Clinical Phenotype Spectrum in Two Large Chinese Families With Rippling Muscle Disease Caused by CAV-3 c.80G>A.

Rippling muscle disease (RMD) is a rare benign myotonic myopathy caused by pathogenic variants in the caveolin-3 (CAV-3) gene and is characterized by highly irritable muscles, transient localized muscle bulges, and ripple-like contractions. There is still a lack of systematic understanding of the phenotypic spectrum of RMD. In this study, clinical data were collected from patients with RMD. The analysis of the pathogenic variants in the CAV-3 gene was conducted by next-generation sequencing and Sanger sequencing. Changes in the expression of the CAV3 protein were analyzed by immunohistochemistry and western blotting. In addition, we performed a literature review of previously reported RMD patients. A total of 12 patients with RMD were clinically diagnosed in two families. All patients presented with childhood-onset exercise intolerance, muscle stiffness, and myalgia after exercise. Percussion-induced rapid muscle mounding and contractions were observed in all patients. Electromyography revealed myogenic damage in Patient 1 and Patient 2. Muscle MRI of the thigh and leg suggested mild muscle atrophy in Patient 2. Muscle pathology revealed nonspecific myopathy-like changes in Patient 2. A heterozygous variant c.80G>A (p.Arg27Gln) in the CAV3 gene was identified in all patients with RMD. Immunohistochemical and western blot analyses revealed reduced expression of the CAV3 protein in muscle tissue. These results demonstrated the clinical, electromyographical, and pathological features of RMD patients in two large Chinese families, with reviewing the literature, provide a better understanding of the variable RMD phenotypes. Trial Registration: SJNKHDJ20221213160659.