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Canadian Journal of Anaesthesia =... Jul 2017Two potentially fatal syndromes, malignant hyperthermia (MH), an adverse reaction to general anesthesia, and exertional rhabdomyolysis (ER) share some clinical features,... (Review)
Review
INTRODUCTION
Two potentially fatal syndromes, malignant hyperthermia (MH), an adverse reaction to general anesthesia, and exertional rhabdomyolysis (ER) share some clinical features, including hyperthermia, muscle rigidity, tachycardia, and elevated serum creatine kinase. Some patients with ER have experienced an MH event and/or have been diagnosed as MH susceptible (MHS). In order to assess the relationship between ER and MH further, we conducted a retrospective cohort study summarizing clinical and genetic information on Canadian patients with ER who were diagnosed as MHS. In addition, a systematic literature review was performed to compile further evidence on MH susceptibility and RYR1 and CACNA1S variants associated with rhabdomyolysis.
METHODS
Demographic, clinical, and genetic information was collected on Canadian MHS patients who presented with rhabdomyolysis. In addition, we performed a systematic review of the literature published during 1995-2016 on genetic screening of the RYR1 and CACNA1S genes in patients with ER.
RESULTS
Retrospective data on Canadian MHS patients with ER showed that ten out of 17 patients carried RYR1 or CACNA1S variants that were either known MH-causative mutations or potentially pathogenic variants. The systematic review revealed 39 different rare RYR1 variants, including 13 MH-causative/associated mutations and five rare potentially deleterious CACNA1S variants in 78% of patients with ER.
CONCLUSION
Findings from the Canadian patient cohort and the systematic review all signal a potential association between MH susceptibility and ER. The presence of MH-causative mutations and putative deleterious RYR1 variants in ER patients without a history of adverse anesthetic reactions suggests their possible increased risk for MH.
Topics: Calcium Channels; Calcium Channels, L-Type; Canada; Cohort Studies; Female; Genetic Predisposition to Disease; Humans; Male; Malignant Hyperthermia; Mutation; Physical Exertion; Retrospective Studies; Rhabdomyolysis; Ryanodine Receptor Calcium Release Channel
PubMed: 28326467
DOI: 10.1007/s12630-017-0865-5 -
Orphanet Journal of Rare Diseases May 2020Pathogenic variations in the gene encoding the skeletal muscle ryanodine receptor (RyR1) are associated with malignant hyperthermia (MH) susceptibility, a... (Review)
Review
BACKGROUND
Pathogenic variations in the gene encoding the skeletal muscle ryanodine receptor (RyR1) are associated with malignant hyperthermia (MH) susceptibility, a life-threatening hypermetabolic condition and RYR1-related myopathies (RYR1-RM), a spectrum of rare neuromuscular disorders. In RYR1-RM, intracellular calcium dysregulation, post-translational modifications, and decreased protein expression lead to a heterogenous clinical presentation including proximal muscle weakness, contractures, scoliosis, respiratory insufficiency, and ophthalmoplegia. Preclinical model systems of RYR1-RM and MH have been developed to better understand underlying pathomechanisms and test potential therapeutics.
METHODS
We conducted a comprehensive scoping review of scientific literature pertaining to RYR1-RM and MH preclinical model systems in accordance with the PRISMA Scoping Reviews Checklist and the framework proposed by Arksey and O'Malley. Two major electronic databases (PubMed and EMBASE) were searched without language restriction for articles and abstracts published between January 1, 1990 and July 3, 2019.
RESULTS
Our search yielded 5049 publications from which 262 were included in this review. A majority of variants tested in RYR1 preclinical models were localized to established MH/central core disease (MH/CCD) hot spots. A total of 250 unique RYR1 variations were reported in human/rodent/porcine models with 95% being missense substitutions. The most frequently reported RYR1 variant was R614C/R615C (human/porcine total n = 39), followed by Y523S/Y524S (rabbit/mouse total n = 30), I4898T/I4897T/I4895T (human/rabbit/mouse total n = 20), and R163C/R165C (human/mouse total n = 18). The dyspedic mouse was utilized by 47% of publications in the rodent category and its RyR1-null (1B5) myotubes were transfected in 23% of publications in the cellular model category. In studies of transfected HEK-293 cells, 57% of RYR1 variations affected the RyR1 channel and activation core domain. A total of 15 RYR1 mutant mouse strains were identified of which ten were heterozygous, three were compound heterozygous, and a further two were knockout. Porcine, avian, zebrafish, C. elegans, canine, equine, and drosophila model systems were also reported.
CONCLUSIONS
Over the past 30 years, there were 262 publications on MH and RYR1-RM preclinical model systems featuring more than 200 unique RYR1 variations tested in a broad range of species. Findings from these studies have set the foundation for therapeutic development for MH and RYR1-RM.
