title: RYR1-related malignant hyperthermia with marked cerebellar involvement - a paradigm of heat-induced CNS injury?
abstract: Heat-induced CNS injury has been recognized for more than 50 years but the biological basis for the marked selectivity of CNS damage is currently uncertain. We present clinical, imaging, autopsy and genetic findings of a 14-year-old male who developed fatal cerebellar swelling in the course of a malignant hyperthermia (MH) episode caused by triggering anaesthetics. Unaccustomed intense exercise in the days prior to general anaesthesia was a probable confounding factor for the MH reaction. Autopsy findings demonstrated pronounced degeneration of cerebellar Purkinje cells. Post mortem genetic analysis revealed a mutation (c.6502G>A; p.Val2168Met) in the skeletal muscle ryanodine receptor (RYR1) gene previously associated with the MH trait. RYR1 mutations appear to be associated with heat-induced CNS injury in a distribution compatible with known expression pattern of the RyR1 isoform in cerebellar Purkinje cells. Recent exercise in genetically predisposed individuals may prime abnormal muscle prior to general anaesthesia and contribute to the severity of MH reactions.
authors.affiliation: Department of Paediatric Neurology, Southampton Children's Hospital, Southampton University Hospitals NHS Trust, Southampton, UK.
authors.forename: Katharine M L
authors.initials: KM
authors.lastname: Forrest
authors.affiliation: Department of Genetics, Princess Anne Hospital, Southampton University Hospitals NHS Trust, Southampton, UK; Department of Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Foulds
authors.affiliation: Department of Neuroradiology, Southampton University Hospitals NHS Trust, Southampton, UK.
authors.forename: John S
authors.initials: JS
authors.lastname: Millar
authors.affiliation: Department of Anaesthetics, Southampton University Hospitals NHS Trust, Southampton, UK.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Sutherland
authors.affiliation: Paediatric Intensive Care Unit, Southampton University Hospitals NHS Trust, Southampton, UK.
authors.forename: V John
authors.initials: VJ
authors.lastname: Pappachan
authors.affiliation: Department of Cellular Pathology, Southampton University Hospitals NHS Trust, Southampton, UK.
authors.forename: Samantha
authors.initials: S
authors.lastname: Holden
authors.affiliation: GSTS Pathology, Guy's Hospital, London, UK.
authors.forename: Rachael
authors.initials: R
authors.lastname: Mein
authors.affiliation: Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Hopkins
authors.affiliation: Department of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's & St. Thomas' Hospital NHS Foundation Trust, London, UK; Randall Division of Cell and Molecular Biophysics, Muscle Signalling Section, King's College, London, UK; Department of Clinical and Basic Neuroscience, IoPPN, King's College, London, UK. Electronic address: Heinz.Jungbluth@gstt.nhs.uk.
authors.forename: Heinz
authors.initials: H
authors.lastname: Jungbluth
mesh_terms: D000293:Adolescent; D001062:Appendectomy; D002531:Cerebellum / Q000473:pathology*; D005334:Fever / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel
keywords: Cerebellum; Heat-induced injury; Malignant hyperthermia (MH); Malignant hyperthermia susceptibility (MHS); Skeletal muscle ryanodine receptor (RYR1) gene