From JCI, Journal of Clinical Investigation, after a brief history of the disease the following article presents a unique overview of myasthenia gravis and how treatment may be likely to proceed.
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 the mechanisms 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.
A Brief History of Myasthenia Gravis
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 ...Continue >>>
Bianca M. Conti-Fine1, Monica Milani1 and Henry J. Kaminski2
1Department 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.
Address correspondence to: Bianca M. Conti-Fine, Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church St. SE, Minneapolis, Minnesota 55455, USA. Phone: (612) 624-6796; Fax: (612) 625-2163; E-mail: conti001@umn.edu.
Published November 1, 2006
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