Human motor neuron diseases include hereditary spinal muscular atrophies of infants and children, and in adults, amyotrophic lateral sclerosis and the postpolio syndrome. Hereditary Canine Spinal Muscular Atrophy (HCSMA) is a dominantly inherited lower motor neuron disease which produces weakness, muscle atrophy, and paralysis. Clinically and pathologically it resembles the spinal muscular atrophies of infancy and childhood. Previous studies have focused on the pathologic changes in the spinal cord and proximal ventral roots and have not provided a satisfactory morphological basis for the profound weakness in affected individuals. Recent electrophysiological and morphological studies of individuals homozygous for HCSMA suggest that the clinical deficits may be related to abnormal conduction or degeneration in the distal portion of the motor axon or insufficient release of ACh at motor terminals or perhaps involvement of muscle itself, possibilities which have not been evaluated systematically to date. Several of these mechanisms have been suggested to play a role in the postpolio syndrome. The proposed studies will use intracellular recording and stimulation techniques to characterize further the nature and site of motor unit function deficits as the clinical course evolves. Complementary morphologic studies will use immunocytochemical and ultrastructural methods to determine the temporal evolution of the pathologic changes in the neuromuscular junction, distal axons, and skeletal muscle and compare them with electrophysiological data obtained on the same animals. The HCSMA model provides a unique opportunity to investigate an inherited motoneuron disease early in the disease while motoneurons are dysfunctional but viable and while secondary phenomena do not obscure the primary deficits.
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