title: Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis.
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.
authors.affiliation: Department of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's & St. Thomas' Hospital NHS Foundation Trust, London, UK.
authors.forename: N
authors.initials: N
authors.lastname: Dlamini
authors.forename: N C
authors.initials: NC
authors.lastname: Voermans
authors.forename: S
authors.initials: S
authors.lastname: Lillis
authors.forename: K
authors.initials: K
authors.lastname: Stewart
authors.forename: E-J
authors.initials: EJ
authors.lastname: Kamsteeg
authors.forename: G
authors.initials: G
authors.lastname: Drost
authors.forename: R
authors.initials: R
authors.lastname: Quinlivan
authors.forename: M
authors.initials: M
authors.lastname: Snoeck
authors.forename: F
authors.initials: F
authors.lastname: Norwood
authors.forename: A
authors.initials: A
authors.lastname: Radunovic
authors.forename: V
authors.initials: V
authors.lastname: Straub
authors.forename: M
authors.initials: M
authors.lastname: Roberts
authors.forename: A F J E
authors.initials: AF
authors.lastname: Vrancken
authors.forename: W L
authors.initials: WL
authors.lastname: van der Pol
authors.forename: R I F M
authors.initials: RI
authors.lastname: de Coo
authors.forename: A Y
authors.initials: AY
authors.lastname: Manzur
authors.forename: S
authors.initials: S
authors.lastname: Yau
authors.forename: S
authors.initials: S
authors.lastname: Abbs
authors.forename: A
authors.initials: A
authors.lastname: King
authors.forename: M
authors.initials: M
authors.lastname: Lammens
authors.forename: P M
authors.initials: PM
authors.lastname: Hopkins
authors.forename: S
authors.initials: S
authors.lastname: Mohammed
authors.forename: S
authors.initials: S
authors.lastname: Treves
authors.forename: F
authors.initials: F
authors.lastname: Muntoni
authors.forename: E
authors.initials: E
authors.lastname: Wraige
authors.forename: M R
authors.initials: MR
authors.lastname: Davis
authors.forename: B
authors.initials: B
authors.lastname: van Engelen
authors.forename: H
authors.initials: H
authors.lastname: Jungbluth
mesh_terms: D015444:Exercise / Q000502:physiology; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000150:complications / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D012206:Rhabdomyolysis / Q000150:complications / Q000235:genetics*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel