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Abstract Details

Identification of Calcium Dysregulation in Immune-mediated Rippling Muscle Disease
Neuromuscular and Clinical Neurophysiology (EMG)
P8 - Poster Session 8 (5:30 PM-6:30 PM)
11-001
To investigate the pathophysiologic mechanisms underlying immune-mediated Rippling Muscle Disease (iRMD).
Rippling Muscle Disease (RMD) is a rare skeletal myopathy characterized by abnormal muscular excitability manifesting with wave-like muscle contractions and stretch-induced muscle mounding. Hereditary RMD is associated with caveolin-3 or cavin-1 mutations. Recently we discovered anti-cavin 4 autoantibodies as a biomarker of iRMD, but the underlying disease-mechanisms are poorly understood.
Transcriptomic studies were performed on muscle biopsies of 8 patients (5 males; 3 females; ages 26-to-80) with iRMD.  Subsequent pathway analysis compared iRMD to human non-disease control and disease-control (dermatomyositis) muscle samples. Confirmatory immunohistochemistry for protein level quantification was performed.
Transcriptomic studies demonstrated changes in key pathways of muscle homeostasis, including muscle development, protein quality control, and autoimmunity. All iRMD samples had significantly upregulated cavin-4 expression compared to controls, likely compensatory for autoantibody-mediated protein degradation. Excitation-Contraction coupling genes (including SERCA1, PMCA, PLN and CACNA1S) were significantly upregulated in iRMD compared to controls. These changes were validated with immunofluorescent staining for SERCA1, PMCA, PLN and CACNA1S which confirmed increased protein levels except for CACNA1S. Comparison of iRMD to dermatomyositis transcriptomics demonstrated significant overlap in autoimmunity pathways including MHC2 antigen presentation and innate immune response.
This study represents the first muscle transcriptomic analysis of iRMD patients and elucidates the underlying disease mechanisms. Increases of sarcolemmal and cellular calcium channels as well as PLN, an inhibitor of the SERCA pump for calcium into the sarcoplasm, likely alter the calcium dynamics in iRMD. These changes in crucial components of Excitation-Contraction coupling and muscle relaxation pathways may underlie rippling by altering calcium flux. We propose a model in which autoantibody mediated cavin-4 destruction leads to RMD through alterations in key genes regulating Excitation-Contraction coupling. 

Authors/Disclosures
Samir R. Nath, MD, PhD (Mayo Clinic)
PRESENTER 		An immediate family member of Dr. Nath has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Update Neurology.
Aneesha Dasgupta (IUPUI) No disclosure on file
Divyanshu Dubey, MD, FAAN (Mayo Clinic) The institution of Dr. Dubey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Argenx. The institution of Dr. Dubey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arialys. The institution of Dr. Dubey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB . Dr. Dubey has received research support from Department of Defense . Dr. Dubey has received research support from Department of Defense . Dr. Dubey has received research support from UCB. Dr. Dubey has received research support from David J. Tomassoni ALS Research Grant Program . Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care.
Eileen Kokesh (Mayo Clinic) No disclosure on file
Teerin Liewluck, MD, FAAN (Department of Neurology, Mayo Clinic) Dr. Liewluck has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta Therapeutics. Dr. Liewluck has received publishing royalties from a publication relating to health care.
Grayson B. Beecher, MD (University of Alberta) Dr. Beecher has nothing to disclose.
Sean J. Pittock, MD, FAAN (Mayo Clinic Dept of Neurology) Dr. Pittock has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arialys. The institution of Dr. Pittock has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. The institution of Dr. Pittock has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. The institution of Dr. Pittock has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche/Genentech. The institution of Dr. Pittock has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Alexion/AstraZeneka. The institution of Dr. Pittock has received research support from NIH. Dr. Pittock has received intellectual property interests from a discovery or technology relating to health care. Dr. Pittock has received intellectual property interests from a discovery or technology relating to health care. Dr. Pittock has received publishing royalties from a publication relating to health care.
Jason Doles (Indiana University) No disclosure on file
William J. Litchy, MD, FAAN Dr. Litchy has nothing to disclose.
Margherita Milone, MD, FAAN (Mayo Clinic) Dr. Milone has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cartesian Therapeutics. Dr. Milone has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology Genetics, AAN. The institution of Dr. Milone has received research support from Mayo Clinic, CCaTS-CBD. The institution of Dr. Milone has received research support from Mayo Clinic, SGP Award. The institution of Dr. Milone has received research support from MDA for Care Center grant. The institution of Dr. Milone has received research support from Regenerative medicine Minnesota.