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

ABSTRACT: 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.De novo R3983C variant in RYR1 was identified in two unrelated children who experienced fatal, nonanesthetic awake episodes associated with febrile illness and heat stress. One of the children also had a second novel, maternally inherited D4505H variant located on a separate haplotype. Effects of all possible heterotypic expression conditions on RYR1 sensitivity to caffeine-induced Ca release were determined in expressing RYR1-null myotubes.Compared with wild-type RYR1 alone (EC50 = 2.85 ± 0.49 mM), average (± SEM) caffeine sensitivity of Ca release was modestly increased after coexpression with either R3983C (EC50 = 2.00 ± 0.39 mM) or D4505H (EC50 = 1.64 ± 0.24 mM). Remarkably, coexpression of wild-type RYR1 with the double mutant in cis (R3983C-D4505H) produced a significantly stronger sensitization of caffeine-induced Ca release (EC50 = 0.64 ± 0.17 mM) compared with that observed after coexpression of the two variants on separate subunits (EC50 = 1.53 ± 0.18 mM).The R3983C mutation potentiates D4505H-mediated sensitization of caffeine-induced RYR1 Ca release when the mutations are in cis (on the same subunit) but not when present on separate subunits. Nevertheless, coexpression of the two variants on separate subunits still resulted in a ?2-fold increase in caffeine sensitivity, consistent with the observed awake episodes and heat sensitivity.

SUBMITTER: Groom L

PROVIDER: S-EPMC3203251 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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

Groom Linda L Muldoon Sheila M SM Tang Zhen Zhi ZZ Brandom Barbara W BW Bayarsaikhan Munkhuu M Bina Saiid S Lee Hee-Suk HS Qiu Xing X Sambuughin Nyamkhishig N Dirksen Robert T RT

Anesthesiology 20111101 5

<h4>Background</h4>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.<h4>Methods</h4>De novo R3983C variant in RYR1 was identified in two unrelated children who exper ...[more]

PMID: 21918424

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Project description:BackgroundWe investigated the potential safety of remimazolam and propofol in malignant hyperthermia- (HM-) susceptible patients using ryanodine receptor 1- (RYR1-) expressing human embryonic kidney- (HEK-) 293 cells.MethodsWe compared the enhanced responsiveness of HEK-293 cells expressing wild-type RYR1 with that of mutant RYR1 to caffeine following perfusion with remimazolam or propofol. Furthermore, we investigated whether RYR1 enhanced the responsiveness of cells to remimazolam or propofol and compared the median effective concentration (EC50; i.e., the concentration required to reach half-maximal activation) using an unpaired two-tailed t-test while a P < 0.05 was considered significant.ResultsRemimazolam and propofol did not promote the caffeine-induced increase in intracellular Ca2+ levels in HEK-293 cells expressing mutant RYR1 even with exposure to approximately 100-fold the clinically used concentration. In wild-type RYR1, EC50 values of remimazolam following refusion vs. nonperfusion were 2.86?mM vs. 2.75?mM (P = 0.76) while for propofol perfusion vs. nonperfusion, they were 2.76?mM vs. 2.75?mM, respectively (P = 0.83). In mutant RYR1, EC50 values of remimazolam refusion vs. nonperfusion were 1.58?mM vs. 1.71?mM, respectively (P = 0.63) while for propofol perfusion vs. nonperfusion, they were 1.65?mM vs. 1.71?mM, respectively (P = 0.73). Remimazolam and propofol increased intracellular Ca2+ levels in a concentration-dependent manner, but the effect was not enhanced by RYR1. EC50 values of remimazolam with non-RYR1 vs. wild-type RYR1 were 1.00?mM vs. 0.92?mM, respectively (P = 0.91) while those of propofol were 1.09?mM vs. 1.05?mM, respectively (P = 0.84).ConclusionsThe increase in intracellular Ca2+ concentration caused by remimazolam or propofol was not considered an RYR1-mediated reaction. We conclude that remimazolam and propofol can be safely used as an anesthetic in MH-susceptible patients with RYR1-mutation without causing MH and may be safely substituted for an MH-triggering anesthetic when RYR1-mediated MH occurs.

Project description:Objective: To establish and broaden the phenotypic spectrum of secretory carrier membrane protein (SCAMP5) associated with epilepsy and neurodevelopmental delay. Methods: A Chinese patient was identified at the First Hospital of Peking University, and the three unrelated patients were recruited from two different countries (Italy and United States) through GeneMatcher. SCAMP5 pathogenic variants were identified by whole exome sequencing; clinical data of the patients were retrospectively collected and analyzed. Result: The onset age of seizures was ranged from 6 to 15 months. Patients had different types of seizures, including focal seizures, generalized tonic-clonic seizures and tonic seizure. One patient showed typical autism spectrum disorder (ASD) symptoms. Electroencephalogram (EEG) findings presented as focal or multifocal discharges, sometimes spreading to generalization. Brain magnetic resonance imaging (MRI) abnormalities were present in each patient. Severe intellectual disability and language and motor developmental disorders were found in our patients, with all patients having poor language development and were nonverbal at last follow-up. All but one of the patients could walk independently in childhood, but the ability to walk independently in one patient had deteriorated with age. All patients had abnormal neurological exam findings, mostly signs of extrapyramidal system involvement. Dysmorphic features were found in 2/4 patients, mainly in the face and trunk. All four unrelated patients were found to have the same heterozygous pathogenic SCAMP5 de novo variant (p. Gly180Trp). Conclusion: Epilepsy, severe developmental delay, abnormal neurological exam findings, with or without ASD or variably dysmorphic features and were common in patients with SCAMP5 variant. The onset time and type of seizure varied greatly. The EEG and brain MRI findings were not consistent, but diverse and nonspecific. The motor ability of patients with heterozygous SCAMP5 variant might have a regressive course; language development was more severely affected.

Dataset Information

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

Publications

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

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