title: A novel late-onset axial myopathy associated with mutations in the skeletal muscle ryanodine receptor (RYR1) gene.
abstract: Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are a common cause of inherited neuromuscular disorders and have been associated with a wide clinical spectrum, ranging from various congenital myopathies to the malignant hyperthermia susceptibility (MHS) trait without any associated weakness. RYR1-related myopathies are usually of early-childhood onset. Here we present 11 patients from 8 families with a late-onset axial myopathy associated with RYR1 variants. Patients presented between the third and seventh decade of life to neuromuscular centres in Norway, the Netherlands and the United Kingdom with predominant axial muscle involvement, comprising variable degrees of lumbar hyperlordosis, scapular winging and/or camptocormia. Marked myalgia was commonly associated. Serum creatine kinase levels were normal or moderately elevated. Muscle imaging showed consistent involvement of the lower paravertebral muscles and the posterior thigh. Muscle biopsy findings were often discrete, featuring variability in fibre size, increased internal nuclei and unevenness of oxidative enzyme staining, but only rarely overt cores. RYR1 sequencing revealed heterozygous missense variants, either previously associated with the MHS trait or localizing to known MHS mutational hotspots. These findings indicate that MHS-related RYR1 mutations may present later in life with prominent axial weakness but not always typical histopathological features. We propose a combined effect of RyR1 dysfunction, aging and particular vulnerability of axial muscle groups as a possible pathogenic mechanism. RYR1 is a candidate for cases with "idiopathic" camptocormia or bent spine syndrome (BSS).
authors: Department of Neurology and Neurophysiology, University Hospital of North Norway, Tromsø, Norway.
authors: Sissel
authors: S
authors: Løseth
authors: Nicol C
authors: NC
authors: Voermans
authors: Torberg
authors: T
authors: Torbergsen
authors: Sue
authors: S
authors: Lillis
authors: Christoffer
authors: C
authors: Jonsrud
authors: Sigurd
authors: S
authors: Lindal
authors: Erik-Jan
authors: EJ
authors: Kamsteeg
authors: Martin
authors: M
authors: Lammens
authors: Marcus
authors: M
authors: Broman
authors: Gabriele
authors: G
authors: Dekomien
authors: Paul
authors: P
authors: Maddison
authors: Francesco
authors: F
authors: Muntoni
authors: Caroline
authors: C
authors: Sewry
authors: Aleksandar
authors: A
authors: Radunovic
authors: Marianne
authors: M
authors: de Visser
authors: Volker
authors: V
authors: Straub
authors: Baziel
authors: B
authors: van Engelen
authors: Heinz
authors: H
authors: Jungbluth
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008875:Middle Aged; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D010375:Pedigree; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel