Ryanodine-related myopathies: Clinical, histopathologic and genetic heterogeneity among 16 patients from a Portuguese tertiary centre

Mutations in the ryanodine receptor 1 (RYR1) gene are an important cause of congenital myopathy. The phenotype has been expanded beyond the classical autosomal dominant (AD) central core myopathy. Additionally, some RYR1 variants confer susceptibility to malignant hyperthermia (MHS) – a life threatening condition. We report the clinical, histopathological and genetic features of a heterogeneous group of 16 RYR1-related paediatric and adult myopathic patients (11 families) from our centre. Patients were grouped according to three distinctive clinical characteristics: extraocular muscle (EOM) weakness (n = 5), predominant axial muscle weakness (n = 2) and excessive joint laxity (n = 5). The remaining four patients had less disabling tetraparesis with or without facial weakness. There was no significant association between EOM weakness and clinical severity. Muscle biopsy performed in 13 patients revealed four different histopathological patterns: centronuclear (n = 4), central core (n = 4), type 1 fibre predominance as the only feature (n = 4) and congenital fibre type disproportion (n = 1) myopathy. Each index case had a different mutation and three had not been previously reported. Three genetic variants known to confer MHS were detected. The compound heterozygote cases with more dispersed mutations along the RYR1 gene and autosomal recessive inheritance were more frequently found within the group with EOM involvement; all cases with a centronuclear histopathological pattern were found in this group. In the remaining patients, there was a higher incidence of mutations in hotspot 3 (exons 93–106) accompanied by AD inheritance; all patients with a central core histopathological presentation were found in this group. Although we have some clinical features to assist diagnosis of RYR1-related congenital myopathy, there is a great variability in clinical presentation and muscle biopsy findings. A multidisciplinary effort is thus particularly important in these cases.