title: RYR1-related myopathies: a wide spectrum of phenotypes throughout life.
abstract: OBJECTIVE
  Although several recent studies have implicated RYR1 mutations as a common cause of various myopathies and the malignant hyperthermia susceptibility (MHS) trait, many of these studies have been limited to certain age groups, confined geographical regions or specific conditions. The aim of the present study was to investigate the full spectrum of RYR1-related disorders throughout life and to use this knowledge to increase vigilance concerning malignant hyperthermia.
  
  
  METHODS
  A retrospective cohort study was performed on the clinical, genetic and histopathological features of all paediatric and adult patients in whom an RYR1 mutation was detected in a national referral centre for both malignant hyperthermia and inherited myopathies (2008-2012).
  
  
  RESULTS
  The cohort of 77 non-related patients (detection rate 28%) included both congenital myopathies with permanent weakness and 'induced' myopathies such as MHS and non-anaesthesia-related episodes of rhabdomyolysis or hyperCKemia, manifested throughout life and triggered by various stimuli. Sixty-one different mutations were detected, of which 24 were novel. Some mutations are present in both dominant (MHS) and recessive modes (congenital myopathy) of inheritance, even within families. Histopathological features included an equally wide spectrum, ranging from only subtle abnormalities to prominent cores.
  
  
  CONCLUSIONS
  This broad range of RYR1-related disorders often presents to the general paediatric and adult neurologist. Its recognition is essential for genetic counselling and improving patients' safety during anaesthesia. Future research should focus on in vitro testing by the in vitro contracture test and functional characterization of the large number of RYR1 variants whose precise effects currently remain uncertain.
authors.affiliation: National MH Investigation Unit, Department of Anesthesiology, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Snoeck
authors.affiliation: Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: B G M
authors.initials: BG
authors.lastname: van Engelen
authors.affiliation: Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands.|Department of Pathology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Küsters
authors.affiliation: Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands.|Department of Pathology, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Lammens
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Meijer
authors.affiliation: Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: J P F
authors.initials: JP
authors.lastname: Molenaar
authors.affiliation: Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands.|Department of Neurology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Raaphorst
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: C C
authors.initials: CC
authors.lastname: Verschuuren-Bemelmans
authors.affiliation: Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: C S M
authors.initials: CS
authors.lastname: Straathof
authors.affiliation: Department of Neuropediatrics, Juliana Children's Hospital/Haga Hospital, The Hague, Nijmegen, The Netherlands.
authors.forename: L T L
authors.initials: LT
authors.lastname: Sie
authors.affiliation: Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: I F
authors.initials: IF
authors.lastname: de Coo
authors.affiliation: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: W L
authors.initials: WL
authors.lastname: van der Pol
authors.affiliation: Department of Neurology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: de Visser
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Scheffer
authors.affiliation: Departments of Anesthesia and Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Treves
authors.affiliation: Department of Paediatric Neurology, Neuromuscular Service, Evelina Children's Hospital, Guy's and St Thomas' Hospital NHS Foundation Trust, London, UK.|Randall Division for Cell and Molecular Biophysics, Muscle Signalling Section, King's College, London, UK.|Department of Basic and Clinical Neuroscience, IoPPN, King's College, London, UK.
authors.forename: H
authors.initials: H
authors.lastname: Jungbluth
authors.affiliation: Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: N C
authors.initials: NC
authors.lastname: Voermans
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: E-J
authors.initials: EJ
authors.lastname: Kamsteeg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics*; D008875:Middle Aged; D009135:Muscular Diseases / Q000151:congenital / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D055815:Young Adult
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel
keywords: RYR1; anaesthesia; congenital myopathy; core myopathy; malignant hyperthermia susceptibility; ryanodine receptor