title: RYR1-Related Myopathies: Clinical, Histopathologic and Genetic Heterogeneity Among 17 Patients from a Portuguese Tertiary Centre.
abstract: Pathogenic variants in ryanodine receptor type 1 (RYR1) gene are an important cause of congenital myopathy. The clinical, histopathologic and genetic spectrum is wide.
  
  
  
  Review a group of the patients diagnosed with ryanodinopathy in a tertiary centre from North Portugal, as an attempt to define some phenotypical patterns that may help guiding future diagnosis.
  
  
  
  Patients were identified from the database of the reference centre for Neuromuscular Disorders in North Portugal. Their data (clinical, histological and genetic) was retrospectively accessed.
  
  
  
  Seventeen RYR1-related patients (including 4 familial cases) were identified. They were divided in groups according to three distinctive clinical characteristics: extraocular muscle (EOM) weakness (N = 6), disproportionate axial muscle weakness (N = 2) and joint laxity (N = 5). The fourth phenotype includes patients with mild tetraparesis and no distinctive clinical features (N = 4). Four different histopathological patterns were found: centronuclear (N = 5), central core (N = 4), type 1 fibres predominance (N = 4) and congenital fibre type disproportion (N = 1) myopathies. Each index case, except two patients, had a different RYR1 variant. Four new genetic variants were identified. All centronuclear myopathies were associated with autosomal recessive inheritance and EOM weakness. All central core myopathies were caused by pathogenic variants in hotspot 3 with autosomal dominant inheritance. Three genetic variants were reported to be associated to malignant hyperthermia susceptibility.
  
  
  
  Distinctive clinical features were recognized as diagnostically relevant: extraocular muscle weakness (and centronuclear pattern on muscle biopsy), severe axial weakness disproportionate to the ambulatory state and mild tetraparesis associated with (proximal) joint laxity. There was a striking genetic heterogeneity, including four new RYR1 variants.
authors.affiliation: Department of Neurology, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Samões
authors.affiliation: Unidade de Genética Molecular, Centro de Genética Médica, Centro Hospitalar do Porto, Porto, Portugal.|Unidade Multidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Oliveira
authors.affiliation: Neuropathology Unit, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Taipa
authors.affiliation: Department of Neurophysiology and Neuromuscular Disorders Outpatient Clinic, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Teresa
authors.initials: T
authors.lastname: Coelho
authors.affiliation: Department of Neurophysiology and Neuromuscular Disorders Outpatient Clinic, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Márcio
authors.initials: M
authors.lastname: Cardoso
authors.affiliation: Unidade de Genética Molecular, Centro de Genética Médica, Centro Hospitalar do Porto, Porto, Portugal.|Unidade Multidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Gonçalves
authors.affiliation: Unidade de Genética Molecular, Centro de Genética Médica, Centro Hospitalar do Porto, Porto, Portugal.|Unidade Multidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.|UCIBIO/REQUIMTE, Departamento de Ciências Biológicas, Laboratório de Bioquímica, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
authors.forename: Rosário
authors.initials: R
authors.lastname: Santos
authors.affiliation: Neuropathology Unit, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Manuel
authors.initials: M
authors.lastname: Melo Pires
authors.affiliation: Neuromuscular Disorders Outpatient Clinic and Department of Neuropaediatrics, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Manuela
authors.initials: M
authors.lastname: Santos
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D018740:Genetic Heterogeneity; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D007593:Joint Instability / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D018908:Muscle Weakness / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology*; D009135:Muscular Diseases / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D020914:Myopathies, Structural, Congenital / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D020512:Myopathy, Central Core / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009801:Oculomotor Muscles / Q000473:pathology / Q000503:physiopathology*; D010291:Paresis / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D010641:Phenotype; D011174:Portugal; D012189:Retrospective Studies; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D012720:Severity of Illness Index; D062606:Tertiary Care Centers; D055815:Young Adult
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel
keywords: Central core; RYR1; centronuclear; congenital myopathies; joint laxity; malignant hyperthermia; myopathy; ryanodine receptor 1