A Rare Case of Severe Congenital RYR1-Associated Myopathy

Abstract

Congenital myopathies are a group of rare inherited diseases, defined by hypotonia and muscle weakness. We report clinical and genetic characteristics of a male preterm newborn, whose phenotype was characterized by severe hypotonia and hyporeactivity, serious respiratory distress syndrome that required mechanical ventilation, clubfoot, and other dysmorphic features. The diagnostic procedure was completed with the complete exome sequencing of the proband and of his parents and his sister, which showed new mutations in the ryanodine receptor gene (RYR1), which maps to chromosome 19q13.2 and encodes the skeletal muscle isoform of a calcium-release channel in the sarcoplasmic reticulum (RyR1). This report confirms that early diagnosis and accurate study of genomic disorders are very important, enabling proper genetic counselling of the reproductive risk, as well as disease prognosis and patient management.

Severe Neonatal RYR1 Myopathy With Pathological Features of Congenital Muscular Dystrophy

“…These cases highlight the value for considering RYR1 pathogenic variants in the evaluation of patients with severe neonatal dystrophic disease, as the identification of these variants may significantly impact clinical decision-making. The clinical and electrodiagnostic features of the patient reported here are also consistent with a patient with a severe congenital muscular dystrophy, in-cluding the macrocephaly reported elsewhere in congenital RYR1 mutations (5)(6)(7).…”

“…While the pathological findings of a congenital muscular dystrophy are not typically associated with RYR1 muscle disease, the clinical phenotype observed in this patient is consistent with the natural clinical course seen in severe RYR1 myopathy. In addition, a recent report described a patient with a similarly severe neonatal course due to RYR1 pathogenic variant, with reported pathology including myofiber atrophy, adipose tissue infiltration, and endomysial fibrosis (5). While classic features of muscular dystrophy including active degeneration and recent regeneration were not described, the previously reported paper likely represents another example of a dystrophic phenotype in the context of a RYR1 pathogenic variant.…”

“…Patients with susceptibility to MH typically show no clinical symptoms unless there is exposure to succinylcholine or inhaled anesthetics, which can then induce life-threatening reactions including rhabdomyolysis, acidosis, muscle rigor, tachycardia, and bleeding abnormalities (4). RYR1 myopathies typically present with early onset muscle weakness and hypotonia of varying severity, possibly accompanied by macrocephaly, ophthalmoplegia, elevated creatine kinase, and type 1 fiber predominance (5)(6)(7). Depending on a patient's RYR1 mutation, they may be predisposed for MH, RYR1 myopathy, or both (3).…”

iPSC-derived progenitor stromal cells provide new insights into aberrant musculoskeletal development and resistance to cancer in down syndrome

“…We also observed a significant down-regulation of Endothelin 1 (EDN1) and Ryanodine receptor 1 (RYR1), which is associated with congenital myopathies 47 , 48 . Within our dataset, this was one of the most down-regulated genes in DS mesodermal progenitor cells (FC = − 6.57, pV = 3.23 × 10 −84 ).…”

Inherited Neuromuscular Disorders: Which Role for Serum Biomarkers?

“…As a result, patients experience recurrent episodes of hyperCKemia and rhabdomyolysis [ 11 , 89 , 90 ]. RYR1-related central core myopathy usually shows elevation of CK [ 91 , 92 , 93 , 94 ], and, in some cases, it can be also normal [ 95 ], AST, ALT and γGT may be elevated or normal [ 93 , 96 ].…”