Increasing the number of diagnostic mutations in malignant hyperthermia

Levano, Soledad; Vukcevic, Mirko; Singer, Martine; Matter, Anja; Treves, Susan; Urwyler, Albert; Girard, Thierry

doi:10.1002/humu.20878

Cited by 64 publications

(61 citation statements)

References 32 publications

(42 reference statements)

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“…13 The high RYR1 mutation detection rate observed in this study can be explained by the stringent selection criteria for enrolment into the study and by the mutation screening strategy, which consisted of sequence analysis of complete RYR1 transcripts. Comparable detection rates (70% to 86%) have been reported recently for other MHS populations [8][9][10] where genetic screening included the entire coding sequence of the gene. On the other hand, if only established MH causative mutations from the EMHG database (www.emhg.org) were considered, then the mutation detection rates or the diagnostic sensitivity of the genetic testing would be 42% in this study and from 28% to 33% in other studies.…”

Section: Discussionsupporting

confidence: 71%

“…On the other hand, if only established MH causative mutations from the EMHG database (www.emhg.org) were considered, then the mutation detection rates or the diagnostic sensitivity of the genetic testing would be 42% in this study and from 28% to 33% in other studies. [8][9][10] This does not compare favourably with a reported sensitivity of 97% to 99% for CHCT and in vitro contracture test (IVCT), respectively. 36,37 Published data indicate that the frequency of MH-causative RyR1 mutations is population-specific, with only a few mutations accounting for the majority of MH cases in some populations.…”

Section: Discussionmentioning

confidence: 65%

“…Despite being labelled as MHS on the basis of their CHCT results and representing families with a clear history of MH, five individuals in this study (14%) carried neither mutations in RYR1 nor known mutations in CACNA1S. The absence of RYR1 mutations in MHS individuals, together with the presence of discordant cases in families C-18 and C-27 and other MH families worldwide, 8,10 may be explained by the sensitivity and specificity of the CHCT, which identifies both false negatives and false positives at a low rate. 36,37,49 Another reason might be the possible involvement of as yet unrecognized genetic and environmental factors in the MHS phenotype.…”

Section: Discussionmentioning

confidence: 84%

“…In addition, p.Arg2336His found in cis with a novel mutation, p.Glu209Lys, in a Canadian MHS proband was recently reported to be causal for MH in several Swiss families. 10 The p.Val4847Leu that co-segregated well with an MHS phenotype within a large French-Canadian family, C-27, is positioned within the putative transmembrane segment and maps to the HS3b ''mutation hot spot'' region in RyR1. 13,38 At least three other closely spaced MH/CCD mutations are located within the same transmembrane segment 33,39,40 (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…7 Malignant hyperthermia genetic research has shown that RYR1 is the major causal gene for MH as well as for a congenital myopathy, central core disease (CCD). 3,6 Malignant hyperthermia-associated RYR1 mutations have been found in 60% to 86% of MH families with diverse ethnicity, [8][9][10][11] and their distribution and frequency have been shown to be population-specific. 6 Recent improvements in molecular genetics methods have facilitated genetic analysis of the entire coding region of RYR1, which is *159,000 nucleotides long and contains 106 exons that are spliced into a 15 kb RYR1 mRNA transcript.…”

Section: Résumémentioning

confidence: 99%

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Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

Kraeva

Riazi

Loke

et al. 2011

Can J Anesth/J Can Anesth

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Purpose Malignant hyperthermia (MH) is an autosomal dominant pharmacogenetic disorder that is manifested on exposure of susceptible individuals to halogenated anesthetics or succinylcholine. Since MH is associated primarily with mutations in the ryanodine receptor type 1 (RYR1) gene, the purpose of this study was to determine the distribution and frequency of MH causative RyR1 mutations in the Canadian MH susceptible (MHS) population. Methods In this study, we screened a representative cohort of 36 unrelated Canadian MHS individuals for RYR1 mutations by sequencing complete RYR1 transcripts and selected regions of CACNA1S transcripts. We then analyzed the correlation between caffeine-halothane contracture test (CHCT) results and RYR1 genotypes within MH families. Results Eighty-six percent of patients had at least one RyR1 mutation (31 out of 36), five of which were unrelated individuals who were double-variant carriers. Fifteen of the 27 mutations identified in RYR1 were novel. Eight novel mutations, involving highly conserved amino acid residues, were predicted to be causal. Two of the mutations co-segregated with the MHS phenotype within two large independent families (a total of 79 individuals). Fourteen percent of MHS individuals (five out of 36) carried neither RYR1 nor known CACNA1S mutations. Conclusions The distribution and frequency of MH causative RyR1 mutations in the Canadian MHS population are close to those of European MHS populations. Novel mutations described in this study will contribute to the worldwide pool of MH-associated mutations in the RYR1 gene, ultimately increasing the value of MH genetic diagnostic testing. RésuméObjectif L'hyperthermie maligne (HM) est une maladie pharmacoge´ne´tique he´re´ditaire dominante autosomique qui se manifeste lors de l'exposition des personnes susceptibles a`des anesthe´siques haloge´ne´s ou à la succinylcholine. E´tant donne´que l'HM est principalement associe´e aux mutations au niveau du ge`ne des re´cepteurs de ryanodine de type 1 (RYR1), l'objectif de cette e´tude e´tait de de´terminer la distribution et la fre´quence des mutations RyR1 causant une HM chez la population canadienne susceptible a`l'HM (SHM). Méthode Dans cette e´tude, nous avons examine´une cohorte repre´sentative de 36 personnes canadiennes SHM This article is accompanied by an editorial. Please see Can J Anesth 2011; 58: 6.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Résumémentioning

confidence: 99%

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Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

