, New Zealand
| | - Cornelia Roesl
- School of Fundamental Sciences, Massey University, Manawatu, New Zealand.,Present address: LifeArc, Nine, Edinburgh BioQuarter, Edinburgh, United Kingdom
| | - Neil Pollock
- Department of Anaesthesia and Intensive Care, Palmerston North Hospital, Manawatu, New Zealand.,Now retired
| | | | - Terasa Bulger
- Department of Anaesthesia and Intensive Care, Palmerston North Hospital, Manawatu, New Zealand
| | - Kathryn M Stowell
- School of Fundamental Sciences, Massey University, Manawatu, New Zealand
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Yang L, Tautz T, Zhang S, Fomina A, Liu H. The current status of malignant hyperthermia. J Biomed Res 2020; 34:75-85. [PMID: 32305961 DOI: 10.7555/jbr.33.20180089] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Malignant hyperthermia (MH) is a rare and life-threatening pharmacogenetic disorder triggered by volatile anesthetics, the depolarizing muscle relaxant succinylcholine, and rarely by strenuous exercise or environmental heat. The exact prevalence of MH is unknown, and it varies from 1:16 000 in Denmark to 1:100 000 in New York State. The underlying mechanism of MH is excessive calcium release from the sarcoplasmic reticulum (SR), leading to uncontrolled skeletal muscle hyper-metabolism. Genetic mutations in ryanodine receptor type 1 ( RYR1) and CACNA1S have been identified in approximately 50% to 86% and 1% of MH-susceptible (MHS) individuals, respectively. Classic clinical symptoms of MH include hypercarbia, sinus tachycardia, masseter spasm, hyperthermia, acidosis, muscle rigidity, hyperkalemia, myoglobinuria, and etc. There are two types of testing for MH: a genetic test and a contracture test. Contracture testing is still being considered as the gold standard for MH diagnosis. Dantrolene is the only available drug approved for the treatment of MH through suppressing the calcium release from SR. Since clinical symptoms of MH are highly variable, it can be difficult to establish a diagnosis of MH. Nevertheless, prompt diagnosis and treatments are crucial to avoid a fatal outcome. Therefore, it is very important for anesthesiologists to raise awareness and understand the characteristics of MH. This review summarizes epidemiology, clinical symptoms, diagnosis and treatments of MH and any new developments.
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Affiliation(s)
- Lukun Yang
- Department of Anesthesiology, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong 519000, China;Department of Anesthesiology and Pain Medicine, University of California Davis Health, Sacramento, CA 95817, USA
| | - Timothy Tautz
- Department of Anesthesiology and Pain Medicine, University of California Davis Health, Sacramento, CA 95817, USA
| | - Shulin Zhang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Kentucky, Lexington, KY 40506, USA
| | - Alla Fomina
- Department of Physiology and Membrane Biology, University of California Davis Health, Sacramento, CA 95817, USA
| | - Hong Liu
- Department of Anesthesiology and Pain Medicine, University of California Davis Health, Sacramento, CA 95817, USA
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25
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Affiliation(s)
- Kyeong Seon M Kim
- UC Davis Department of Anesthesiology and Pain Medicine, UC Davis Medical Center, PSSB Suite 1200, Sacramento, CA 95817, USA
| | - Robert Scott Kriss
- UC Davis Department of Anesthesiology and Pain Medicine, UC Davis Medical Center, PSSB Suite 1200, Sacramento, CA 95817, USA
| | - Timothy J Tautz
- UC Davis Department of Anesthesiology and Pain Medicine, UC Davis Medical Center, PSSB Suite 1200, Sacramento, CA 95817, USA.
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An Assessment of Penetrance and Clinical Expression of Malignant Hyperthermia in Individuals Carrying Diagnostic Ryanodine Receptor 1 Gene Mutations. Anesthesiology 2019; 131:983-991. [PMID: 31206373 PMCID: PMC9912949 DOI: 10.1097/aln.0000000000002813] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND Malignant hyperthermia (MH) is a potentially lethal disorder triggered by certain anesthetics. Mutations in the ryanodine receptor 1 (RYR1) gene account for about half of MH cases. Discordance between the low incidence of MH and a high prevalence of mutations has been attributed to incomplete penetrance, which has not been quantified yet. The authors aimed to examine penetrance of MH-diagnostic RYR1 mutations and the likelihood of mutation carriers to develop MH, and to identify factors affecting severity of MH clinical expression. METHODS In this multicenter case-control study, data from 125 MH pedigrees between 1994 and 2017 were collected from four European registries and one Canadian registry. Probands (survivors of MH reaction) and their relatives with at least one exposure to anesthetic triggers, carrying one diagnostic RYR1 mutation, were included. Penetrance (percentage of probands among all genotype-positive) and the probability of a mutation carrier to develop MH were obtained. MH onset time and Clinical Grading Scale score were used to assess MH reaction severity. RESULTS The overall penetrance of nine RYR1 diagnostic mutations was 40.6% (93 of 229), without statistical differences among mutations. Likelihood to develop MH on exposure to triggers was 0.25 among all RYR1 mutation carriers, and 0.76 in probands (95% CI of the difference 0.41 to 0.59). Penetrance in males was significantly higher than in females (50% [62 of 124] vs. 29.7% [30 of 101]; P = 0.002). Males had increased odds of developing MH (odds ratio, 2.37; 95% CI, 1.36 to 4.12) despite similar levels of exposure to trigger anesthetics. Proband's median age was 12 yr (interquartile range 6 to 32.5). CONCLUSIONS Nine MH-diagnostic RYR1 mutations have sex-dependent incomplete penetrance, whereas MH clinical expression is influenced by patient's age and the type of anesthetic. Our quantitative evaluation of MH penetrance reinforces the notion that a previous uneventful anesthetic does not preclude the possibility of developing MH.
