An unusual ryanodine receptor 1 (RYR1) phenotype: Mild calf-predominant myopathy

Abstract

<div><p><strong>Objective</strong> To identify the genetic defect causing a distal calf myopathy with cores.</p></div><div><p><strong>Methods</strong> Families with a genetically undetermined calf-predominant myopathy underwent detailed clinical evaluation, including EMG/nerve conduction studies, muscle biopsy, laboratory investigations, and muscle MRI. Next-generation sequencing and targeted Sanger sequencing were used to identify the causative genetic defect in each family.</p></div><div><p><strong>Results</strong> A novel deletion-insertion mutation in ryanodine receptor 1 (<em>RYR1</em>) was found in the proband of the index family and segregated with the disease in 6 affected relatives. Subsequently, we found 2 more families with a similar calf-predominant myopathy segregating with unique <em>RYR1</em>-mutated alleles. All patients showed a very slowly progressive myopathy without episodes of malignant hyperthermia or rhabdomyolysis. Muscle biopsy showed cores or core-like changes in all families.</p></div><div><p><strong>Conclusions</strong> Our findings expand the spectrum of <em>RYR1</em>-related disorders to include a calf-predominant myopathy with core pathology and autosomal dominant inheritance. Two families had unique and previously unreported <em>RYR1</em> mutations, while affected persons in the third family carried 2 previously known mutations in the same dominant allele.<br /></p></div>