Kraeva

Riazi

Loke

et al. 2011

Can J Anesth/J Can Anesth

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RYR1Mutations as a Cause of Ophthalmoplegia, Facial Weakness, and Malignant Hyperthermia

Shaaban¹,

Ramos‐Platt²,

Gilles³

et al. 2013

JAMA Ophthalmol

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IMPORTANCE Total ophthalmoplegia can result from ryanodine receptor 1 (RYR1) mutations without overt associated skeletal myopathy. Patients carrying RYR1 mutations are at high risk of developing malignant hyperthermia. Ophthalmologists should be familiar with these important clinical associations.OBJECTIVE To determine the genetic cause of congenital ptosis, ophthalmoplegia, facial paralysis, and mild hypotonia segregating in 2 pedigrees diagnosed with atypical Moebius syndrome or congenital fibrosis of the extraocular muscles. DESIGN, SETTING, AND PARTICIPANTS Clinical data including medical and family histories were collected at research laboratories at Boston Children's Hospital and Jules Stein Eye Institute (Engle and Demer labs) for affected and unaffected family members from 2 pedigrees in which patients presented with total ophthalmoplegia, facial weakness, and myopathy.INTERVENTION Homozygosity mapping and whole-exome sequencing were conducted to identify causative mutations in affected family members. Histories, physical examinations, and clinical data were reviewed. MAIN OUTCOME AND MEASURE Mutations in RYR1.RESULTS Missense mutations resulting in 2 homozygous RYR1 amino acid substitutions (E989G and R3772W) and 2 compound heterozygous RYR1 substitutions (H283R and R3772W) were identified in a consanguineous and a nonconsanguineous pedigree, respectively. Orbital magnetic resonance imaging revealed marked hypoplasia of extraocular muscles and intraorbital cranial nerves. Skeletal muscle biopsy specimens revealed nonspecific myopathic changes. Clinically, the patients' ophthalmoplegia and facial weakness were far more significant than their hypotonia and limb weakness and were accompanied by an unrecognized susceptibility to malignant hyperthermia.CONCLUSIONS AND RELEVANCE Affected children presenting with severe congenital ophthalmoplegia and facial weakness in the setting of only mild skeletal myopathy harbored recessive mutations in RYR1, encoding the ryanodine receptor 1, and were susceptible to malignant hyperthermia. While ophthalmoplegia occurs rarely in RYR1-related myopathies, these children were atypical because they lacked significant weakness, respiratory insufficiency, or scoliosis. RYR1-associated myopathies should be included in the differential diagnosis of congenital ophthalmoplegia and facial weakness, even without clinical skeletal myopathy. These patients should also be considered susceptible to malignant hyperthermia, a life-threatening anesthetic complication avoidable if anticipated presurgically.

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Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies

et al. 2012

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Ryanodine receptor 1 (RYR1) mutations are a common cause of congenital myopathies associated with both dominant and recessive inheritance. Histopathological findings frequently feature central cores or multi-minicores, more rarely, type 1 predominance/uniformity, fiber-type disproportion, increased internal nucleation, and fatty and connective tissue. We describe 71 families, 35 associated with dominant RYR1 mutations and 36 with recessive inheritance. Five of the dominant mutations and 35 of the 55 recessive mutations have not been previously reported. Dominant mutations, typically missense, were frequently located in recognized mutational hotspot regions, while recessive mutations were distributed throughout the entire coding sequence. Recessive mutations included nonsense and splice mutations expected to result in reduced RyR1 protein. There was wide clinical variability. As a group, dominant mutations were associated with milder phenotypes; patients with recessive inheritance had earlier onset, more weakness, and functional limitations. Extraocular and bulbar muscle involvement was almost exclusively observed in the recessive group. In conclusion, our study reports a large number of novel RYR1 mutations and indicates that recessive variants are at least as frequent as the dominant ones. Assigning pathogenicity to novel mutations is often difficult, and interpretation of genetic results in the context of clinical, histological, and muscle magnetic resonance imaging findings is essential.

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Increasing the number of diagnostic mutations in malignant hyperthermia

Cited by 64 publications

References 32 publications

Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

RYR1Mutations as a Cause of Ophthalmoplegia, Facial Weakness, and Malignant Hyperthermia

Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies

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