Case Report: RYR1-related myopathy with hypoxic ischemic encephalopathy—a case of severe neonatal presentation due to a de novo variant of uncertain significance

Vollständiger Abstract

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Pathogenic variants in the Ryanodine Receptor 1 (RYR1) gene represent the most common cause of congenital myopathy. The severity of RYR1-related myopathy presenting in the neonatal period is quite variable, ranging from a perinatal lethal type to a benign late-onset form with progressive improvement. We report a newborn infant who presented at birth with severe hypoxic ischemic encephalopathy (HIE), underwent therapeutic hypothermia (TH), and was later diagnosed with RYR1-related myopathy. Exome sequencing identified a de novo variant of uncertain significance (VUS) in the RYR1 gene (c.14564T>G). The clinical course of the patient was complicated by severe generalized hypotonia, persistent respiratory failure requiring mechanical ventilation, hypocalcemia, chylothorax, and eventual redirection of care with death at 1 month of life. The infant's phenotype included congenital fractures, arthrogryposis, macrocephaly, and cryptorchidism. The phenotype overlapped with the clinical findings of RYR1-related myopathy, providing evidence supportive of the pathogenicity of the identified VUS. Our report aims to be the first step in generating evidence for the reclassification of this VUS. We also review the literature on the spectrum of neonatal presentations and outcomes of RYR1-related myopathy, with particular emphasis on HIE, and discuss the role of TH in infants with underlying congenital or genetic disorders.