Genetic variation in RYR1 and malignant hyperthermia phenotypes

Carpenter, Danielle; Robinson, Rachel; Quinnell, Rupert J.; Ringrose, Christopher; Hogg, Marion C.; Casson, F.; Booms, Patrick; Iles, David; Halsall, P.J.; Steele, Derek S.; Shaw, Marie; Hopkins, Philip M.

doi:10.1093/bja/aep204

Cited by 99 publications

(91 citation statements)

References 36 publications

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“…Patient NGS2 showed: c.7063C>T/p.Arg2355Trp, whereas patients NGS3 and NGS4 both showed the mutation c.7304G>A/p.Arg2435His. These latter mutations have been repeatedly associated with MH and/or CCD and have been found to impact on RYR1 function (8)(9)(10)(11). No variants were found in the CACNA1S.…”

Section: Results In Ryr1 or Cacna1smentioning

confidence: 98%

Next‐generation DNA sequencing of a Swedish malignant hyperthermia cohort

et al. 2014

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Malignant hyperthermia (MH)-related mutations have been identified in the ryanodine receptor type 1 gene (RYR1) and in the dihydropyridine gene (CACNA1S), but about half of the patients do not have causative mutations in these genes. We wanted to study the contribution of other muscle genes to the RYR1 phenotypes. We designed a gene panel for sequence enrichment targeting 64 genes of proteins involved in the homeostasis of the striated muscle cell. Next-generation sequencing (NGS) resulted in >50,000 sequence variants which were further analyzed by software filtering criteria to identify causative variants. In four of five patients we identified previously reported RYR1 mutations while the fifth patient did not show any candidate variant in any of the genes investigated. In two patients pathogenic variants were found in other genes known to cause a muscle disorders. All but one patient carried likely benign rare polymorphisms. The NGS technique proved convenient in identifying variants in the RYR1. However, with a clinically variable phenotype-like MH, the pre-selection of genes poses problems in variant interpretation.

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Section: Results In Ryr1 or Cacna1smentioning

confidence: 98%

Next‐generation DNA sequencing of a Swedish malignant hyperthermia cohort

et al. 2014

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“…The editorial in Anaesthesiology [13] focussed on Malignant Hyperthermia in India following publishing a case report of MH in a boy from South India. The author after reviewing three previous case reports of MH in India questions the common misbelief of nonsusceptibility to MH in Indian population [14,15].…”

Section: Discussionmentioning

confidence: 99%

Malignant hyperthermia in India: Time for awakening, useful facts on Dantrolene

Pillai

Koshy

Balakrishnan

et al. 2015

Egyptian Journal of Anaesthesia

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A 33 year old lady with no obvious reason to suspect susceptibility to malignant hyperpyrexia (MH) succumbed to this unexpected complication in spite of attempts to save her life with aggressive supportive measures. We are reporting this case of possible malignant hyperthermia probably the seventh reported case in India and second from Kerala in the last decade (Saxena and Dua, 2007;Punj et al., 2001;Gopalakrishnan et al., 2010;Jain, 2010;Ramakant and Singh, 2012;Sharma et al., 2012). This was the first ever case of MH in our institution in 25 years This emphasises the need to ensure availability of Dantrolene and MH kits, diagnostic centres with appropriate lab controls and above all high index of suspicion and heightened awareness among the anaesthesiologists of this potential albeit rare risk of MH in Indian population.

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“…Malignant hyperthermia (MH), also known as malignant hyperpyrexia, is a potentially lethal pharmacogenetic disorder which affects genetically predisposed individuals 2,33 . …”

Section: Conceptmentioning

confidence: 99%

“…During a crisis of MH, inhalational anesthetics, muscle relaxants depolarizing (succinylcholine) or extreme physical activity in hot environments trigger a massive accumulation of calcium (Ca 2+ ) in myoplasm, which leads to an accelerated metabolism and skeletal muscle contractile activity. This hypermetabolic state generates heat and leads to hypoxemia, metabolic acidosis, rhabdomyolysis, and rapid increase in body temperature that can be fatal if not recognized and treated early 1,2 .…”

Section: Introductionmentioning

confidence: 99%

“…Several mutations in the RyR1 gene have been already identified and implicated in a wide range of channelopathies, and this defect is primarily responsible for susceptibility to MH; however, other genes may be involved 2 . This variation in genes related to susceptibility to MH is the major cause of the syndrome's different manifestations 5 .…”

Section: Introductionmentioning

confidence: 99%

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Hipertermia maligna: aspectos moleculares e clínicos

Correia

Silva

2012

Rev. Bras. Anestesiol.

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Summary: Correia ACC, Silva PCB, Silva BA -Malignant Hyperthermia: Clinical and Molecular Aspects. Content:Malignant hyperthermia (MH) is a potentially lethal pharmacogenetic disorder that affects genetically predisposed individuals. It manifests in susceptible individuals in response to exposure to Inhalant anesthetics, depolarizing muscle relaxants or extreme physical activity in hot environments. During exposure to these triggering agents, there is a rapid and sustained increase of myoplasmic calcium (Ca 2+ ) concentration induced by hyperactivation of ryanodine receptor of skeletal muscle (RyR1), causing a profound change in Ca 2+ homeostasis, featuring a hypermetabolic state. RyR1, Ca 2+ release channels of sarcoplasmic reticulum, is the primary locus for MH susceptibility. Several mutations in the gene encoding the protein RyR1 have been identified; however, other genes may be involved. Actually, the standard method for diagnosing MH susceptibility is the muscle contracture test for exposure to halothane-caffeine (CHCT) and the only treatment is the use of dantrolene. However, with advances in molecular genetics, a full understanding of the disease etiology may be provided, favoring the development of an accurate diagnosis, less invasive, with DNA test, and also will provide the development of new therapeutic strategies for treatment of MH. Thus, this brief review aims to integrate molecular and clinical aspects of MH, gathering input for a better understanding of this channelopathy.

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Genetic variation in RYR1 and malignant hyperthermia phenotypes

Cited by 99 publications

References 36 publications

Next‐generation DNA sequencing of a Swedish malignant hyperthermia cohort

Next‐generation DNA sequencing of a Swedish malignant hyperthermia cohort

Malignant hyperthermia in India: Time for awakening, useful facts on Dantrolene

Hipertermia maligna: aspectos moleculares e clínicos

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