Affiliations: [a] Department of Neurology, Centro Hospitalar do Porto, Porto, Portugal
| [b] Unidade de Genética Molecular, Centro de Genética Médica, Centro Hospitalar do Porto, Porto, Portugal
| [c] Unidade Multidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
| [d] Neuropathology Unit, Centro Hospitalar do Porto, Porto, Portugal
| [e] Department of Neurophysiology and Neuromuscular Disorders Outpatient Clinic, Centro Hospitalar do Porto, Porto, Portugal
| [f] UCIBIO/REQUIMTE, Departamento de Ciências Biológicas, Laboratório de Bioquímica, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| [g] Neuromuscular Disorders Outpatient Clinic and Department of Neuropaediatrics, Centro Hospitalar do Porto, Porto, Portugal
Correspondence to: Raquel Samões, Centro Hospitalar do Porto, Serviço de Neurologia, Largo do Prof. Abel Salazar, 4099-001 Porto, Portugal. Tel.: +351967429395; E-mail: [email protected].
Note:  These authors contributed equally to this work.
Abstract: Background: Pathogenic variants in ryanodine receptor type 1 (RYR1) gene are an important cause of congenital myopathy. The clinical, histopathologic and genetic spectrum is wide. Objective: 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. Methods: 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. Results: 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. Conclusions: 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.