CHANNELOPATHIES AND RELATED DISORDERS: EP.225 Autosomal dominant early onset vacuolar myopathy with granular material, without periodic paralysis, associated with c.1583C>A CACNA1S gene mutation

Abstract

Dominant mutations in CACNA1S gene mainly causes hypokalemic periodic paralysis (PP)(hypoPP). We report a patient with progressive early onset myopathy associated with heterozygous CACNA1S mutation and aim to extend the description of phenotypical spectrum of CACNA1S-related muscle diseases. A 68-year-old man developed progressive proximal weakness from the age of 35 years. He had four siblings including an affected brother. His mother had PP and became wheelchair bound at 55 years. CK level was elevated (<1.5 upper normal value). Electroneuromyography showed axonal sensorimotor polyneuropathy and myogenic potentials. Thigh magnetic resonance imaging showed extensive muscle fatty replacement and muscle biopsy showed atrophic fibers with vacuoles containing granular material. Clinical exome identified the heterozygous c.1583G>A well-known pathogenic variant in CACNA1S. The patient's brother had PP from the age of 27. Neurological examination was normal at the age of 39. Muscle biopsy showed a vacuolar myopathy with granular material. No further medical information was available. The patient died at the age of 72 yrs. Molecular characterisation was not achieved. CACNA1S-HypoPP evolving to fixed myopathy in late adulthood is well described but isolated progressive myopathy was only exceptionally reported and never with an onset <50 years. We hereby report the earliest “myopathy onset” ever described, enlarging the phenotypical spectrum of CACNA1S-related myopathies and suggest considering it even in young adult-onset myopathies, especially when granular vacuoles are present.