Clinical and laboratory studies are conducted to determine etiology (infection, immunity and/or genetics) of chronic diseases of the neuromuscular system and design effective therapies. Current studies involve patients with polymyositis/dermatomyositis (PM/DM), post-polio syndrome, amyotrophic lateral sclerosis (ALS), demyelinating polyneuropathies, neuromuscular diseases associated with HIV infection, and hypokalemic periodic paralysis. The pathogenesis of post-polio syndrome is explored with a series of electrophysiologic, virologic, immunologic and histologic studies. The findings are compared with those seen in patients with acute paralytic poliomyelitis and other motor neuron diseases. Persistent or mutant poliovirus is sought in these patients' tissues using tissue cultures, polymerase chain reaction (PCR), and in situ hybridization. Because abnormal immunoregulation was found in some patients, a double-blind placebo-controlled trial using prednisone is conducted. The mechanism of post-polio fatigue, a common and disabling symptom in many patients, is under study. The spectrum of neuromuscular disorders associated with HIV infection has been studied and the role of the virus as the cause of neuropathy or myopathy is investigated with a variety of immunocytochemical studies, in situ hybridization and PCR. The antiretroviral drug AZT was found to cause a specific myopathy with abnormal mitochondria on the basis of various morphologic, molecular, biochemical and immunocytochemical studies. A longitudinal study of HIV- positive patients that develop myopathic symptoms while on AZT is conducted with serial muscle biopsies to assess factors associated with the development of myopathy and design effective therapies. The metabolic basis of fatigue is studied in patients with mitochondrial myopathies, post-polio syndrome, chronic fatigue syndrome and HIV- or AZT-associated myopathies using exercise magnetic resonance spectroscopy. Randomized-controlled clinical trials are conducted with high-dose intravenous immunoglobulin (IVIg) in patients with PM/DM, chronic inflammatory and paraproteinemic demyelinating polyneuropathies and ALS. A controlled study using dichlorophenamide, a carbonic anhydrase inhibitor, is ready to begin in patients with hypokalemic periodic paralysis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Intramural Research (Z01)
Project #
1Z01NS002038-18
Application #
3846161
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
1992
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
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
Albrecht, J; Atzeni, F; Baldini, C et al. (2006) Skin involvement and outcome measures in systemic autoimmune diseases. Clin Exp Rheumatol 24:S52-9
Dalakas, Marinos C (2006) Mechanisms of disease: signaling pathways and immunobiology of inflammatory myopathies. Nat Clin Pract Rheumatol 2:219-27
Raju, Raghavan; Rakocevic, Goran; Chen, Ziwei et al. (2006) Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome. Brain 129:3270-6
Dalakas, Marinos C (2006) Sporadic inclusion body myositis--diagnosis, pathogenesis and therapeutic strategies. Nat Clin Pract Neurol 2:437-47
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

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