RYR1-related malignant hyperthermia with marked cerebellar involvement - a paradigm of heat-induced CNS injury?

Katharine M L Forrest; Nicola Foulds; John S Millar; Paul D Sutherland; V John Pappachan; Samantha Holden; Rachael Mein; Philip M Hopkins; Heinz Jungbluth

doi:10.1016/j.nmd.2014.10.008

RYR1-related malignant hyperthermia with marked cerebellar involvement - a paradigm of heat-induced CNS injury?

Neuromuscul Disord. 2015 Feb;25(2):138-40. doi: 10.1016/j.nmd.2014.10.008. Epub 2014 Oct 31.

Authors

Katharine M L Forrest¹, Nicola Foulds², John S Millar³, Paul D Sutherland⁴, V John Pappachan⁵, Samantha Holden⁶, Rachael Mein⁷, Philip M Hopkins⁸, Heinz Jungbluth⁹

Affiliations

¹ Department of Paediatric Neurology, Southampton Children's Hospital, Southampton University Hospitals NHS Trust, Southampton, UK.
² 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.
³ Department of Neuroradiology, Southampton University Hospitals NHS Trust, Southampton, UK.
⁴ Department of Anaesthetics, Southampton University Hospitals NHS Trust, Southampton, UK.
⁵ Paediatric Intensive Care Unit, Southampton University Hospitals NHS Trust, Southampton, UK.
⁶ Department of Cellular Pathology, Southampton University Hospitals NHS Trust, Southampton, UK.
⁷ GSTS Pathology, Guy's Hospital, London, UK.
⁸ Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
⁹ 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.

PMID: 25466363
DOI: 10.1016/j.nmd.2014.10.008

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.

Keywords: Cerebellum; Heat-induced injury; Malignant hyperthermia (MH); Malignant hyperthermia susceptibility (MHS); Skeletal muscle ryanodine receptor (RYR1) gene.

Publication types

Case Reports

MeSH terms

Adolescent
Appendectomy
Cerebellum / pathology*
Fever / genetics*
Fever / pathology*
Humans
Magnetic Resonance Imaging
Male
Mutation / genetics*
Ryanodine Receptor Calcium Release Channel / genetics*

Substances

Ryanodine Receptor Calcium Release Channel