The broad aim of this proposal is to examine the neurobiology of congenital myasthenic syndromes (CMS). The CMS are heterogeneous and disabling disorders in which the safety margin of neuro-muscular transmission is compromised by one or more specific mechanism(s). The CMS are not uncommon but are seldom diagnosed or treated correctly. Clinical, morphologic and electrophysiologic analysis can determine whether a CMS is presynaptic, synaptic, or postsynaptic in origin and point to a defect in an endplate (EP) specific protein, such as the acetylcholine receptor (AChR), acetylcholinesterase (AChE), or choline acetyltransferase. The CMS are investigated by: (1) Clinical assessment, including electromyography and tests for anti-AChR antibodies; (2) morphologic assessment, including immunocytochemical localization of AChR, AChE, and other EP- specific proteins, estimate of the number of AChR per EP, ultrastructural analysis of the EP, and evaluation of the density and distribution of AChR on the junctional folds; (3) electrophysiologic assessment, consisting of conventional microelectrode studies of EP potentials and currents, estimates of parameters of quantal release, and evaluation of AChR channel kinetics through single channel patch-clamp recordings; (4) mutation analysis when the preceding studies point to an EP- specific protein; and (5) expression studies using genetically engineered mutants. (6) When CMS patients identified at centers in the US or abroad cannot come to Mayo but the available data point to a candidate gene or molecule, we still search for mutations; if we detect mutation(s), we confirm pathogenicity as in (5) above. The proposed studies important for diagnosis and prevention of the CMS, for investigating disease pathophysiology, for developing strategies for therapy, and for gaining insights into structure-function relationships of EP-specific proteins.
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