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Abstract & Commentary
Source: Romi F, et al. Eur J Neurol. 2002;9:55-61.
Among 43 patients with onset of generalized myasthenia gravis (MG) older than age 50, 21 were thymectomized and 22 nonthymectomized. Serum anti-muscle antibodies were assessed annually, pre- and post-operatively, for 2-5 years to determine whether their presence was of prognostic value. By design, all patients were acetylcholine receptor (AChR) antibody-positive. Titin and ryanodine receptor (RyR) antibodies were measured by ELISA, the latter confirmed by Western blot. Chi-square and t-test provided statistical analysis.
Disease severity was comparable in all patients throughout the study period. Six antibody negative patients underwent remission, 4 with thymectomy alone, 2 with thymectomy plus immunosuppressive medication. Three non operated, titin-positive patients also experienced remission. No patient with both titin and RyR antibodies experienced remission. Three titin-positive thymectomized patients died from myasthenic respiratory complications in the 2 years following surgery and 3, 2 of whom were titin-positive, died from non-myasthenic causes. Presence or absence of titin or RyR antibodies was not predictive of outcome to surgery nor of treatment necessary to control symptoms. However, all deaths were seen in titin-positive patients.
Muscle antibodies are generally used to predict the presence of thymoma. RyR antibodies are present in 70% of thymoma cases, but also in 14% of late onset patients overall, and titin antibodies in 95% and 58%, respectively (Romi F, et al. J Neurol. 2000;247:369-375). Although ryanodine receptor and titin are intracellular proteins, their antibodies fix complement and correlate with disease severity (Romi F, et al. J Neuroimmunol. 2000;111:169-176; Romi F, et al. Arch Neurol. 2000;57:1596-1600). Their precise role in disease pathogenesis remains unclear.
RyR and titin antibodies are absent in seronegative MG patients, defined as those with absent AchR antibodies (Romi F, et al. J Neurol. 2000;247:369-375). Nonetheless, these patients respond to immunosuppression and their immunoglobulin fraction transfers their weakness to mice, suggesting that their disease is also autoantibody mediated (Mossman S, et al. Lancet. 1986;1:116-119). Antibodies to muscle-specific receptor tyrosine kinase (MuSK, muscle specific kinase) have been demonstrated in 70% of these seronegative patients, but not in AchR positive patients. MuSK is one of a group of transmembrane receptors with tyrosine kinase activity, known as receptor tyrosine kinases (RTKs). It is skeletal muscle specific and highly localized to the motor endplate, suggesting a role in neuromuscular transmission (Valenzuela DM, et al. Neuron. 1995;15:573-584). Like RyR and titin, its role in pathogenesis remains to be elucidated (Palace J, et al. Curr Opin Neurol. 2001;14:583-589). —Michael Rubin
Dr. Rubin, Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, is Assistant Editor of Neurology Alert.