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Sadhasivam S, Brandom BW, Henker RA, McAuliffe JJ. Bayesian modeling to predict malignant hyperthermia susceptibility and pathogenicity of RYR1, CACNA1S and STAC3 variants. Pharmacogenomics 2019; 20:989-1003. [PMID: 31559918 PMCID: PMC7006767 DOI: 10.2217/pgs-2019-0055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 07/17/2019] [Indexed: 11/21/2022] Open
Abstract
Aim: Identify variants in RYR1, CACNA1S and STAC3, and predict malignant hyperthermia (MH) pathogenicity using Bayesian statistics in individuals clinically treated as MH susceptible (MHS). Materials & methods: Whole exome sequencing including RYR1, CACNA1S and STAC3 performed on 64 subjects with: MHS; suspected MH event or first-degree relative; and MH negative. Variant pathogenicity was estimated using in silico analysis, allele frequency and prior data to calculate Bayesian posterior probabilities. Results: Bayesian statistics predicted CACNA1S variant p.Thr1009Lys and RYR1 variants p.Ser1728Phe and p.Leu4824Pro are likely pathogenic, and novel STAC3 variant p.Met187Thr has uncertain significance. Nearly a third of MHS subjects had only benign variants. Conclusion: Bayesian method provides new approach to predict MH pathogenicity of genetic variants.
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Affiliation(s)
- Senthilkumar Sadhasivam
- Department of Anesthesia, Riley Hospital for Children at Indiana University Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Barbara W Brandom
- The North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States (MHAUS), Department of Nurse Anesthesia, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Richard A Henker
- The North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States (MHAUS), Department of Nurse Anesthesia, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - John J McAuliffe
- Department of Anesthesia, Cincinnati Children's Hospital Medical Center, The University of Cincinnati, Cincinnati, OH 45229, USA
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Abstract
Congenital myopathies (CM) are a genetically heterogeneous group of neuromuscular disorders most commonly presenting with neonatal/childhood-onset hypotonia and muscle weakness, a relatively static or slowly progressive disease course, and originally classified into subcategories based on characteristic histopathologic findings in muscle biopsies. This enduring concept of disease definition and classification based on the clinicopathologic phenotype was pioneered in the premolecular era. Advances in molecular genetics have brought into focus the increased blurring of the original seemingly "watertight" categories through broadening of the clinical phenotypes in existing genes, and continuous identification of novel genetic backgrounds. This review summarizes the histopathologic landscape of the 4 "classical" subtypes of CM-nemaline myopathies, core myopathies, centronuclear myopathies, and congenital fiber type disproportion and some of the emerging and novel genetic diseases with a CM presentation.
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Affiliation(s)
- Rahul Phadke
- Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children and Division of Neuropathology, National Hospital for Neurology and Neurosurgery, London, UK; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
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29
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Merritt A, Booms P, Shaw MA, Miller DM, Daly C, Bilmen JG, Stowell KM, Allen PD, Steele DS, Hopkins PM. Assessing the pathogenicity of RYR1 variants in malignant hyperthermia. Br J Anaesth 2018; 118:533-543. [PMID: 28403410 DOI: 10.1093/bja/aex042] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/31/2017] [Indexed: 12/16/2022] Open
Abstract
Background . Missense variants in the ryanodine receptor 1 gene ( RYR1 ) are associated with malignant hyperthermia but only a minority of these have met the criteria for use in predictive DNA diagnosis. We examined the utility of a simplified method of segregation analysis and a functional assay for determining the pathogenicity of recurrent RYR1 variants associated with malignant hyperthermia. Methods . We identified previously uncharacterised RYR1 variants found in four or more malignant hyperthermia families and conducted simplified segregation analyses. An efficient cloning and mutagenesis strategy was used to express ryanodine receptor protein containing one of six RYR1 variants in HEK293 cells. Caffeine-induced calcium release, measured using a fluorescent calcium indicator, was compared in cells expressing each variant to that in cells expressing wild type ryanodine receptor protein. Results. We identified 43 malignant hyperthermia families carrying one of the six RYR1 variants. There was segregation of genotype with the malignant hyperthermia susceptibility phenotype in families carrying the p.E3104K and p.D3986E variants, but the number of informative meioses limited the statistical significance of the associations. HEK293 functional assays demonstrated an increased sensitivity of RyR1 channels containing the p.R2336H, p.R2355W, p.E3104K, p.G3990V and p.V4849I compared with wild type, but cells expressing p.D3986E had a similar caffeine sensitivity to cells expressing wild type RyR1. Conclusions . Segregation analysis is of limited value in assessing pathogenicity of RYR1 variants in malignant hyperthermia. Functional analyses in HEK293 cells provided evidence to support the use of p.R2336H, p.R2355W, p.E3104K, p.G3990V and p.V4849I for diagnostic purposes but not p.D3986E.
