Spinal muscular atrophy (SMA) is a currently untreatable, autosomal recessive motor neuron disease. SMA is the leading inherited cause of infant mortality. The cardinal signs of SMA in all patients are muscle weakness and atrophy due to motor neuron loss. The pattern of weakness is symmetrical and proximal, with the legs more affected than the arms and the arms more affected than the facial muscles and diaphragm. It has long been recognized that SMA disease severity is widely heterogeneous, prompting debate as to whether this represented a single entity or multiple different diseases. This chapter provides an overview of research efforts that have led to the discovery of the genetic basis of SMA, an understanding of some of the functions of the survival motor neuron (SMN) protein, and the development of SMA animal models that closely mimic the human disease. Although more work is needed to fully understand the mechanism of SMA disease pathogenesis, promising targets for SMA therapeutics are identified and early clinical trials of compounds directed to these targets are ongoing in SMA patients.
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