Miastenia Grave

Páginas: 48 (11862 palabras) Publicado: 13 de abril de 2011
Science in medicine

Myasthenia gravis: past, present, and future
Bianca M. Conti-Fine,1 Monica Milani,1 and Henry J. Kaminski2

of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA. 2Departments of Neurology and Neurosciences, Case Western Reserve University, Louis Stokes Cleveland Veterans Affairs Medical Center,Cleveland, Ohio, USA.

Myasthenia gravis (MG) is an autoimmune syndrome caused by the failure of neuromuscular transmission, which results from the binding of autoantibodies to proteins involved in signaling at the neuromuscular junction (NMJ). These proteins include the nicotinic AChR or, less frequently, a muscle-specific tyrosine kinase (MuSK) involved in AChR clustering. Much is known about themechanisms that maintain self tolerance and modulate anti-AChR Ab synthesis, AChR clustering, and AChR function as well as those that cause neuromuscular transmission failure upon Ab binding. This insight has led to the development of improved diagnostic methods and to the design of specific immunosuppressive or immunomodulatory treatments.
Acquired  myasthenia  gravis  (MG)  is  an uncommon  disorder  (200–400 cases per million; ref. 1). Its symptoms are caused by a  characteristic muscle weakness that worsens after use of affected  muscles. In about two-thirds of patients, the extrinsic ocular  muscles (EOMs) present the initial symptoms. The symptoms  usually  progress  to  the  other  bulbar  muscles  and  limb muscles, resulting in generalized MG (gMG). In about 10% of MG  patients, symptoms remain limited to the EOM, and this condition is termed ocular MG (oMG). MG fulfills the strict criteria of an Ab-mediated autoimmune  disorder: (a) Abs are present at the site of pathology, the neuromuscular junction (NMJ); (b) Ig from MG patients or anti-AChR Abs from experimental animals cause MG symptoms when injected into rodents; (c) immunization of animals with AChR reproduces the disease; and (d) therapies that remove Abs decrease the  severity of MG symptoms. Historical perspective The first described case of MG is likely that of the Native American  Chief Opechancanough, who died in 1664, as reported by Virginian chroniclers: “The excessive fatigue he encountered wrecked  his constitution; his flesh became macerated; his sinews lost their  tone and elasticity; and his eyelids were so heavy that he could not see unless they were lifted up by his attendants . . . he was unable  to walk; but his spirit rising above the ruins of his body directed  from the litter on which he was carried by his Indians” (2). In 1672,  the English physician Thomas Willis described a patient with the “fatiguable weakness” of limbs and bulbar muscles characteristic of MG (3). In the late 1800s, the first modern descriptions of  patients with myasthenic symptoms were published (3), and the  name myasthenia gravis was coined by fusing the Greek terms for  muscle and weakness to yield the noun myasthenia and adding the  Latin adjective gravis, which means severe (4). Attempts at rational treatments of MG began in the 1930s. A  major step forward occurred in 1934 when Mary Walker realized  that MG symptoms were similar to those of curare poisoning, Nonstandard abbreviations used: AChE, acetylcholinesterase; APL, altered peptide  ligand; EAMG, experimental autoimmune MG; EOM, extrinsic ocular muscle; EPP,  endplate potential; gMG, generalized MG; IVIg, intravenous Ig; MG, myasthenia   gravis; MuSK, muscle-specific tyrosine kinase; NMJ, neuromuscular junction;   oMG, ocular MG. Conflict ofinterest: The authors have declared that no conflict of interest exists. Citation for this article: J. Clin. Invest. 116:2843–2854 (2006). doi:10.1172/JCI29894. 

which was treated with physostigmine, a cholinesterase inhibitor. She showed that physostigmine promptly improved myasthenic symptoms (5), making anticholinesterase drugs a staple ...
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