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Affiliation(s)
- A Merritt
- Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, UK
| | - P Booms
- Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, UK
| | - M-A Shaw
- Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, UK
| | - D M Miller
- Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, UK.,Malignant Hyperthermia Unit, St James's University Hospital, Leeds, UK
| | - C Daly
- Malignant Hyperthermia Unit, St James's University Hospital, Leeds, UK
| | - J G Bilmen
- Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, UK.,Malignant Hyperthermia Unit, St James's University Hospital, Leeds, UK
| | - K M Stowell
- Institute of Fundamental Sciences, Massey University, Palmerston North, New Zealand
| | - P D Allen
- Department of Molecular Biosciences, UC Davis, Davis, CA, USA
| | - D S Steele
- School of Biomedical Sciences, University of Leeds, Leeds, UK
| | - P M Hopkins
- Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, UK.,Malignant Hyperthermia Unit, St James's University Hospital, Leeds, UK
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30
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Isackson PJ, Wang J, Zia M, Spurgeon P, Levesque A, Bard J, James S, Nowak N, Lee TK, Vladutiu GD. RYR1 and CACNA1S genetic variants identified with statin-associated muscle symptoms. Pharmacogenomics 2018; 19:1235-1249. [PMID: 30325262 PMCID: PMC6563124 DOI: 10.2217/pgs-2018-0106] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 08/31/2018] [Indexed: 11/21/2022] Open
Abstract
AIM To examine the genetic differences between subjects with statin-associated muscle symptoms and statin-tolerant controls. MATERIALS & METHODS Next-generation sequencing was used to characterize the exomes of 76 subjects with severe statin-associated muscle symptoms and 50 statin-tolerant controls. RESULTS 12 probably pathogenic variants were found within the RYR1 and CACNA1S genes in 16% of cases with severe statin-induced myopathy representing a fourfold increase over variants found in statin-tolerant controls. Subjects with probably pathogenic RYR1 or CACNA1S variants had plasma CK 5X to more than 400X the upper limit of normal in addition to having muscle symptoms. CONCLUSIONS Genetic variants within the RYR1 and CACNA1S genes are likely to be a major contributor to the susceptibility to statin-associated muscle symptoms.
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Affiliation(s)
- Paul J Isackson
- Department of Pediatrics, State University of New York at Buffalo, NY 14203, USA
| | - Jianxin Wang
- Center for Computational Research, State University of New York at Buffalo, NY 14203, USA
| | - Mohammad Zia
- Center for Computational Research, State University of New York at Buffalo, NY 14203, USA
| | - Paul Spurgeon
- Center for Computational Research, State University of New York at Buffalo, NY 14203, USA
| | - Adrian Levesque
- Center for Computational Research, State University of New York at Buffalo, NY 14203, USA
| | - Jonathan Bard
- Center for Computational Research, State University of New York at Buffalo, NY 14203, USA
| | - Smitha James
- New York State Center of Excellence in Bioinformatics & Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203, USA
| | - Norma Nowak
- New York State Center of Excellence in Bioinformatics & Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203, USA
- Department of Biochemistry, Jacobs School of Medicine & Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14203, USA
| | - Tae Keun Lee
- Department of Pediatrics, State University of New York at Buffalo, NY 14203, USA
| | - Georgirene D Vladutiu
- Department of Pediatrics, State University of New York at Buffalo, NY 14203, USA
- Departments of Neurology & Pathology & Anatomical Sciences, University at Buffalo, Buffalo, NY 14214, USA
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31
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Role of STIM1/ORAI1-mediated store-operated Ca 2+ entry in skeletal muscle physiology and disease. Cell Calcium 2018; 76:101-115. [PMID: 30414508 DOI: 10.1016/j.ceca.2018.10.004] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 10/23/2018] [Accepted: 10/23/2018] [Indexed: 11/23/2022]
Abstract
Store-operated Ca2+ entry (SOCE) is a Ca2+ entry mechanism activated by depletion of intracellular Ca2+ stores. In skeletal muscle, SOCE is mediated by an interaction between stromal-interacting molecule-1 (STIM1), the Ca2+ sensor of the sarcoplasmic reticulum, and ORAI1, the Ca2+-release-activated-Ca2+ (CRAC) channel located in the transverse tubule membrane. This review focuses on the molecular mechanisms and physiological role of SOCE in skeletal muscle, as well as how alterations in STIM1/ORAI1-mediated SOCE contribute to muscle disease. Recent evidence indicates that SOCE plays an important role in both muscle development/growth and fatigue. The importance of SOCE in muscle is further underscored by the discovery that loss- and gain-of-function mutations in STIM1 and ORAI1 result in an eclectic array of disorders with clinical myopathy as central defining component. Despite differences in clinical phenotype, all STIM1/ORAI1 gain-of-function mutations-linked myopathies are characterized by the abnormal accumulation of intracellular membranes, known as tubular aggregates. Finally, dysfunctional STIM1/ORAI1-mediated SOCE also contributes to the pathogenesis of muscular dystrophy, malignant hyperthermia, and sarcopenia. The picture to emerge is that tight regulation of STIM1/ORAI1-dependent Ca2+ signaling is critical for optimal skeletal muscle development/function such that either aberrant increases or decreases in SOCE activity result in muscle dysfunction.
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32
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Hering S, Zangerl-Plessl EM, Beyl S, Hohaus A, Andranovits S, Timin EN. Calcium channel gating. Pflugers Arch 2018; 470:1291-1309. [PMID: 29951751 PMCID: PMC6096772 DOI: 10.1007/s00424-018-2163-7] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 05/28/2018] [Accepted: 05/30/2018] [Indexed: 12/11/2022]
Abstract
Tuned calcium entry through voltage-gated calcium channels is a key requirement for many cellular functions. This is ensured by channel gates which open during membrane depolarizations and seal the pore at rest. The gating process is determined by distinct sub-processes: movement of voltage-sensing domains (charged S4 segments) as well as opening and closure of S6 gates. Neutralization of S4 charges revealed that pore opening of CaV1.2 is triggered by a "gate releasing" movement of all four S4 segments with activation of IS4 (and IIIS4) being a rate-limiting stage. Segment IS4 additionally plays a crucial role in channel inactivation. Remarkably, S4 segments carrying only a single charged residue efficiently participate in gating. However, the complete set of S4 charges is required for stabilization of the open state. Voltage clamp fluorometry, the cryo-EM structure of a mammalian calcium channel, biophysical and pharmacological studies, and mathematical simulations have all contributed to a novel interpretation of the role of voltage sensors in channel opening, closure, and inactivation. We illustrate the role of the different methodologies in gating studies and discuss the key molecular events leading CaV channels to open and to close.
