Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the neuromuscular junction. In approximately 80% of patients, auto-antibodies to the muscle nicotinic acetylcholine receptor (AChR) are present. These antibodies cause loss of AChR numbers and function, and lead to failure of neuromuscular transmission with muscle weakness. The pathogenic mechanisms acting in the 20% of patients with generalized MG who are seronegative for AChR-antibodies (AChR-Ab) have not been elucidated, but there is evidence that they also have an antibody-mediated disorder, with the antibodies directed towards another, previously unidentified muscle-surface-membrane target. Here we show that 70% of AChR-Ab-seronegative MG patients, but not AChR-Ab-seropositive MG patients, have serum auto-antibodies against the muscle-specific receptor tyrosine kinase, MuSK. MuSK mediates the agrin-induced clustering of AChRs during synapse formation, and is also expressed at the mature neuromuscular junction. The MuSK antibodies were specific for the extracellular domains of MuSK expressed in transfected COS7 cells and strongly inhibited MuSK function in cultured myotubes. Our results indicate the involvement of MuSK antibodies in the pathogenesis of AChR-Ab-seronegative MG, thus defining two immunologically distinct forms of the disease. Measurement of MuSK antibodies will substantially aid diagnosis and clinical management.

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The clinical and electrophysiological features of 50 consecutive patients with the Lambert-Eaton myasthenic syndrome (LEMS) have been analysed. Carcinoma was detected (CD group) in 25, of whom 21 had small cell lung cancer (SCLC). SCLC was evident within 2 yrs of onset of LEMS symptoms in 20/21 cases, and at 3.8 yrs in 1/21. In the cases in whom no carcinoma was detected (NCD group), 14/25 had a history of LEMS greater than 5 yrs. The dominant neurological features were similar in the CD and NCD groups, and consisted of proximal lower limb weakness (100%), depressed tendon reflexes (92%) with posttetanic potentiation (78%), autonomic features, especially dryness of the mouth (74%) and mild/moderate ptosis (54%). The compound evoked muscle action potential amplitude in abductor digiti minimi was below the lower limit of control values in 48/50, and the increment following maximum voluntary contraction above the upper limit of control values in 48/50. Single fibre electromyographic abnormalities were found in 29/29 cases. The analysis indicates that a patient presenting with LEMS has a 62% risk of an underlying SCLC, and that this risk declines sharply after 2 yrs, becoming very low at 4 to 5 yrs. It is argued that in SCLC cases antigenic determinants on tumour cells initiate the autoimmune response, often early in the course of the malignancy, but that the association of LEMS with tumours other than SCLC may be fortuitous. In the latter, and in NCD patients, the initiating factor(s) are unknown.