Clinical and laboratory studies are conducted to determine etiology (infection, immunity and/or genetics) of various diseases of the neuromuscular system and design effective therapies. Current studies involve patients with polymyositis, dermatomyositis, inclusion body myositis, motor neuron diseases including post-polio syndrome, demyelinating polyneuropathies, neuromuscular diseases associated with HIV infection, metabolic myopathies, hypokalemic periodic paralysis, certain dystrophies, myasthenia gravis, diabetic neuropathies and stiff-man syndrome. Persistent or mutant poliovirus is sought in patients with post-polio syndrome and ALS. The mechanism of post-polio fatigue, a common and disabling symptom in many patients, is examined by analysis of the neuroendocrine axis, magnetic resonance spectroscopy and sleep studies. In inflammatory myopathies, the role of cytokines TGF-beta and IL-1 and metalloproteins MMP-2 and MMP-9 in promoting amyloid formation and persistent endomysial inflammation were studied. The antigenic specificity and in situ clonal expansion of the endomysial T cells of patients with inflammatory myopathies and neuropathies was studied by examining the T cell receptor profile and sequencing the CD3 region. The capacity of the muscle fiber or the Schwann cell to behave as antigen-present cells and bind to their ligands, CTLA-4 and CD28, on T cells was examined. The lack of apoptosis in muscle and T cells was explored by studying IAP-like proteins and mRNA expression. The mechanism by which anti-retroviral nucleoside analogs cause mitochondrial dysfunction and mDNA deletion in muscle and nerve was investigated. The cytotoxic basis of anti-GAD antibodies in patients with stiff-man syndrome was investigated and changes in the antibody titers were studied in vivo and in vitro as well as during therapy. The role of amphiphysin and GAD in this disease, as well as other autoimmune disorders affecting synaptic transmission, are being explored. The cause of distal myopathies associated with cardiomyopathies was examined and mutations in the desmin gene were discovered in the same patients. The functional role of these mutations was studied in transfected cell lines. The type of glucolipids recognized as antigens by certain IgM-associated paraproteinemic neuropathies was also examined.Randomized-controlled clinical trials are being conducted with high-dose intravenous immunoglobulin in patients with polymyositis, dermatomyositis, inclusion body myositis, chronic inflammatory and paraproteinemic demyelinating polyneuropathies, and stiff-man syndrome. A similar study in diabetic proximal autoimmune neuropathy will soon begin. Experimentally, the suppression of the endomysial inflammatory response in TGF-beta double knock-out mice was studied using fibronectin peptide motifs as experimental therapies. - Myopathies, Neuropathies, Motor neuron diseases, Immunology, Virology and toxicology of muscle and nerve, Immunotherapies - Human Subjects

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Intramural Research (Z01)
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Special Emphasis Panel (MNB)
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Dalakas, Marinos C; Rakocevic, Goran; Salajegheh, Mohammad et al. (2009) Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein antibody demyelinating neuropathy. Ann Neurol 65:286-93
Lupu, Vitalie D; Mora, Carlos A; Dambrosia, Jim et al. (2007) Terminal latency index in neuropathy with antibodies against myelin-associated glycoproteins. Muscle Nerve 35:196-202
Vasconcelos, O M; Prokhorenko, O A; Salajegheh, M K et al. (2007) Modafinil for treatment of fatigue in post-polio syndrome: a randomized controlled trial. Neurology 68:1680-6
Schreiner, Bettina; Voss, Joachim; Wischhusen, Jorg et al. (2006) Expression of toll-like receptors by human muscle cells in vitro and in vivo: TLR3 is highly expressed in inflammatory and HIV myopathies, mediates IL-8 release and up-regulation of NKG2D-ligands. FASEB J 20:118-20
Goudeau, Bertrand; Rodrigues-Lima, Fernando; Fischer, Dirk et al. (2006) Variable pathogenic potentials of mutations located in the desmin alpha-helical domain. Hum Mutat 27:906-13
Dalakas, Marinos C (2006) Therapeutic targets in patients with inflammatory myopathies: present approaches and a look to the future. Neuromuscul Disord 16:223-36
Dalakas, Marinos C (2006) The role of high-dose immune globulin intravenous in the treatment of dermatomyositis. Int Immunopharmacol 6:550-6
Briani, C; Doria, A; Sarzi-Puttini, P et al. (2006) Update on idiopathic inflammatory myopathies. Autoimmunity 39:161-70
Vasconcelos Jr, Olavo M; Prokhorenko, Olga A; Kelley, Kay F et al. (2006) A comparison of fatigue scales in postpoliomyelitis syndrome. Arch Phys Med Rehabil 87:1213-7
Dalakas, Marinos C (2006) Inflammatory, immune, and viral aspects of inclusion-body myositis. Neurology 66:S33-8

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