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Affiliation(s)
- S Hering
- Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, 1090, Vienna, Austria.
| | - E-M Zangerl-Plessl
- Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, 1090, Vienna, Austria
| | - S Beyl
- Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, 1090, Vienna, Austria
| | - A Hohaus
- Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, 1090, Vienna, Austria
| | - S Andranovits
- Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, 1090, Vienna, Austria
| | - E N Timin
- Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, 1090, Vienna, Austria
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33
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Genetic epidemiology of malignant hyperthermia in the UK. Br J Anaesth 2018; 121:944-952. [PMID: 30236257 DOI: 10.1016/j.bja.2018.06.028] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Revised: 06/01/2018] [Accepted: 06/20/2018] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Gaps in our understanding of genetic susceptibility to malignant hyperthermia (MH) limit the application and interpretation of genetic diagnosis of the condition. Our aim was to define the prevalence and role of variants in the three genes implicated in MH susceptibility in the largest comprehensively phenotyped MH cohort worldwide. METHODS We initially included one individual from each positive family tested in the UK MH Unit since 1971 to detect variants in RYR1, CACNA1S, or STAC3. Screening for genetic variants has been ongoing since 1991 and has involved a range of techniques, most recently next generation sequencing. We assessed the pathogenicity of variants using standard guidelines, including family segregation studies. The prevalence of recurrent variants of unknown significance was compared with the prevalence reported in a large database of sequence variants in low-risk populations. RESULTS We have confirmed MH susceptibility in 795 independent families, for 722 of which we have a DNA sample. Potentially pathogenic variants were found in 555 families, with 25 RYR1 and one CACNA1S variants previously unclassified recurrent variants significantly over-represented (P<1×10-7) in our cohort compared with the Exome Aggregation Consortium database. There was genotype-phenotype discordance in 86 of 328 families suitable for segregation analysis. We estimate non-RYR1/CACNA1S/STAC3 susceptibility occurs in 14-23% of MH families. CONCLUSIONS Our data provide current estimates of the role of variants in RYR1, CACNA1S, and STAC3 in susceptibility to MH in a predominantly white European population.
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34
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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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35
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Perez CF, Eltit JM, Lopez JR, Bodnár D, Dulhunty AF, Aditya S, Casarotto MG. Functional and structural characterization of a novel malignant hyperthermia-susceptible variant of DHPR-β 1a subunit (CACNB1). Am J Physiol Cell Physiol 2017; 314:C323-C333. [PMID: 29212769 DOI: 10.1152/ajpcell.00187.2017] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Malignant hyperthermia (MH) susceptibility has been recently linked to a novel variant of β1a subunit of the dihydropyridine receptor (DHPR), a channel essential for Ca2+ regulation in skeletal muscle. Here we evaluate the effect of the mutant variant V156A on the structure/function of DHPR β1a subunit and assess its role on Ca2+ metabolism of cultured myotubes. Using differential scanning fluorimetry, we show that mutation V156A causes a significant reduction in thermal stability of the Src homology 3/guanylate kinase core domain of β1a subunit. Expression of the variant subunit in β1-null mouse myotubes resulted in increased sensitivity to caffeine stimulation. Whole cell patch-clamp analysis of β1a-V156A-expressing myotubes revealed a -2 mV shift in voltage dependence of channel activation, but no changes in Ca2+ conductance, current kinetics, or sarcoplasmic reticulum Ca2+ load were observed. Measurement of resting free Ca2+ and Na+ concentrations shows that both cations were significantly elevated in β1a-V156A-expressing myotubes and that these changes were linked to increased rates of plasmalemmal Ca2+ entry through Na+/Ca2+ exchanger and/or transient receptor potential canonical channels. Overall, our data show that mutant variant V156A results in instability of protein subdomains of β1a subunit leading to a phenotype of Ca2+ dysregulation that partly resembles that of other MH-linked mutations of DHPR α1S subunit. These data prove that homozygous expression of variant β1a-V156A has the potential to be a pathological variant, although it may require other gene defects to cause a full MH phenotype.
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Affiliation(s)
- Claudio F Perez
- Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts
| | - Jose M Eltit
- Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University , Richmond, Virginia
| | - Jose R Lopez
- Department of Molecular Biosciences, University of California , Davis, California
| | - Dóra Bodnár
- Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts
| | - Angela F Dulhunty
- John Curtin School of Medical Research, Australian National University , Canberra , Australia
| | - Shouvik Aditya
- John Curtin School of Medical Research, Australian National University , Canberra , Australia
| | - Marco G Casarotto
- John Curtin School of Medical Research, Australian National University , Canberra , Australia
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36
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Monteleone S, Lieb A, Pinggera A, Negro G, Fuchs JE, Hofer F, Striessnig J, Tuluc P, Liedl KR. Mechanisms Responsible for ω-Pore Currents in Ca v Calcium Channel Voltage-Sensing Domains. Biophys J 2017; 113:1485-1495. [PMID: 28978442 PMCID: PMC5627182 DOI: 10.1016/j.bpj.2017.08.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 06/28/2017] [Accepted: 08/07/2017] [Indexed: 12/27/2022] Open
Abstract
Mutations of positively charged amino acids in the S4 transmembrane segment of a voltage-gated ion channel form ion-conducting pathways through the voltage-sensing domain, named ω-current. Here, we used structure modeling and MD simulations to predict pathogenic ω-currents in CaV1.1 and CaV1.3 Ca2+ channels bearing several S4 charge mutations. Our modeling predicts that mutations of CaV1.1-R1 (R528H/G, R897S) or CaV1.1-R2 (R900S, R1239H) linked to hypokalemic periodic paralysis type 1 and of CaV1.3-R3 (R990H) identified in aldosterone-producing adenomas conducts ω-currents in resting state, but not during voltage-sensing domain activation. The mechanism responsible for the ω-current and its amplitude depend on the number of charges in S4, the position of the mutated S4 charge and countercharges, and the nature of the replacing amino acid. Functional characterization validates the modeling prediction showing that CaV1.3-R990H channels conduct ω-currents at hyperpolarizing potentials, but not upon membrane depolarization compared with wild-type channels.
