Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis

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Abstract

Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are a common cause of neuromuscular disease, ranging from various congenital myopathies to the malignant hyperthermia (MH) susceptibility trait without associated weakness.

We sequenced RYR1 in 39 unrelated families with rhabdomyolysis and/or exertional myalgia, frequent presentations in the neuromuscular clinic that often remain unexplained despite extensive investigations. We identified 9 heterozygous RYR1 mutations/variants in 14 families, 5 of them (p.Lys1393Arg; p.Gly2434Arg; p.Thr4288_Ala4290dup; p.Ala4295Val; and p.Arg4737Gln) previously associated with MH. Index cases presented from 3 to 45 years with rhabdomyolysis, with or without exertional myalgia (n = 12), or isolated exertional myalgia (n = 2). Rhabdomyolysis was commonly triggered by exercise and heat and, less frequently, viral infections, alcohol and drugs. Most cases were normally strong and had no personal MH history. Inconsistent additional features included heat intolerance, and cold-induced muscle stiffness. Muscle biopsies showed mainly subtle changes. Familial RYR1 mutations were confirmed in relatives with similar or no symptoms. These findings suggest that RYR1 mutations may account for a substantial proportion of patients presenting with unexplained rhabdomyolysis and/or exertional myalgia. Associated clinico-pathological features may be subtle and require a high degree of suspicion. Additional family studies are paramount in order to identify potentially MH susceptible relatives.

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

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