Spinal Muscular Atrophy: Present State

Abstract Spinal muscular atrophy (SMA) is a hereditary neurodegenerative disease caused by homozygous deletions or mutations in the SMN1 gene on Chr.5q13. SMA spans from severe Werdnig-Hoffmann disease (SMA 1) to relatively benign Kugelberg-Welander disease (SMA 3). Onset before birth possibly aggravates the clinical course, because immature motoneurons do not show compensatory sprouting and collateral reinnervation, and motor units in SMA 1, in contrast to those in SMA 3, are not enlarged. Genetic evidence indicates that SMN2, a gene 99% identical to SMN1, can attenuate SMA severity: in patients, more SMN2 copies and higher SMN protein levels are correlated with milder SMA. There is evidence that SMN plays a role in motoneuron RNA metabolism, but it has also been linked to apoptosis. Several mouse models with motoneuron disease have been successfully treated with neurotrophic factors. None of these models is, however, homologous to SMA. Recently, genetic mouse models of SMA have been created by introducing human SMN2 transgenes into Smn knockout mice or by targeting the Smn gene knockout to neurons. These mice not only provide important insights into the pathogenesis of SMA but are also crucial for testing new therapeutic strategies. These include SMN gene transfer, molecules capable to up-regulate SMN expression and trophic or antiapoptotic factors.