title: Ryanodine myopathies without central cores--clinical, histopathologic, and genetic description of three cases.
abstract: BACKGROUND
  Mutations in ryanodine receptor 1 gene (RYR1) are frequent causes of myopathies. They classically present with central core disease; however, clinical variability and histopathologic overlap are being increasingly recognized.
  
  
  METHODS
  Patient 1 is a 15-year-old girl with mild proximal, four-limb weakness from age 5, presenting with a progressive scoliosis starting at age 10. Patient 2 is an 18-year-old girl with progressively worsening muscle hypotrophy and mild proximal, four-limb weakness. She developed a rapidly progressive scoliosis from age 11 and needed surgical treatment at age 14 years. Patient 3 is an 11-year-old boy with moderate proximal limb weakness and progressive neck flexor weakness, first noticed at age 2. Muscle biopsies revealed type 1 fiber predominance (Patients 1 and 2) or abnormal type 1 fiber uniformity (Patient 3). Different RYR1 variants were identified in all patients. In Patients 1 and 3, these changes were validated as being pathogenic.
  
  
  CONCLUSIONS
  These patients illustrate early-onset, progressive myopathies with predominant axial involvement. Histopathologic findings were abnormal but not specific for a diagnosis, particularly central core myopathy. Genetic testing helped broaden the range of phenotypes included in the RYR1-related myopathies. Our patients reinforce the need to recognize the broad histopathologic variability of RYR1-related myopathies and sometimes lack of pathognomonic findings that may reduce the diagnostic threshold of this disease. We suggest that the predominance of type 1 fibers and involvement of axial muscles may be an important element to consider the RYR1 gene as candidate.
authors.affiliation: Department of Neurology, Hospital de Braga, Braga, Portugal. Electronic address: joaomrocha@gmail.com.
authors.forename: João
authors.initials: J
authors.lastname: Rocha
authors.affiliation: Neuropathology Unit, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Taipa
authors.affiliation: Neuropathology Unit, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Manuel
authors.initials: M
authors.lastname: Melo Pires
authors.affiliation: Molecular Genetics Unit, Centro de Genética Médica Dr. Jacinto Magalhães, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Oliveira
authors.affiliation: Molecular Genetics Unit, Centro de Genética Médica Dr. Jacinto Magalhães, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Rosário
authors.initials: R
authors.lastname: Santos
authors.affiliation: Neuromuscular Diseases Unit, Department of Pediatric Neurology, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Manuela
authors.initials: M
authors.lastname: Santos
mesh_terms: D000293:Adolescent; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel
keywords: RYR1; muscle biopsy; myopathy; ryanodine receptor