title: Late-onset axial myopathy with cores due to a novel heterozygous dominant mutation in the skeletal muscle ryanodine receptor (RYR1) gene.
abstract: Mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been associated with a wide range of phenotypes including the malignant hyperthermia (MH) susceptibility trait, Central Core Disease (CCD) and other congenital myopathies characterized by early onset and predominant proximal weakness. We report a patient presenting at 77 years with a predominant axial myopathy associated with prominent involvement of spine extensors, confirmed on MRI and muscle biopsy, compatible with a core myopathy. RYR1 mutational analysis revealed a novel heterozygous missense mutation (c.119G>T; p.Gly40Val) affecting the RYR1 N-terminus, previously predominantly associated with MH susceptibility. This case expands the spectrum of RYR1-related phenotypes and suggests that MH-related RYR1 mutations may give rise to overt neuromuscular symptoms later in life, with clinical features not typically found in CCD due to C-terminal hotspot mutations. Late-onset congenital myopathies may be under-recognised and diagnosis requires a high degree of clinical suspicion.
authors.affiliation: Clinical Neuroscience Division, King's College, London, UK. Heinz.Jungbluth@gstt.nhs.uk
authors.forename: Heinz
authors.initials: H
authors.lastname: Jungbluth
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lillis
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhou
authors.forename: Stephen
authors.initials: S
authors.lastname: Abbs
authors.forename: Caroline
authors.initials: C
authors.lastname: Sewry
authors.forename: Michael
authors.initials: M
authors.lastname: Swash
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
mesh_terms: D000367:Age Factors; D017668:Age of Onset; D000368:Aged; D020013:Calcium Signaling / Q000235:genetics; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005799:Genes, Dominant / Q000235:genetics; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D020512:Myopathy, Central Core / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D019837:Ryanodine Receptor Calcium Release Channel