Long-term Natural History of Pediatric Dominant and Recessive RYR1 Related Myopathy.

Abstract

RYR1-related myopathies are the most common congenital myopathies, but long term natural history data is still scarce. We aim to describe the natural history of dominant and recessive RYR1-related myopathies. Cross-sectional and longitudinal retrospective data analysis of pediatric cases with RYR1-related myopathies seen between 1992-2019 in two large UK centres. Patients were identified and data collected from individual medical records. 69 patients were included in the study, 63 in both cross-sectional and longitudinal studies, and 6 in the cross-sectional analysis only. Onset ranged from birth to 7 years. Twenty-nine patients had an autosomal dominant RYR1-related myopathy, 31 recessive, 6 de novo dominant and 3 uncertain inheritance. Median age at first and last appointment was 4.0 and 10.8 years, respectively. Fifteen% of patients older than 2 years never walked (5 recessive, 4 de novo dominant and 1 dominant patient) and 7% lost ambulation during follow up. Scoliosis and spinal rigidity were present in 30% and 17% of patients, respectively. Respiratory involvement was observed in 22% of patients, and 12% needed ventilatory support from a median age of 7 years. Feeding difficulties were present in 30% of patients and 57% of those needed gastrostomy or tube feeding. There were no anaesthetic-induced malignant hyperthermia episodes reported in this cohort. We observed a higher prevalence of prenatal/neonatal features in recessive patients, in particular hypotonia and respiratory difficulties. Clinical presentation, respiratory and feeding outcomes were consistently more severe at presentation and in the recessive group. Conversely, longitudinal analysis suggested a less progressive course for motor and respiratory function in recessive patients. Annual change in forced vital capacity was -0.2%/year in recessive vs -1.4%/year in dominant patients. This clinical study provides long-term data on disease progression in RYR1-related myopathies that may inform management and provide essential milestones for future therapeutic interventions.