Effect of Norepinephrine on Intracellular Ca Levels in Malignant Hyperthermia-Susceptible B Cells: Pilot Study in the Search for a New Diagnostic Test for Malignant Hyperthermia.

Malignant hyperthermia (MH) crises may induce morbidity or death in MH-susceptible (MHS) individuals. The only sensitive method of determining susceptibility is the caffeine-halothane contracture test, requiring muscle biopsy. Early research on MH demonstrated an abnormal response to catecholamines in MHS individuals.

Return of secondary findings in genomic sequencing: Military implications.

Background: Genomic sequencing has become a widely used tool in clinical and research settings in both civilian and military healthcare systems.

Methods: In this paper, we consider potential military-specific implications of returning genomic sequencing secondary findings to ensure the proper protections, policies, and processes are in place for the use of this information.

Results: We specifically use two examples to highlight potential military implications of the return of secondary findings.

Pathogenic and rare deleterious variants in multiple genes suggest oligogenic inheritance in recurrent exertional rhabdomyolysis.

Exertional rhabdomyolysis is a metabolic event characterized by the release of muscle content into the circulation due to exercise-driven breakdown of skeletal muscle. Recurrent exertional rhabdomyolysis has been associated with metabolic myopathies and mitochondrial disorders, a clinically and genetically heterogeneous group of predominantly autosomal recessive, monogenic conditions. Although genetics factors are well recognized in recurrent rhabdomyolysis, the underlying causes and mechanisms of exercise-driven muscle breakdown remain unknown in a substantial number of cases.

Round Table on Malignant Hyperthermia in Physically Active Populations: Meeting Proceedings.

Context:   Recent case reports on malignant hyperthermia (MH)-like syndrome in physically active populations indicate potential associations among MH, exertional heat stroke (EHS), and exertional rhabdomyolysis (ER). However, an expert consensus for clinicians working with these populations is lacking.

Objective:   To provide current expert consensus on the (1) definition of MH; (2) history, etiology, and pathophysiology of MH; (3) epidemiology of MH; (4) association of MH with EHS and ER; (5) identification of an MH-like syndrome; (6) recommendations for acute management of an MH-like syndrome; (7) special considerations for physically active populations; and (8) future directions for research.

Exome analysis identifies Brody myopathy in a family diagnosed with malignant hyperthermia susceptibility.

Whole exome sequencing (WES) was used to determine the primary cause of muscle disorder in a family diagnosed with a mild, undetermined myopathy and malignant hyperthermia (MH) susceptibility (MHS). WES revealed the compound heterozygous mutations, p.Ile235Asn and p.

Improving awareness of nonanesthesia-related malignant hyperthermia presentations: a tale of two brothers.

A 30-year-old man developed unexplained rhabdomyolysis, persistently increased creatine kinase and severe debilitating muscle cramps. After a nondiagnostic neurologic evaluation, he was referred for a muscle biopsy, to include histology/histochemistry, a myoglobinuria panel, and a caffeine halothane contracture test. Only the caffeine halothane contracture test was positive, and a subsequent ryanodine receptor type 1 gene evaluation revealed a mutation functionally causative for malignant hyperthermia.

Is lymphocyte adenosine a diagnostic marker of clinical malignant hyperthermia? A pilot study.

Objective: Malignant hyperthermia is a pharmacogenetic disorder typically triggered by potent inhalation anesthetics and/or the depolarizing muscle relaxant succinylcholine in malignant hyperthermia-susceptible individuals. Since lymphocytes express the same Ca channel mutation found in malignant hyperthermia-susceptible muscle, we investigated agonist-induced adenosine formation in lymphocytes as an index of sarcoplasmic reticulum Ca-release-induced adenosine 5'-triphosphate turnover as a potential minimally invasive functional malignant hyperthermia assay.

Design: Application of lymphocytes for malignant hyperthermia diagnosis.

Malignant hyperthermia and the clinical significance of type-1 ryanodine receptor gene (RYR1) variants: proceedings of the 2013 MHAUS Scientific Conference.

The Malignant Hyperthermia Association of the United States and the Department of Anesthesia at the University of Toronto sponsored a Scientific Conference on November 1-2, 2013 in Toronto, ON, Canada. The multidisciplinary group of experts, including clinicians, geneticists, and physiologists involved in research related to malignant hyperthermia (MH), shared new insights into the pathophysiology of diseases linked to the type-1 ryanodine receptor gene (RYR1) as well as the relationship between MH and "awake MH" conditions, such as exertional rhabdomyolysis and exertional heat illness. In addition, the molecular genetics of MH and clinical issues related to the diagnosis and management of disorders linked to RYR1 were presented.

Delayed onset of suspected malignant hyperthermia during sevoflurane anesthesia in an Afghan trauma patient: a case report.

Malignant hyperthermia (MH) is a rare pathologic hypermetabolic pharmacogenetic disorder of skeletal muscle calcium regulation following exposure to depolarizing muscle relaxants and/or volatile anesthetics. Although its pathogenesis is relatively well understood, there is wide variability in both the time of onset and the presentation of clinical signs and symptoms. In some circumstances the delayed onset of the hypermetabolic state may hinder timely recognition and treatment.

Unexpected MH deaths without exposure to inhalation anesthetics in pediatric patients.