Topics: Animals; Caenorhabditis elegans; Dogs; HEK293 Cells; Horses; Humans; Hyperthermia; Malignant Hyperthermia; Mice; Muscular Diseases; Mutation; Rabbits; Ryanodine Receptor Calcium Release Channel; Swine; Zebrafish
PubMed: 32381029
DOI: 10.1186/s13023-020-01384-x -
Frontiers in Cardiovascular Medicine 2021Atrial fibrillation (AF) is associated with calcium (Ca) handling remodeling and increased spontaneous calcium release events (SCaEs). Nevertheless, its exact mechanism...
Atrial fibrillation (AF) is associated with calcium (Ca) handling remodeling and increased spontaneous calcium release events (SCaEs). Nevertheless, its exact mechanism remains unclear, resulting in suboptimal primary and secondary preventative strategies. We searched the PubMed database for studies that investigated the relationship between SCaEs and AF and/or its risk factors. Meta-analysis was used to examine the Ca mechanisms involved in the primary and secondary AF preventative groups. We included a total of 74 studies, out of the identified 446 publications from inception (1982) until March 31, 2020. Forty-five were primary and 29 were secondary prevention studies for AF. The main Ca release events, calcium transient (standardized mean difference (SMD) = 0.49; = 35%; confidence interval (CI) = 0.33-0.66; < 0.0001), and spark amplitude (SMD = 0.48; = 0%; CI = -0.98-1.93; = 0.054) were enhanced in the primary diseased group, while calcium transient frequency was increased in the secondary group. Calcium spark frequency was elevated in both the primary diseased and secondary AF groups. One of the key cardiac currents, the L-type calcium current (I) was significantly downregulated in primary diseased (SMD = -1.07; = 88%; CI = -1.94 to -0.20; < 0.0001) and secondary AF groups (SMD = -1.28; = 91%; CI = -2.04 to -0.52; < 0.0001). Furthermore, the sodium-calcium exchanger (I) and NCX1 protein expression were significantly enhanced in the primary diseased group, while only NCX1 protein expression was shown to increase in the secondary AF studies. The phosphorylation of the ryanodine receptor at S2808 (pRyR-S2808) was significantly elevated in both the primary and secondary groups. It was increased in the primary diseased and proarrhythmic subgroups (SMD = 0.95; = 64%; CI = 0.12-1.79; = 0.074) and secondary AF group (SMD = 0.66; = 63%; CI = 0.01-1.31; < 0.0001). Sarco/endoplasmic reticulum Ca-ATPase (SERCA) expression was elevated in the primary diseased and proarrhythmic drug subgroups but substantially reduced in the secondary paroxysmal AF subgroup. Our study identified that I is reduced in both the primary and secondary diseased groups. Furthermore, pRyR-S2808 and NCX1 protein expression are enhanced. The remodeling leads to elevated Ca functional activities, such as increased frequencies or amplitude of Ca spark and Ca transient. The main difference identified between the primary and secondary diseased groups is SERCA expression, which is elevated in the primary diseased group and substantially reduced in the secondary paroxysmal AF subgroup. We believe our study will add new evidence to AF mechanisms and treatment targets.
PubMed: 34355025
DOI: 10.3389/fcvm.2021.662914 -
Human Reproduction Update Jul 2019Approximately 50% of pregnancy losses are caused by chromosomal abnormalities, such as aneuploidy. The remainder has an apparent euploid karyotype, but it is plausible...
BACKGROUND
Approximately 50% of pregnancy losses are caused by chromosomal abnormalities, such as aneuploidy. The remainder has an apparent euploid karyotype, but it is plausible that there are cases of pregnancy loss with other genetic aberrations that are not currently routinely detected. Studies investigating the use of exome sequencing and chromosomal microarrays in structurally abnormal pregnancies and developmental disorders have demonstrated their clinical application and/or potential utility in these groups of patients. Similarly, there have been several studies that have sought to identify genes that are potentially causative of, or associated with, spontaneous pregnancy loss, but the evidence has not yet been synthesized.
OBJECTIVE AND RATIONALE
The objective was to identify studies that have recorded monogenic genetic contributions to pregnancy loss in euploid pregnancies, establish evidence for genetic causes of pregnancy loss, identify the limitations of current evidence, and make recommendations for future studies. This evidence is important in considering additional research into Mendelian causes of pregnancy loss and appropriate genetic investigations for couples experiencing recurrent pregnancy loss.
