04INVSpinal muscular atrophy: systemic disease, focal treatment – or vice versa?

Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by reduced levels of the survival motor neuron (SMN) protein due to bi-allelic loss of function of the SMN1 gene. While the clinical phenotype is predominantly characterized by lower motor neuron degeneration, SMN is ubiquitously expressed, and evidence from preclinical models indicates that reduced SMN levels can affect multiple organ systems. Furthermore, SMN expression is developmentally regulated, with higher levels required during early stages of development, suggesting a temporal window of vulnerability. In animal studies, tissue-specific depletion of SMN results in organ-specific abnormalities, supporting the hypothesis that SMA may represent a multisystem disorder. However, the relevance of these findings to the human phenotype remains uncertain. Available SMA treatments (nusinersen, risdiplam, and onasemnogene abeparvovec) differ significantly in both the distribution and duration of SMN expression across tissues. If this has an impact on the clinical presentation is still not clear. In clinical practice, patients receiving central nervous system-targeted therapy with antisense oligonucleotides typically demonstrate stabilization or improvement of motor function, and progressive systemic involvement is not commonly observed. Nevertheless, isolated reports of extra-neuronal complications have emerged, raising questions about their clinical significance. This presentation will critically review current evidence regarding the systemic versus motor neuron-specific manifestations of SMA, synthesizing preclinical data on organ involvement and clinical experience with CNS-targeted therapies.