By Federica Montagnese
JAMA Neurol. 2022;79(8):808-816.
Identification of Caveolae-Associated Protein 4 Autoantibodies as a Biomarker of Immune-Mediated Rippling Muscle Disease in Adults
Divyanshu Dubey et al.
Immune-mediated rippling muscle disease (iRMD) is a rare myopathy characterized by abnormal muscle excitability. It is usually electrically silent, exhibiting wavelike muscle contractions (rippling) and percussion- or stretch-induced muscle mounding. In contrast to hereditary rippling muscle disease (hRMD), associated to date with pathogenic variants in caveolin-3 (CAV3) or, less frequently, cavin-1 (CAVIN1) genes, patients with iRMD lack a defined genetic defect. Biopsied muscles of patients with iRMD demonstrates a mosaic pattern of caveolin-3 deficiency and endomysial lymphocytic inflammatory exudate in some patients suggesting an immune-mediated pathogenesis, further supported by its responsiveness to immunotherapy. A disease-causing or disease-associated antibody has however not been identified thus far.
In this recently published manuscript, the authors retrospectively examined the sera and clinical features of 10 patients with iRMD. Phage immunoprecipitation sequencing was used to identify IgG specific for caveolae associated protein 4 (cavin-4) in sera of iRMD patients compared to patients with other autoimmune myopathies, neuromuscular junction disorders and healthy controls. The cavin-4–reactive IgG was found in 8/10 iRMD patients and was of IgG1 subclass. None of the sera from disease-control individuals (98 with immune-mediated myopathy or neuromuscular junction disorders and 20 with autoimmune CNS diseases) or 123 healthy control individuals contained cavin-4–reactive IgG.
The authors then described the clinical and histopathological characteristics of patients with iRMD and Cavin-4 IgG. Patchy sarcolemmal deficiency of cavin-4 immunoreactivity in more than 50% of muscle fibers was documented in all patients with cavin-4 IgG with available muscle histopathology.
In summary, this study 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.
Dr. Divyanshu Dubey is an Associate Professor of Neurology and Laboratory Medicine & Pathology at Mayo Clinic, Rochester, MN. His research focus is peripheral and central autoimmune neurological conditions. This includes search for novel biomarkers and analysis of clinical and radiological features of autoimmune neurological disorders. He has played a crucial role in the discovery of multiple neural specific antibody biomarkers of neurological autoimmunity including KLHL11 IgG, LUZP4 IgG and cavin-4 IgG.
Published on 25 August 2022.
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This article is presented by the Publication Highlights Committee.