C.P.4 Congenital fiber type disproportion with myofibrillar disorganization and altered internal nuclei is caused by RYR1 mutation

Abstract

Mutations in the gene encoding skeletal muscle ryanodine receptor (RYR1) have been implicated in various forms of neuromuscular diseases including congenital myopathy. There is a broad range of clinical and pathological features including central core disease, congenital neuromuscular disease with uniform type 1, multiminicore disease, core-rod myopathy, and malignant hyperthermia susceptibility. Here we describe a group of patients with RYR1 mutations showing a unique muscle pathology. We chose seven unrelated Japanese patients among 12,000 frozen muscle biopsies in NCNP, based on the characteristic pathological findings including fiber type disproportion), marked type 1 fiber predominance, and scattered fibers with abnormal internal nuclei. On NADH-TR stain, myofibrillar disorganization was commonly seen. Unique fibers characterized by darkly-stained central portion with multiple small vacuoles were seen in three patients. On electron microscopy, center of muscle fibers were frequently occupied by aggregations of enlarged, vacuolated sarcoplasmic reticulum and abnormal shaped nuclei. Clinically, all seven patients showed axial and proximal dominant muscle weakness of variable severity from neonatal period, and often required respiratory supports. Muscle weakness was stable or rather improved during childhood. In addition, some patients revealed ptosis and/or ophthalmoparesis. All patients had compound heterozygous mutations in the central portion of RYR1 distributed between 18 and 66. In conclusion, mutations in RYR1 gene are associated with a unique myopathy characterized as congenital fiber type disproportion associated with myofibrillar disorganization and altered internal nuclei. These pathological changes may be closely related to degeneration of sarcoplasmic reticulum.