Atypical periodic paralysis and myalgia: A novel RYR1 phenotype

Abstract

Objective: To characterize the phenotype of patients with symptoms of periodic paralysis (PP) and ryanodine receptor (RYR1) gene mutations.

Methods: Cases with a possible diagnosis of PP but additional clinicopathologic findings previously associated with RYR1-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.

Results: Three cases with episodic muscle paralysis or weakness and additional findings compatible with a RYR1-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. RYR1 analysis confirmed likely pathogenic variants in all 3 cases.

Conclusions: RYR1 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 RYR1-associated PP. We propose that clinicopathologic features suggestive of RYR1-related disorders should be sought in genetically undefined PP cases and that RYR1 gene testing be considered in those in whom mutations in SCN4A, CACNA1S, and KCNJ2 have already been excluded.

Figure 1. Histology slides of muscle biopsies taken from case 1 at age (A) 34 and (B) 42 years

(A) Histologic examination of a right quadriceps muscle biopsy performed at age 34 years showed variation in fiber diameter and internalized nuclei with hematoxylin and eosin staining. (B) ATPase histochemistry at pH 4.3 indicated type I fiber predominance with decreased myofibrillar ATPase activity in core-like areas in up to 15% of type I fibers (red arrow). (C) Central absence of staining suggestive of cores was apparent in type I and II fibers in the nicotinamide dinucleotide tetrazolium reductase preparation (black arrows), and central reduction in oxidative enzyme activity was confirmed by succinate dehydrogenase staining (D, black arrow). Scale bar in A represents 100 μm in (A) and (C), 200 μm in (B), and 50 μm in (D).

Figure 2. Histologic examination of a right biceps muscle biopsy

Histologic examination of a right biceps muscle biopsy performed at age 42 years showed (A) variation in fiber diameter and increased internal nuclei with (B) occasional fibers showing central basophilia (arrow) and (C) a small number of necrotic fibers.Gomori trichrome staining suggested regions with reduced mitochondrial staining (arrow). (E) ATPase histochemistry indicated focal type I fiber predominance (darkly stained fibers). (F) Mild central pallor suggestive of cores was apparent in type I and II fibers in the nicotinamide adenine dinucleotide tetrazolium reductase preparation (arrows), and (G) central reduction in oxidative enzyme activity was confirmed by cytochrome oxidase histochemistry. Scale bar in represents 260 μm in (E); 100 μm in (A), (F), and (G); and 50 μm in (B–D).