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Neuromuscul Disord. 2015 Jul;25(7):567-76. doi: 10.1016/j.nmd.2015.04.007. Epub 2015 Apr 27.

Compound RYR1 heterozygosity resulting in a complex phenotype of malignant hyperthermia susceptibility and a core myopathy.

Author information

1
Malignant Hyperthermia Investigation Unit, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
2
Laboratory of Neurogenetics and Biobank, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium; Laboratory of Ultrastructural Neuropathology and Biobank, Institute Born-Bunge (IBB), University of Antwerp, Antwerpen, Belgium; MH Research Unit, University of Antwerp, Antwerpen, Belgium.
3
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, London, UK; Department of Clinical and Basic Neuroscience, IoPPN, King's College London, London, UK; Children's Neuroscience Centre, St Thomas' Hospital, London, UK.
4
Departments of Anesthesia and Biomedizin, ZLF Lab 408, Universitätsspital Basel, Basel, Switzerland.
5
Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands.
6
Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
7
Laboratory of Ultrastructural Neuropathology and Biobank, Institute Born-Bunge (IBB), University of Antwerp, Antwerpen, Belgium.
8
Laboratory of Neurogenetics and Biobank, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium; Department of Neurology, University Hospital Antwerp, Belgium; Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium.
9
Malignant Hyperthermia Investigation Unit, Toronto General Hospital, University Health Network, Toronto, ON, Canada; Department of Anesthesia and Pain Management, University of Toronto, Toronto, ON, Canada. Electronic address: Sheila.Riazi@uhn.on.ca.

Abstract

Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic myopathy triggered by exposure to volatile anesthetics and/or depolarizing muscle relaxants. Susceptibility to MH is primarily associated with dominant mutations in the ryanodine receptor type 1 gene (RYR1). Recent genetic studies have shown that RYR1 variants are the most common cause of dominant and recessive congenital myopathies - central core and multi-minicore disease, congenital fiber type disproportion, and centronuclear myopathy. However, the MH status of many patients, especially with recessive RYR1-related myopathies, remains uncertain. We report the occurrence of a triplet of RYR1 variants, c.4711A>G (p.Ile1571Val), c.10097G>A (p.Arg3366His), c.11798A>G (p.Tyr3933Cys), found in cis in four unrelated families, one from Belgium, one from The Netherlands and two from Canada. Phenotype-genotype correlation analysis indicates that the presence of the triplet allele alone confers susceptibility to MH, and that the presence of this allele in a compound heterozygous state with the MH-associated RYR1 variant c.14545G>A (p.Val4849Ile) results in the MH susceptibility phenotype and a congenital myopathy with cores and rods. Our study underlines the notion that assigning pathogenicity to individual RYR1 variants or combination of variants, and counseling in RYR1-related myopathies may require integration of clinical, histopathological, in vitro contracture testing, MRI and genetic findings.

KEYWORDS:

Compound RYR1 heterozygosity; Core myopathies; Malignant hyperthermia

PMID:
25958340
DOI:
10.1016/j.nmd.2015.04.007
[Indexed for MEDLINE]

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