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Affiliation(s)
- Stefania Monteleone
- Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innsbruck, Austria
| | - Andreas Lieb
- Department of Pharmacology and Toxicology, Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria; Institute of Neurology, University College London, London, United Kingdom
| | - Alexandra Pinggera
- Department of Pharmacology and Toxicology, Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria; Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
| | - Giulia Negro
- Department of Pharmacology and Toxicology, Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria
| | - Julian E Fuchs
- Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innsbruck, Austria
| | - Florian Hofer
- Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innsbruck, Austria
| | - Jörg Striessnig
- Department of Pharmacology and Toxicology, Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria
| | - Petronel Tuluc
- Department of Pharmacology and Toxicology, Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria.
| | - Klaus R Liedl
- Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innsbruck, Austria.
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Mullins MF. Malignant Hyperthermia: A Review. J Perianesth Nurs 2017; 33:582-589. [PMID: 30236564 DOI: 10.1016/j.jopan.2017.04.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2015] [Revised: 03/19/2017] [Accepted: 04/02/2017] [Indexed: 02/06/2023]
Abstract
Malignant hyperthermia is an uncommon, but potentially lethal condition that may be encountered during the perioperative period. There is wide variability in the manner in which malignant hyperthermia may manifest. For a patient to survive a malignant hyperthermia crisis, prompt recognition and treatment is of paramount importance. Perioperative nurses play a pivotal role in the successful management of malignant hyperthermia. The fictitious case study presented in this paper describes the identification, presentation, pathophysiology, and treatment of a general anesthesia patient with fulminant malignant hyperthermia.
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Michelucci A, Paolini C, Boncompagni S, Canato M, Reggiani C, Protasi F. Strenuous exercise triggers a life-threatening response in mice susceptible to malignant hyperthermia. FASEB J 2017; 31:3649-3662. [PMID: 28465322 DOI: 10.1096/fj.201601292r] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 04/17/2017] [Indexed: 12/26/2022]
Abstract
In humans, hyperthermic episodes can be triggered by halogenated anesthetics [malignant hyperthermia (MH) susceptibility] and by high temperature [environmental heat stroke (HS)]. Correlation between MH susceptibility and HS is supported by extensive work in mouse models that carry a mutation in ryanodine receptor type-1 (RYR1Y522S/WT) and calsequestrin-1 knockout (CASQ1-null), 2 proteins that control Ca2+ release in skeletal muscle. As overheating episodes in humans have also been described during exertion, here we subjected RYR1Y522S/WT and CASQ1-null mice to an exertional-stress protocol (incremental running on a treadmill at 34°C and 40% humidity). The mortality rate was 80 and 78.6% in RYR1Y522S/WT and CASQ1-null mice, respectively, vs. 0% in wild-type mice. Lethal crises were characterized by hyperthermia and rhabdomyolysis, classic features of MH episodes. Of importance, pretreatment with azumolene, an analog of the drug used in humans to treat MH crises, reduced mortality to 0 and 12.5% in RYR1Y522S/WT and CASQ1-null mice, respectively, thanks to a striking reduction of hyperthermia and rhabdomyolysis. At the molecular level, azumolene strongly prevented Ca2+-dependent activation of calpains and NF-κB by lowering myoplasmic Ca2+ concentration and nitro-oxidative stress, parameters that were elevated in RYR1Y522S/WT and CASQ1-null mice. These results suggest that common molecular mechanisms underlie MH crises and exertional HS in mice.-Michelucci, A., Paolini, C., Boncompagni, S., Canato, M., Reggiani, C., Protasi, F. Strenuous exercise triggers a life-threatening response in mice susceptible to malignant hyperthermia.
