Molecular mechanisms of spinal muscular atrophy.

Significant strides have been made during the past decade in the understanding of the molecular mechanisms that lead to the autosomal recessive motor neuron disease spinal muscular atrophy. Genetic studies revealed that spinal muscular atrophy is caused by mutation of the telomeric copy of the survival motor neuron gene ( SMN1), with all patients retaining at least one copy of the centromeric form of the gene, SMN2. SMN2 produces reduced amounts of full-length SMN messenger ribonucleic acid because of alterative splicing of SMN2 -derived transcripts, a process that is governed by specific cisand trans-acting factors. The resulting insufficient expression level of full-length SMN protein likely causes the disease manifestations of spinal muscular atrophy; however, the mechanism for the selective vulnerability of the motor unit to deficiency of this ubiquitously expressed protein remains unknown. It also remains unclear specifically when and where in the motor unit SMN is required. Despite the remaining questions, progress has been made in developing therapeutic strategies targeted to specific points along the pathogenetic pathway of spinal muscular atrophy. Histone deacetylase inhibitors will be discussed as an example.