Atypical periodic paralysis and myalgia: A novel <i>RYR1</i> phenotype.

Abstract

To characterize the phenotype of patients with symptoms of periodic paralysis (PP) and ryanodine receptor (<i>RYR1</i>) gene mutations. Cases with a possible diagnosis of PP but additional clinicopathologic findings previously associated with <i>RYR1-</i>related disorders were referred for a tertiary neuromuscular clinical assessment in which they underwent detailed clinical evaluation, including neurophysiologic assessment, muscle biopsy, and muscle MRI. Genetic analysis with next-generation sequencing and/or targeted Sanger sequencing was performed. Three cases with episodic muscle paralysis or weakness and additional findings compatible with a <i>RYR1</i>-related myopathy were identified. The McManis test, used in the diagnosis of PP, was positive in 2 of 3 cases. Genetic analysis of known PP genes was negative. <i>RYR1</i> analysis confirmed likely pathogenic variants in all 3 cases. <i>RYR1</i> mutations can cause late-onset atypical PP both with and without associated myopathy. Myalgia and cramps are prominent features. The McManis test may be a useful diagnostic tool to indicate <i>RYR1</i>-associated PP. We propose that clinicopathologic features suggestive of <i>RYR1</i>-related disorders should be sought in genetically undefined PP cases and that <i>RYR1</i> gene testing be considered in those in whom mutations in <i>SCN4A, CACNA1S</i>, and <i>KCNJ2</i> have already been excluded.