Rippling muscle disease (RMD) is a rare disorder of muscle hyperexcitability. It is characterized by rippling wave-like muscle contractions induced by mechanical stretch or voluntary contraction followed by sudden stretch, painful muscle stiffness, percussion-induced rapid muscle contraction (PIRC), and percussion-induced muscle mounding (PIMM). RMD can be hereditary (hRMD) or immune-mediated (iRMD). hRMD is caused by pathogenic variants in caveolin-3 (CAV3) or caveolae-associated protein 1/ polymerase I and transcript release factor (CAVIN1/PTRF). CAV3 pathogenic variants are autosomal dominant or less frequently recessive while CAVIN1/PTRF pathogenic variants are autosomal recessive. CAV3-RMD manifests with a wide spectrum of clinical phenotypes, ranging from asymptomatic creatine kinase elevation to severe muscle weakness. Overlapping phenotypes are common. Muscle caveolin-3 immunoreactivity is often absent or diffusely reduced in CAV3-RMD. CAVIN1/PTRF-RMD is characterized by congenital generalized lipodystrophy (CGL, type 4) and often accompanied by several extra-skeletal muscle manifestations. Muscle cavin-1/PTRF immunoreactivity is absent or reduced while caveolin-3 immunoreactivity is reduced, often in a patchy way, in CAVIN1/PTRF-RMD. iRMD is often accompanied by other autoimmune disorders, including myasthenia gravis. Anti-cavin-4 antibodies are the serological marker while the mosaic expression of caveolin-3 and cavin-4 is the pathological feature of iRMD. Most patients with iRMD respond to immunotherapy. Rippling, PIRC, and PIMM are usually electrically silent. Different pathogenic mechanisms have been postulated to explain the disease mechanisms. In this article, we review the spectrum of hRMD and iRMD, including clinical phenotypes, electrophysiological characteristics, myopathological findings, and pathogenesis.

Rippling muscle disease (RMD) is characterized by muscle stiffness, muscle hypertrophy, and rippling muscle induced by stretching or percussion. Hereditary RMD is due to sequence variants in the CAV3 and PTRF/CAVIN1 genes encoding Caveolin-3 or Cavin-1, respectively; a few series of patients with acquired autoimmune forms of RMD (iRMD) associated with AChR antibody-positive myasthenia gravis and/or thymoma have also been described. Recently, MURC/caveolae-associated protein 4 (Cavin-4) autoantibody was identified in 8 of 10 patients without thymoma, highlighting its potential both as a biomarker and as a triggering agent of this pathology. Here, we report the case of a patient with iRMD-AchR antibody negative associated with thymoma. We suspected a paraneoplastic origin and investigated the presence of specific autoantibodies targeting muscle antigens through a combination of Western blotting and affinity purification coupled with mass spectrometry-based proteomic approaches. We identified circulating MURC/Cavin-4 autoantibodies and found strong similarities between histologic features of the patient's muscle and those commonly reported in caveolinopathies. Strikingly, MURC/Cavin-4 autoantibody titer strongly decreased after tumor resection and immunotherapy correlating with complete disappearance of the rippling phenotype and full patient remission. MURC/Cavin-4 autoantibodies may play a pathogenic role in paraneoplastic iRMD associated with thymoma.

In February 2020, a 51-year-old woman experienced leg myalgia and noticed calf muscle movements that resembled a rippling wave while crouching down. In June 2020, she complained of bilateral arm myalgia. In August 2020, she developed left ptosis, had difficulty raising her bilateral arms, and developed diplopia and was admitted to our hospital. Anti-acetylcholine receptor antibodies turned out to be positive. We made a diagnosis of myasthenia gravis and acquired rippling muscle disease (RMD). Her myasthenia gravis symptoms and myalgia decreased with oral prednisolone. Contrast-enhanced computed tomography revealed thymoma. She underwent extended thymectomy and was discharged from the hospital. Her myalgia worsened, but it was responsive to methylprednisolone pulse therapy. CAV3 gene mutations are recognized as causes of congenial RMD whereas acquired RMD is associated with myasthenia gravis. Acquired RMD is rarely reported in Japan, but should be kept in mind as a condition treatable with immunotherapy.

Immune-mediated rippling muscle disease (iRMD) is a rare myopathy characterized by wavelike muscle contractions (rippling) and percussion- or stretch-induced muscle mounding. A serological biomarker of this disease is lacking. To describe a novel autoantibody biomarker of iRMD and report associated clinicopathological characteristics. This retrospective cohort study evaluated archived sera from 10 adult patients at tertiary care centers at the Mayo Clinic, Rochester, Minnesota, and Brigham & Women's Hospital, Boston, Massachusetts, who were diagnosed with iRMD by neuromuscular specialists in 2000 and 2021, based on the presence of electrically silent percussion- or stretch-induced muscle rippling and percussion-induced rapid muscle contraction with or without muscle mounding and an autoimmune basis. Sera were evaluated for a common biomarker using phage immunoprecipitation sequencing. Myopathology consistent with iRMD was documented in most patients. The median (range) follow-up was 18 (1-30) months. Diagnosis of iRMD. Detection of a common autoantibody in serum of patients sharing similar clinical and myopathological features. Seven male individuals and 3 female individuals with iRMD were identified (median [range] age at onset, 60 [18-76] years). An IgG autoantibody specific for caveolae-associated protein 4 (cavin-4) was identified in serum of patients with iRMD using human proteome phage immunoprecipitation sequencing. Immunoassays using recombinant cavin-4 confirmed cavin-4 IgG seropositivity in 8 of 10 patients with iRMD. Results for healthy and disease-control individuals (n = 241, including myasthenia gravis and immune-mediated myopathies) were cavin-4 IgG seronegative. Six of the 8 individuals with cavin-4 IgG were male, and the median (range) age was 60 (18-76) years. Initial symptoms included rippling of lower limb muscles in 5 of 8 individuals or all limb muscles in 2 of 8 sparing bulbar muscles, fatigue in 9 of 10, mild proximal weakness in 3 of 8, and isolated myalgia in 1 of 8, followed by development of diffuse rippling. All patients had percussion-induced muscle rippling and half had percussion- or stretch-induced muscle mounding. Four of the 10 patients had proximal weakness. Plasma creatine kinase was elevated in all but 1 patient. Six of the 10 patients underwent malignancy screening; cancer was detected prospectively in only 1. Muscle biopsy was performed in 7 of the 8 patients with cavin-4 IgG; 6 of 6 specimens analyzed immunohistochemically revealed a mosaic pattern of sarcolemmal cavin-4 immunoreactivity. Three of 6 patients whose results were seropositive and who received immunotherapy had complete resolution of symptoms, 1 had mild improvement, and 2 had no change. The findings indicate that cavin-4 IgG may be the first specific serological autoantibody biomarker identified in iRMD. Depletion of cavin-4 expression in muscle biopsies of patients with iRMD suggests the potential role of this autoantigen in disease pathogenesis.