Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis
Introduction
Rhabdomyolysis is a syndrome characterized by muscle breakdown as the common endpoint of multifactorial etiologies and accounts for up to 7% of all cases of acute renal failure (ARF). The reported annual incidence is 26,000 cases in the United States alone [1]. Exertional myalgia with or without rhabdomyolysis is a common presenting complaint in neurological practice. The underlying cause remains often elusive, particularly in the absence of associated weakness and once an underlying metabolic disorder has been excluded [2].
Mutations in the skeletal muscle ryanodine receptor (RYR1) gene have recently emerged as one of the most common causes of inherited neuromuscular disease, associated with a wide clinical spectrum ranging from the malignant hyperthermia susceptibility (MHS) trait, a pharmacogenetic hypermetabolic reaction to volatile anesthetics and muscle relaxants [for review [3]], to various congenital myopathies [4]. Whilst muscle pain is a commonly associated complaint in RYR1-related myopathies, rhabdomyolysis and/or exertional myalgia as the sole presenting feature of RYR1 mutations have only been reported in isolated cases in the anesthesia literature [5], [6], [7], [8], [9].
Here we report clinical, histopathological and genetic findings from 14 families presenting with rhabdomyolysis and/or exertional myalgia but no or only little associated weakness. RYR1 mutations were identified in all index cases but also in some relatives with only subtle or no symptoms.
Section snippets
Patients
Patients were selected from a cohort of 39 families where one or more family member had presented with rhabdomyolysis and/or exertional myalgia to a tertiary neurological centre in the United Kingdom or The Netherlands. All index cases had been comprehensively investigated for common etiologies of rhabdomyolysis and/or exertional myalgia, including disorders of lipid metabolism, glycogenoses, mitochondrial or other metabolic myopathies, but no underlying cause had been identified prior to RYR1
Clinical features
The main clinical findings from the 14 families presenting with rhabdomyolysis and/or exertional myalgia where RYR1 mutations were identified are summarized in Table 1. More detailed histories for each of the 14 families are provided in Supplemental file S1. Family 7 is shown in Fig. 1.
We identified RYR1 mutations in a total of 24 individuals from 14 families, 14 index cases and 10 relatives in families 1, 3, 5, 7, 10, 11 and 13. The 14 index cases presented with isolated exertional myalgia (n =
Discussion
A link with exertional rhabdomyolysis (ERM) has been suggested in the anesthesia literature almost since the recognition of the malignant hyperthermia susceptibility (MHS) trait as a distinct entity, but overall is considered rare. ERM and MHS are both syndromes characterized by an uncontrolled rise in intracellular skeletal muscle calcium [1] as the pivotal mechanism leading from accelerated mechanical, chemical or oxidative stress to irreversible muscle breakdown. Moreover, ERM is often
Acknowledgements
The authors wish to thank all participating families. Family members gave consent to the publication of their photographs and information. Part of this work was supported by a grant from the Guy’s and St Thomas’ Charitable Foundation to S.A. and H.J. (Grant number 070404) and of the Muscular Dystrophy Association (MDA) of the USA to H.J. and F.M. (Grant number 68762). Support from the National Commissioning Group (NCG) of the United Kingdom to the Dubowitz Neuromuscular Centre and Guy’s
References (40)
- et al.
Malignant hyperthermia associated with exercise-induced rhabdomyolysis or congenital abnormalities and a novel RYR1 mutation in New Zealand and Australian pedigrees
Br. J. Anaesth.
(2002) - et al.
Mutation screening of the RYR1-cDNA from peripheral B-lymphocytes in 15 Swedish malignant hyperthermia index cases
Br. J. Anaesth.
(2009) - et al.
RyR1 S-nitrosylation underlies environmental heat stroke and sudden death in Y522S RyR1 knockin mice
Cell
(2008) - et al.
In vitro contraction test for malignant hyperthermia in patients with unexplained recurrent rhabdomyolysis
J. Neurol. Sci.
(1991) - et al.
Hypothermia and rhabdomyolysis following olanzapine injection in an adolescent with schizophreniform disorder
Gen. Hosp. Psychiatry
(2009) - et al.
Genetic risk for malignant hyperthermia in non-anesthesia-induced myopathies
Mol. Genet. Metab.
(2011) - et al.
Late-onset axial myopathy with cores due to a novel heterozygous dominant mutation in the skeletal muscle ryanodine receptor (RYR1) gene
Neuromuscul. Disord.
(2009) - et al.
Magnetic resonance imaging of muscle in congenital myopathies associated with RYR1 mutations
Neuromuscul. Disord.
(2004) - et al.
Rhabdomyolysis
- et al.
Rhabdomyolysis: a review
Muscle Nerve
(2002)
Clinical utility gene card for: malignant hyperthermia
Eur. J. Hum. Genet.
Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies
Hum. Mutat.
Evidence for susceptibility to malignant hyperthermia in patients with exercise-induced rhabdomyolysis
Anesthesiology
Multiminicore disease in a family susceptible to malignant hyperthermia: histology, in vitro contracture tests, and genetic characterization
Arch. Neurol.
The ryanodine receptor type 1 gene variants in African American men with exertional rhabdomyolysis and malignant hyperthermia susceptibility
Clin. Genet.
Exertional rhabdomyolysis and malignant hyperthermia in a patient with ryanodine receptor type 1 gene, L-type calcium channel alpha-1 subunit gene, and calsequestrin-1 gene polymorphisms
Anesthesiology
RYR1 mutations are a common cause of congenital myopathies with central nuclei
Annal. Neurol.
Mutation screening in the ryanodine receptor 1 gene (RYR1) in patients susceptible to malignant hyperthermia who show definite IVCT results: identification of three novel mutations
Acta Anaesthesiol. Scand.
A double mutation of the ryanodine receptor type 1 gene in a malignant hyperthermia family with multiminicore myopathy
J. Clin. Neurol. (Seoul, Korea)
Mutations in RYR1 in malignant hyperthermia and central core disease
Hum. Mutat.
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