SEARCH METHODS
A systematic review was conducted in MEDLINE (1946 to May 2018) and Embase (1974 to May 2018). The search terms 'spontaneous abortion', 'miscarriage', 'pregnancy loss', or 'lethal' were used to identify pregnancy loss terms. These were combined with search terms to identify the genetic contribution including 'exome', 'human genome', 'sequencing analysis', 'sequencing', 'copy number variation', 'single-nucleotide polymorphism', 'microarray analysis', and 'comparative genomic hybridization'. Studies were limited to pregnancy loss up to 20 weeks in humans and excluded if the genetic content included genes that are not lethal in utero, PGD studies, infertility studies, expression studies, aneuploidy with no recurrence risk, methodologies where there is no clinical relevance, and complex genetic studies. The quality of the studies was assessed using a modified version of the Newcastle-Ottawa scale.
OUTCOMES
A total of 50 studies were identified and categorized into three themes: whole-exome sequencing studies; copy number variation studies; and other studies related to pregnancy loss including recurrent molar pregnancies, epigenetics, and mitochondrial DNA aberrations. Putatively causative variants were found in a range of genes, including CHRNA1 (cholinergic receptor, nicotinic, alpha polypeptide 1), DYNC2H1 (dynein, cytoplasmic 2, heavy chain 1), and RYR1 (ryanodine receptor 1), which were identified in multiple studies. Copy number variants were also identified to have a causal or associated link with recurrent miscarriage.
WIDER IMPLICATIONS
Identification of genes that are causative of or predisposing to pregnancy loss will be of significant individual patient impact with respect to counselling and treatment. In addition, knowledge of specific genes that contribute to pregnancy loss could also be of importance in designing a diagnostic sequencing panel for patients with recurrent pregnancy loss and also in understanding the biological pathways that can cause pregnancy loss.
Topics: Abortion, Habitual; Abortion, Spontaneous; DNA Copy Number Variations; Female; Genetic Predisposition to Disease; Genomic Instability; Humans; Karyotyping; Ploidies; Pregnancy; Risk Factors
PubMed: 31150545
DOI: 10.1093/humupd/dmz015 -
Medicine Sep 2018We sought to identify common ion channel single nucleotide polymorphisms (SNPs) associated with the occurrence of sudden cardiac death (SCD) to predict the incidence of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
We sought to identify common ion channel single nucleotide polymorphisms (SNPs) associated with the occurrence of sudden cardiac death (SCD) to predict the incidence of SCD in clinical settings.
METHODS
This study involved a systematic review and meta-analysis of ion channel SNPs and risk of SCD in adults. We searched public databases for studies published up to September 19, 2017. We examined relationships between SNPs in common ion channel genes and the incidence of SCD.
RESULTS
We collected data for 22 trials that included a total of 4149 patients who experienced SCD or had a high risk of SCD and assessed these data in our meta-analysis. An allelic model showed that rs11720524 in SCN5A clearly protected against SCD (odds ratio [OR]: 0.76; 95% confidence interval [95% CI]: 0.67-0.85; P < .001). Subgroup analysis showed that rs11720524 in SCN5A protected against SCD in Europeans and Caucasians but not in Koreans. The allelic model indicated that rs12296050 in KCNQ1 also had significant protective effects against SCD (OR: 0.85; 95% CI: 0.76-0.96; P = .007). Moreover, this model demonstrated that rs2283222 in KCNQ1 had a significant negative relationship with SCD (OR: 0.73; 95% CI: 0.62-0.85; P < .001). Rs12296050 in KCNQ1 protected against SCD in Koreans and Americans. Our results also showed that rs790896 in RYR2 was negatively associated with SCD in a dominant model (OR: 0.66; 95% CI: 0.45-0.97; P = .033).
CONCLUSIONS
Rs11720524 in SCN5A is negatively related to SCD in Europeans and Caucasians, and rs12296050 and rs2283222 in KCNQ1 and rs790896 in RYR2 clearly have protective effects against SCD.
Topics: Adult; Alleles; Asian People; Death, Sudden, Cardiac; Female; Humans; Incidence; Ion Channels; KCNQ1 Potassium Channel; Male; NAV1.5 Voltage-Gated Sodium Channel; Observational Studies as Topic; Polymorphism, Single Nucleotide; Predictive Value of Tests; Ryanodine Receptor Calcium Release Channel; White People
PubMed: 30235722
DOI: 10.1097/MD.0000000000012428 -
Frontiers in Physiology 2023Calcium uptake research has a long history. However, the mitochondrial calcium uniporter (MCU) protein was first discovered in 2011. As investigations of mitochondrial...