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Affiliation(s)
- Antonio Michelucci
- Center for Research on Ageing and Translational Medicine (CeSI-MeT), Department of Neuroscience, Imaging, and Clinical Sciences (DNICS), Università degli Studi G. d'Annunzio, Chieti, Italy
| | - Cecilia Paolini
- Center for Research on Ageing and Translational Medicine (CeSI-MeT), Department of Neuroscience, Imaging, and Clinical Sciences (DNICS), Università degli Studi G. d'Annunzio, Chieti, Italy
| | - Simona Boncompagni
- Center for Research on Ageing and Translational Medicine (CeSI-MeT), Department of Neuroscience, Imaging, and Clinical Sciences (DNICS), Università degli Studi G. d'Annunzio, Chieti, Italy
| | - Marta Canato
- Department of Biomedical Sciences, University of Padova, Padua, Italy
| | - Carlo Reggiani
- Department of Biomedical Sciences, University of Padova, Padua, Italy
| | - Feliciano Protasi
- Center for Research on Ageing and Translational Medicine (CeSI-MeT), Department of Neuroscience, Imaging, and Clinical Sciences (DNICS), Università degli Studi G. d'Annunzio, Chieti, Italy; .,Department of Medicine and Aging Science, University G. d' Annunzio of Chieti, Chieti, Italy
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39
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Prevalence of malignant hyperthermia diagnosis in hospital discharge records in California, Florida, New York, and Wisconsin. J Clin Anesth 2017; 39:10-14. [PMID: 28494877 DOI: 10.1016/j.jclinane.2017.03.016] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Revised: 03/03/2017] [Accepted: 03/07/2017] [Indexed: 01/14/2023]
Abstract
STUDY OBJECTIVE Malignant hyperthermia (MH) is a rare yet potentially fatal pharmacogenetic disorder triggered by exposure to inhalational anesthetics and the depolarizing neuromuscular blocking agent succinylcholine. Epidemiologic data on the geographic variation in MH prevalence is scant. The objective of this study is to examine the prevalence of recorded MH diagnosis in patients discharged from hospitals in four states in the United States. DESIGN Observational study. SETTING Healthcare Cost and Utilization Project (HCUP) State Inpatient Database (SID) for California (2011), Florida (2011), New York (2012) and Wisconsin (2012). PATIENTS A total of 164 hospital discharges that had a recorded diagnosis of MH using the International Classification of Disease, 9th Revision, Clinical Modification code 995.86. METHODS MH prevalence was assessed by patient demographic and clinical characteristics. MAIN RESULTS The prevalence of MH per 100,000 hospital discharges ranged from 1.23 (95% Confidence Interval [CI], 0.80-1.66) in New York to 1.91 (95% CI, 1.48-2.34) in California, and the prevalence of MH per 100,000 surgical discharges ranged from 1.47 (95% CI, 0.93-2.02) in New York to 2.86 (95% CI, 2.00-3.71) in Florida. The prevalence of MH in male patients was more than twice the prevalence in female patients. Of the 164 patients with MH diagnosis, 11% were dead on discharge. CONCLUSIONS There exists a modest variation in the prevalence of recorded MH diagnosis in hospital discharges in California, Florida, New York and Wisconsin. Epidemiologic patterns of MH diagnosis in hospital discharges appear to be similar across the four states. Further research is needed to better understand the geographic variation and contributing factors of MH in different populations.
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Levano S, Gonzalez A, Singer M, Demougin P, Rüffert H, Urwyler A, Girard T. Resequencing array for gene variant detection in malignant hyperthermia and butyrylcholinestherase deficiency. Neuromuscul Disord 2017; 27:492-499. [PMID: 28259615 DOI: 10.1016/j.nmd.2017.02.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 12/20/2016] [Accepted: 02/15/2017] [Indexed: 11/30/2022]
Abstract
Malignant hyperthermia (MH) and butyrylcholinestherase (BCHE) deficiency are two relevant pharmacogenetic disorders in anesthetic practice linked with sequence variants, the former in the RyR1 and CACNA1S genes, the latter in the BCHE gene. Genotyping for known pathogenic variants in these genes is useful to help identify susceptible individuals, and others may exist but remain unknown, because full-length sequence of these genes is, in general, not investigated. To facilitate this task, we developed a resequencing DNA array, the perioperative patient safety (POPS) array, to be able to screen the entire coding sequences of the RyR1, CACNA1S and BCHE genes. MH-susceptible individuals (n = 121) identified with the in vitro contracture test, the standard diagnostic tool for MH susceptibility, were genotyped with the arrays. Compared with capillary sequencing, call rates with the arrays could achieve 100% at maximal sensitivity, although to reduce false positive rates, sensitivity was adjusted to 0.85, 0.87 and 0.66 for RyR1, CACNA1S and BCHE respectively, with overall base call specificity exceeding 99%. Detection of 29 predetermined RyR1 variants in 44 individuals was successful in 97% of the cases, among them all 16 variants of established diagnostic value. In a trial application of the arrays, 21 MH-susceptible subjects with no known RyR1 or CACNA1S variants were screened, resulting in the discovery of new variants, all confirmed by capillary sequencing. In conclusion, arrays offer an efficient high-throughput alternative for diagnostic genotyping of candidate genes affecting MH susceptibility, BCHE deficiency and other neuromuscular disorders, simultaneously enabling a comprehensive search for rare variants in these genes.
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Affiliation(s)
- Soledad Levano
- Department of Biomedicine, University Hospital Basel, Switzerland; Department Anesthesiology, University Hospital Basel, Switzerland
| | - Asensio Gonzalez
- Department of Biomedicine, University Hospital Basel, Switzerland; Department Anesthesiology, University Hospital Basel, Switzerland.
| | - Martine Singer
- Department of Biomedicine, University Hospital Basel, Switzerland; Department Anesthesiology, University Hospital Basel, Switzerland
| | - Philippe Demougin
- Biozentrum, Life Sciences Training Facility, University of Basel, Switzerland
| | - Henrik Rüffert
- University of Leipzig, Helios Kliniken Leipziger Land Leipzig, Germany
| | - Albert Urwyler
- Department of Biomedicine, University Hospital Basel, Switzerland; Department Anesthesiology, University Hospital Basel, Switzerland
| | - Thierry Girard
- Department of Biomedicine, University Hospital Basel, Switzerland; Department Anesthesiology, University Hospital Basel, Switzerland
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Heytens K, De Bleecker J, Verbrugghe W, Baets J, Heytens L. Exertional rhabdomyolysis and heat stroke: Beware of volatile anesthetic sedation. World J Crit Care Med 2017; 6:21-27. [PMID: 28224104 PMCID: PMC5295166 DOI: 10.5492/wjccm.v6.i1.21] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 09/27/2016] [Accepted: 11/17/2016] [Indexed: 02/06/2023] Open
Abstract
In view of the enormous popularity of mass sporting events such as half-marathons, the number of patients with exertional rhabdomyolysis or exercise-induced heat stroke admitted to intensive care units (ICUs) has increased over the last decade. Because these patients have been reported to be at risk for malignant hyperthermia during general anesthesia, the intensive care community should bear in mind that the same risk of life-threatening rhabdomyolysis is present when these patients are admitted to an ICU, and volatile anesthetic sedation is chosen as the sedative technique. As illustrated by the three case studies we elaborate upon, a thorough diagnostic work-up is needed to clarify the subsequent risk of strenuous exercise, and the anesthetic exposure to volatile agents in these patients and their families. Other contraindications for the use of volatile intensive care sedation consist of known malignant hyperthermia susceptibility, congenital myopathies, Duchenne muscular dystrophy, and intracranial hypertension.
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Muscular body build and male sex are independently associated with malignant hyperthermia susceptibility. Can J Anaesth 2017; 64:396-401. [DOI: 10.1007/s12630-017-0815-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 11/05/2016] [Accepted: 01/01/2017] [Indexed: 10/20/2022] Open
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Beam TA, Loudermilk EF, Kisor DF. Pharmacogenetics and pathophysiology of CACNA1S mutations in malignant hyperthermia. Physiol Genomics 2016; 49:81-87. [PMID: 28011884 DOI: 10.1152/physiolgenomics.00126.2016] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 12/14/2016] [Indexed: 12/27/2022] Open
Abstract
A review of the pharmacogenetics (PGt) and pathophysiology of calcium voltage-gated channel subunit alpha1 S (CACNA1S) mutations in malignant hyperthermia susceptibility type 5 (MHS5; MIM #60188) is presented. Malignant hyperthermia (MH) is a life-threatening hypermetabolic state of skeletal muscle usually induced by volatile, halogenated anesthetics and/or the depolarizing neuromuscular blocker succinylcholine. In addition to ryanodine receptor 1 (RYR1) mutations, several CACNA1S mutations are known to be risk factors for increased susceptibility to MH (MHS). However, the presence of these pathogenic CACNA1S gene variations cannot be used to positively predict MH since the condition is genetically heterogeneous with variable expression and incomplete penetrance. At present, one or at most six CACNA1S mutations display significant linkage or association either to clinically diagnosed MH or to MHS as determined by contracture testing. Additional pathogenic variants in CACNA1S, either alone or in combination with genes affecting Ca2+ homeostasis, are likely to be discovered in association to MH as whole exome sequencing becomes more commonplace.
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Affiliation(s)
- Teresa A Beam
- Department of Pharmaceutical Sciences, Manchester University College of Pharmacy, Natural and Health Sciences, Fort Wayne, Indiana; and
| | - Emily F Loudermilk
- Department of Pharmaceutical and Biomedical Sciences, Ohio Northern University, College of Pharmacy, Ada, Ohio
| | - David F Kisor
- Department of Pharmaceutical Sciences, Manchester University College of Pharmacy, Natural and Health Sciences, Fort Wayne, Indiana; and
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Abstract
Malignant hyperthermia is a life-threatening disorder caused by exposure to certain anesthetics. Prompt recognition and intervention is crucial. This article focuses on preoperative patient screening as well as perioperative and postoperative recognition and management.
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Bannister RA. Bridging the myoplasmic gap II: more recent advances in skeletal muscle excitation-contraction coupling. ACTA ACUST UNITED AC 2016; 219:175-82. [PMID: 26792328 DOI: 10.1242/jeb.124123] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
In skeletal muscle, excitation-contraction (EC) coupling relies on the transmission of an intermolecular signal from the voltage-sensing regions of the L-type Ca(2+) channel (Ca(V)1.1) in the plasma membrane to the channel pore of the type 1 ryanodine receptor (RyR1) nearly 10 nm away in the membrane of the sarcoplasmic reticulum (SR). Even though the roles of Ca(V)1.1 and RyR1 as voltage sensor and SR Ca(2+) release channel, respectively, have been established for nearly 25 years, the mechanism underlying communication between these two channels remains undefined. In the course of this article, I will review current viewpoints on this topic with particular emphasis on recent studies.
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Affiliation(s)
- Roger A Bannister
- Department of Medicine-Cardiology Division, University of Colorado Denver-Anschutz Medical Campus, 12700 East 19th Avenue, Room 8006, B-139, Aurora, CO 80045, USA
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Lavorato M, Gupta PK, Hopkins PM, Franzini-Armstrong C. Skeletal Muscle Microalterations in Patients Carrying Malignant Hyperthermia-Related Mutations of the e-c Coupling Machinery. Eur J Transl Myol 2016; 26:6105. [PMID: 28078069 PMCID: PMC5220216 DOI: 10.4081/ejtm.2016.6105] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
We have compared the ultrastructure of skeletal muscle biopsies from patients that have survived a [Malignant Hyperthermia, MH] episode and siblings that test positive for MH susceptibility with those from siblings that tested negatives. The aim is to establish whether life long exposure to the MH-related mutation effects may result in subtle abnormalities even in the absence of active episodes and/or clinically detectable deficiencies. Although a specific ultrastructural signature for MH mutants cannot be demonstrated, an MH related pattern of minor alterations does exist. These include the tendency for micro damage to the contractile apparatus and a higher than normal level of mitochondrial abnormalities.
