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).

Physiology and pathophysiology of excitation–contraction coupling: the functional role of ryanodine receptor

“…2) corresponding to the following domains in the amino acid sequence: regions 1 (C35–R614) and 2 (D2129–R2458) reside in the myoplasmic foot domain of the protein, whereas region 3 (I3916–G4942) is located in the transmembrane/luminal region of the highly conserved carboxy-terminal domain, important for allowing Ca 2+ flux through the channel (Zalk et al 2015). Mutations in RyR1 are also associated with other rare RyR1 related congenital myopathies including centronuclear myopathy, multi-minicore disease, Samaritan myopathy, heat/exercise induced exertional rhabdomyolysis, congenital fiber-type disproportion, late-onset axial myopathy, and atypical periodic paralyses (Bharucha-Goebel et al 2013; Zvaritch et al 2009; Ferreiro et al 2002; Capacchione et al 2010; Zhou et al 2010; Inui et al 1987; Takeshima et al 1989; Loseth et al 2013). …”

Ryanodine Myopathies Without Central Cores—Clinical, Histopathologic, and Genetic Description of Three Cases

“…A marked interpersonal and even intrafamilial variation in phenotype has been evident in previous reports. [3][4][5][6] Typical muscle histopathology includes type 1 muscle fibers with central amorphous areas of sarcomeric disorganization characterized by the absence of mitochondria and of oxidative enzymatic activity ("cores"). 7 In recent years, there has been an increased awareness of a marked clinical variability and histopathologic overlap with other myopathies, precluding a direct diagnosis.…”

Current and future therapeutic approaches to the congenital myopathies

“…Dominant mutations in RYR1 are most commonly associated with the malignant hyperthermia susceptibility (MHS) trait [10], a pharmacogenetic reaction to halogenated anaesthetics and muscle relaxants, and CCD, a relatively mild, predominantly proximal congenital myopathy typically without significant extraocular or cardiorespiratory involvement. MHS-related RYR1 mutations have also been associated with 'induced' or adult-onset neuromuscular phenotypes, in particular exertional rhabdomyolysis [11] and late-onset axial myopathy [12]. Recessive mutations in RYR1 mainly cause Multi-minicore Disease with external ophthalmoplegia [13], but also subgroups of Centronuclear Myopathy (CNM) [14] and Congenital Fibre Type Disproportion (CFTD) [15] (see below).…”