Calcium uptake research has a long history. However, the mitochondrial calcium uniporter (MCU) protein was first discovered in 2011. As investigations of mitochondrial calcium uniporter represent a new research hotspot, a comprehensive and objective perspective of the field is lacking. Hence, this bibliometric analysis aimed to provide the current study status and trends related to mitochondrial calcium uniporter research in the past decade. Articles were acquired from the Web of Science Core Collection database. We quantified and visualized information regarding annual publications, journals, cocited journals, countries/regions, institutions, authors, and cocited authors by using CiteSpace 5.8. R3 and VOSviewer. In addition, we analysed the citation and keyword bursts related to mitochondrial calcium uniporter studies. From 2011 to 2022, 1,030 articles were published by 5,050 authors from 1,145 affiliations and 62 countries or regions. The country with the most published articles was the United States. The institution with the most published articles was the University of Padua. Rosario Rizzuto published the most articles and was also the most cocited author. Cell Calcium published the largest number of articles, whereas had the most cocitations. The top 5 keywords related to pathological processes were oxidative stress, cell death, permeability transition, apoptosis, and metabolism. MICU1, calcium, ryanodine receptor, ATP synthase and cyclophilin D were the top 5 keywords related to molecules. mitochondrial calcium uniporter research has grown stably over the last decade. Current studies focus on the structure of the mitochondrial calcium uniporter complex and its regulatory effect on mitochondrial calcium homeostasis. In addition, the potential role of mitochondrial calcium uniporter in different diseases has been explored. Current studies mostly involve investigations of cancer and neurodegenerative diseases. Our analysis provides guidance and new insights into further mitochondrial calcium uniporter research.
PubMed: 36744031
DOI: 10.3389/fphys.2023.1107328 -
Neuromuscular Disorders : NMD Dec 2020Neuroleptic malignant syndrome and serotonin syndrome are two syndromes whose molecular bases remain poorly understood. The phenotypes of both syndromes overlap with...
Neuroleptic malignant syndrome and serotonin syndrome are two syndromes whose molecular bases remain poorly understood. The phenotypes of both syndromes overlap with other syndromes that have a clear genetic background, in particular RYR1-related malignant hyperthermia. Through a literature review, performed according to the PRISMA guidelines, we aimed to report the clinical features of both syndromes, and the results of genetic testing performed. 10 case series and 99 case reports were included, comprising 134 patients. A male predominance of 58% was found. The median age was 35 (range 4-84) years. Eight patients experienced recurrent episodes of rhabdomyolysis. Genetic analysis was performed in eleven patients (8%), revealing four RYR1 variants, three likely benign (p.Asp849Asn, p.Arg4645Gln, p.Arg4645Gln) and one variant of uncertain significance (p.Ala612Thr). This review underlines that a subset of patients with neuroleptic malignant syndrome and serotonin syndrome develop recurrent episodes of rhabdomyolysis. This recurrent pattern suggests a possible underlying (genetic) susceptibility. However, the genetic background of neuroleptic malignant syndrome and serotonin syndrome has only been investigated to a very limited degree so far. The increasing availability of next generation sequencing offers an opportunity to identify potentially associated genetic backgrounds, especially in patients with recurrent episodes or a positive family history.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Female; Genetic Predisposition to Disease; Genetic Testing; Humans; Male; Malignant Hyperthermia; Middle Aged; Mutation; Neuroleptic Malignant Syndrome; Phenotype; Rhabdomyolysis; Ryanodine Receptor Calcium Release Channel; Serotonin Syndrome; Young Adult
PubMed: 33250373
DOI: 10.1016/j.nmd.2020.10.010 -
MedRxiv : the Preprint Server For... Mar 2024Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmia caused by mutations in the ryanodine receptor type 2 (RyR2). Diagnosis of...
Location of ryanodine receptor type 2 mutation predicts age of onset of sudden death in catecholaminergic polymorphic ventricular tachycardia - A systematic review and meta-analysis of case-based literature.
BACKGROUND
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmia caused by mutations in the ryanodine receptor type 2 (RyR2). Diagnosis of CPVT often occurs after a major cardiac event, thus posing a severe threat to the patient's health.
METHODS
Publication databases, including PubMed, Scopus, and Embase, were searched for articles on patients with RyR2-CPVT mutations and their associated clinical presentation. Articles were reviewed by two independent reviewers and mutations were analyzed for demographic information, mutation distribution, and therapeutics. The human RyR2 cryo-EM structure was used to model CPVT mutations and predict the diagnosis and outcomes of CPVT patients.
FINDINGS
We present a database of 1008 CPVT patients from 227 papers. Data analyses revealed that patients most often experienced exercise-induced syncope in their early teenage years but the diagnosis of CPVT took a decade. Mutations located near key regulatory sites in the channel were associated with earlier onset of CPVT symptoms including sudden cardiac death.
INTERPRETATION
The present study provides a road map for predicting clinical outcomes based on the location of RyR2 mutations in CPVT patients. The study was partially limited by the inconsistency in the depth of information provided in each article, but nevertheless is an important contribution to the understanding of the clinical and molecular basis of CPVT and suggests the need for early diagnosis and creative approaches to disease management.
FUNDING
The work was supported by grant NIH R01HL145473, P01 HL164319 R25HL156002, T32 HL120826.
PubMed: 38559077
DOI: 10.1101/2024.03.15.24304349