Children, later found to have ryanodine receptor type one variants (RYR1), died without exposure to inhalation anesthetics. Family members with the same RYR1 variants had contracture tests consistent with susceptibility to malignant hyperthermia or in vitro testing showed increased sensitivity to RYR1 agonist.

Ryanodine receptor type 1 gene variants in the malignant hyperthermia-susceptible population of the United States.

Background: Mutations in the ryanodine receptor type 1 gene (RYR1) that encodes the skeletal muscle-specific intracellular calcium (Ca(2+)) release channel are a cause of malignant hyperthermia (MH). In this study, we examined RYR1 mutations in a large number of North American MH-susceptible (MHS) subjects without prior genetic diagnosis.

Methods: RYR1 was examined in 120 unrelated MHS subjects from the United States in a tiered manner.

Genetic polymorphisms associated with exertional rhabdomyolysis.

Exertional rhabdomyolysis (ER) occurs in young, otherwise healthy, individuals principally during strenuous exercise, athletic, and military training. Although many risk factors have been offered, it is unclear why some individuals develop ER when participating in comparable levels of physical exertion under identical environmental conditions and others do not. This study investigated possible genetic polymorphisms that might help explain ER.

Exome sequencing reveals SCO2 mutations in a family presented with fatal infantile hyperthermia.

We applied whole-exome sequencing (WES) for identification of an underlying genetic cause of a disease in a family presented with fatal infantile hyperthermia. Analysis of WES results revealed novel, deleterious compound missense mutations, Val160Ala and Pro233Thr, in the synthesis of cytochrome C oxidase 2 gene (SCO2) encoding a mitochondrial protein, Sco2, which is important for cytochrome C oxidase (COX) synthesis. Autosomal recessive mutations in SCO2 are known to be associated with COX deficiency recognized as fatal infantile cardio-encephalomyopathy (604272, OMIM).

Case report: Death in the emergency department: an unrecognized awake malignant hyperthermia-like reaction in a six-year-old.

A healthy 6-year-old boy developed lower extremity rigidity, trismus, and fever after playing in a splash pool. On arrival in the emergency department, he appeared to be seizing. An endotracheal tube was emergently placed using succinylcholine.

Identical de novo mutation in the type 1 ryanodine receptor gene associated with fatal, stress-induced malignant hyperthermia in two unrelated families.

Background: Mutations in the type 1 ryanodine receptor gene (RYR1) result in malignant hyperthermia, a pharmacogenetic disorder typically triggered by administration of anesthetics. However, cases of sudden death during exertion, heat challenge, and febrile illness in the absence of triggering drugs have been reported. The underlying causes of such drug-free fatal "awake" episodes are unknown.

Malignant hyperthermia: human stress triggering.

Letter to the Editor concerns the question of a discussion of awake porcine malignant hyperthermia that erroneously omits the awake human stress reaction of malignant hyperthermia.

Fluoroquinolones influence the intracellular calcium handling in individuals susceptible to malignant hyperthermia.

Introduction: The mechanisms of fluoroquinolone-induced myotoxicity are unknown but an involvement of intracellular calcium handling is suspected. An in vitro contracture test used to investigate cellular processes in malignant hyperthermia (MH) can be applied to study the effects of fluoroquinolones.

Methods: With approval of the local ethics committee, muscle biopsies of 18 MH susceptible (MHS) and 12 MHS non-susceptible (MHN) pigs were performed.

Lymphocyte-based determination of susceptibility to malignant hyperthermia: a pilot study in swine.

Background: Malignant hyperthermia susceptibility (MHS) is diagnosed by an invasive in vitro caffeine-halothane contracture test (CHCT) carried out on biopsied skeletal muscle tissue. We are presenting a novel blood test approach for malignant hyperthermia testing in a swine model. Our main aim was to determine whether adenosine production from lymphocytes after 4-chloro-m-cresol (4CmC) stimulation distinguishes homozygous swine carrying the Arg615Cys mutation in the ryanodine receptor type 1 (RyR1) gene (MHS swine) from normal swine.

The relationship between exertional heat illness, exertional rhabdomyolysis, and malignant hyperthermia.

Exertional heat illness, exertional rhabdomyolysis, and malignant hyperthermia (MH) are complex syndromes with similar pathophysiology. All three are hypermetabolic states that include high demand for adenosine triphosphate, accelerated oxidative, chemical, and mechanical stress of muscle, and uncontrolled increase in intracellular calcium. Although there are no controlled clinical studies to support a relationship, there is evidence to suggest an association between unexpected heat/exercise intolerance and MH susceptibility.

Trauma, systemic inflammatory response syndrome, dietary supplements, illicit steroid use and a questionable malignant hyperthermia reaction.

Background: Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated primarily, but not exclusively, with mutations in the skeletal muscle ryanodine receptor. Associated environmental factors, however, may also be important for expression of the syndrome.

Methods And Results: A 24-yr-old trauma patient developed a fulminant MH crisis after a 3 minute exposure to sevoflurane.

Identification of risk factors for exertional heat illness: a brief commentary on genetic testing.

Objective: This commentary discusses known links between Exertional Heat Illness (EHI), Malignant Hyperthermia (MH), and other hereditary diseases of muscle. Genetic and functional testing is also evaluated as measures of fitness to return to duty/play.

Data Sources: Reviews and research articles from Sports Medicine, Applied Physiology, and Anesthesiology.