The Role of Autoantibodies in Lambert-Eaton Myasthenic Syndrome a BETHAN LANG, b SALLY WATERMAN, b ASHWIN PINTO, b DOMINIC JONES, b FRASER MOSS, c JOHN BOOT, c PAUL BRUST, d MARK WILLIAMS, d KENNETH STAUDERMAN, d MICHAEL HARPOLD, d MASAKATSU MOTOMURA, e J. WIBE MOLL, f ANGELA VINCENT, b AND JOHN NEWSOM-DAVIS b b Neurosciences Group Institute of Molecular Medicine University of Oxford Oxford OX3 9DU, United Kingdom c Lilly Research Center Limited Windlesham, Surrey, United Kingdom d SIBIA Neurosciences Incorporated La Jolla, California 92037 e First Department of Internal Medicine Nagasaki University School of Medicine Nagasaki 852, Japan f Department of Neuro-Oncology Dr. Daniel den Hoed Cancer Center 3075 EA Rotterdam, the Netherlands The Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of neuromuscular transmission that causes fatigable muscle weakness, loss of tendon reflexes, and autonomic dysfunction. 1–3 LEMS antibodies bind to and induce a downregulation of voltage-gated channels (VGCCs), 4,5 resulting in a reduction in the nerve-evoked, Ca 2+ -dependent release of acetylcholine from motor nerve terminals. Approximately 60% of patients have an associated small cell lung carcinoma (SCLC), 6 a tumor that is thought to be neuroendocrine in origin. This strong associa- tion with cancer makes LEMS a member of the group of paraneoplastic disorders. SCLC cells have been shown to express functional VGCCs, 7,8 and preincubation in LEMS sera or IgG reduces the K + -stimulated 45 Ca 2+ flux into these cells. 8–10 596 a This work was supported by the Medical Research Council (United Kingdom), the Myas- thenia Gravis Association (United Kingdom), the Queen’s Trust of Australia, the Leopold Muller Estate, the Sir Jules Thorne Charitable Trust, the Nuffield Foundation, and Jesus Col- lege, Oxford. A. Pinto is a recipient of a Wellcome Trust Research Fellowship and M. Motomu- ra held a Wellcome Trust Research Travelling Fellowship.