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Affiliation(s)
- Manuela Lavorato
- Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine , Philadelphia PA, USA
| | - Pawan K Gupta
- Malignant Hyperthermia Unit, Leeds Institute of Biomedical and Clinical Sciences, St James's University Hospital , Leeds, UK
| | - Philip M Hopkins
- Malignant Hyperthermia Unit, Leeds Institute of Biomedical and Clinical Sciences, St James's University Hospital , Leeds, UK
| | - Clara Franzini-Armstrong
- Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine , Philadelphia PA, USA
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Treves S, Jungbluth H, Voermans N, Muntoni F, Zorzato F. Ca 2+ handling abnormalities in early-onset muscle diseases: Novel concepts and perspectives. Semin Cell Dev Biol 2016; 64:201-212. [PMID: 27427513 DOI: 10.1016/j.semcdb.2016.07.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Accepted: 07/14/2016] [Indexed: 12/17/2022]
Abstract
The physiological process by which Ca2+ is released from the sarcoplasmic reticulum is called excitation-contraction coupling; it is initiated by an action potential which travels deep into the muscle fiber where it is sensed by the dihydropyridine receptor, a voltage sensing L-type Ca2+channel localized on the transverse tubules. Voltage-induced conformational changes in the dihydropyridine receptor activate the ryanodine receptor Ca2+ release channel of the sarcoplasmic reticulum. The released Ca2+ binds to troponin C, enabling contractile thick-thin filament interactions. The Ca2+ is subsequently transported back into the sarcoplasmic reticulum by specialized Ca2+ pumps (SERCA), preparing the muscle for a new cycle of contraction. Although other proteins are involved in excitation-contraction coupling, the mechanism described above emphasizes the unique role played by the two Ca2+ channels (the dihydropyridine receptor and the ryanodine receptor), the SERCA Ca2+ pumps and the exquisite spatial organization of the membrane compartments endowed with the proteins responsible for this mechanism to function rapidly and efficiently. Research over the past two decades has uncovered the fine details of excitation-contraction coupling under normal conditions while advances in genomics have helped to identify mutations in novel genes in patients with neuromuscular disorders. While it is now clear that many patients with congenital muscle diseases carry mutations in genes encoding proteins directly involved in Ca2+ homeostasis, it has become apparent that mutations are also present in genes encoding for proteins not thought to be directly involved in Ca2+ regulation. Ongoing research in the field now focuses on understanding the functional effect of individual mutations, as well as understanding the role of proteins not specifically located in the sarcoplasmic reticulum which nevertheless are involved in Ca2+ regulation or excitation-contraction coupling. The principal challenge for the future is the identification of drug targets that can be pharmacologically manipulated by small molecules, with the ultimate aim to improve muscle function and quality of life of patients with congenital muscle disorders. The aim of this review is to give an overview of the most recent findings concerning Ca2+ dysregulation and its impact on muscle function in patients with congenital muscle disorders due to mutations in proteins involved in excitation-contraction coupling and more broadly on Ca2+ homeostasis.
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Affiliation(s)
- Susan Treves
- Departments of Biomedicine and Anesthesia, Basel University Hospital, 4031 Basel, Switzerland; Department of Life Sciences, General Pathology Section, University of Ferrara, 44100 Ferrara, Italy.
| | - Heinz Jungbluth
- Department of Paediatric Neurology, Neuromuscular Service, Evelina Children's Hospital, St. Thomas' Hospital, London, United Kingdom; Randall Division for Cell and Molecular Biophysics, Muscle Signalling Section, King's College, London, United Kingdom; Department of Basic and Clinical Neuroscience, IoPPN, King's College, London, United Kingdom
| | - Nicol Voermans
- Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Francesco Muntoni
- Dubowitz Neuromuscular Centre, Institute of Child Health, University College London, United Kingdom
| | - Francesco Zorzato
- Departments of Biomedicine and Anesthesia, Basel University Hospital, 4031 Basel, Switzerland; Department of Life Sciences, General Pathology Section, University of Ferrara, 44100 Ferrara, Italy
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Frolov RV, Weckström M. Harnessing the Flow of Excitation: TRP, Voltage-Gated Na(+), and Voltage-Gated Ca(2+) Channels in Contemporary Medicine. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2015; 103:25-95. [PMID: 26920687 DOI: 10.1016/bs.apcsb.2015.11.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cellular signaling in both excitable and nonexcitable cells involves several classes of ion channels. Some of them are of minor importance, with very specialized roles in physiology, but here we concentrate on three major channel classes: TRP (transient receptor potential channels), voltage-gated sodium channels (Nav), and voltage-gated calcium channels (Cav). Here, we first propose a conceptual framework binding together all three classes of ion channels, a "flow-of-excitation model" that takes into account the inputs mediated by TRP and other similar channels, the outputs invariably provided by Cav channels, and the regenerative transmission of signals in the neural networks, for which Nav channels are responsible. We use this framework to examine the function, structure, and pharmacology of these channel classes both at cellular and also at whole-body physiological level. Building on that basis we go through the pathologies arising from the direct or indirect malfunction of the channels, utilizing ion channel defects, the channelopathies. The pharmacological interventions affecting these channels are numerous. Part of those are well-established treatments, like treatment of hypertension or some forms of epilepsy, but many other are deeply problematic due to poor drug specificity, ion channel diversity, and widespread expression of the channels in tissues other than those actually targeted.
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Affiliation(s)
- Roman V Frolov
- Division of Biophysics, Department of Physics, University of Oulu, Oulun Yliopisto, Finland.
| | - Matti Weckström
- Division of Biophysics, Department of Physics, University of Oulu, Oulun Yliopisto, Finland
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Alvarellos ML, McDonagh EM, Patel S, McLeod HL, Altman RB, Klein TE. PharmGKB summary: succinylcholine pathway, pharmacokinetics/pharmacodynamics. Pharmacogenet Genomics 2015; 25:622-30. [PMID: 26398623 PMCID: PMC4631707 DOI: 10.1097/fpc.0000000000000170] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
| | | | - Sephalie Patel
- Department of Anesthesiology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Howard L. McLeod
- DeBartolo Family Personalized Medicine Institute, Moffitt Cancer Center, Tampa, Florida, USA
| | - Russ B. Altman
- Department of Genetics, Stanford University, Stanford, California, USA
- Department of Bioengineering, Stanford University, Stanford, California, USA
| | - Teri E. Klein
- Department of Genetics, Stanford University, Stanford, California, USA
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