The aim of this research is to make a detailed analysis of neuromuscular transmission in human diseases affecting the neuromuscular junction. The proposed studies are concerned particularly with aspects of neuromuscular transmission in five newly recognized congenital myasthenic syndromes and in the myasthenic syndrome sometimes associated with small cell bronchial carcinoma (Lambert-Eaton syndrome, LES). Familial, congenital myasthenia gravis in dogs is being studied as a model for one form of congenital myasthenic syndrome in man. Electrophysiologic methods will be used including electromyographic techniques to study the patient, and intracellular microelectrode techniques to record the events of neuromuscular transmission in single muscle fibers of biopsied muscles. The purpose is to determine in detail which step in the chain of events in neuromuscular transmission is abnormal and to identify causative factors. A continuing search is being made for a circulating factor from small cell carcinomas as a cause of the defect of neuromuscular transmission in LES. The possibility that the defect in LES associated with bronchial carcinoma may result from an immune response to tumor antigens is being tested. In view of the high probability that LES with and without tumor is an organ-specific autoimmune disease, studies are also being directed to identifying the relevant antigen of cholinergic nerve terminals. The effects on neuromuscular tranmission of a compound 3,4-diaminopyridine will be studied; this compound has been found in limited tests by European investigators to be more effective and less toxic than currently available drugs for the treatment of the specific type of defect of neuromuscular transmission in LES. Investigations of the effects on rat neuromuscular transmission of monoclonal antibodies reactive with defined sites of the human muscle acetylcholine receptor (AChR) are aimed at determining in more detail the mechanism of action of antibodies in acquired MG. Studies of neuromuscular transmission in defined strains of mice immunized with AChR will give information about the genetic control of susceptibility to acquired MG. The long term goal is to improve criteria for the diagnosis of different defects of neuromuscular transmission in man and to provide information required for devising appropriate treatment.