Spinal muscular atrophy: A changing phenotype beyond the clinical trials

Abstract

Spinal muscular atrophy is a monogenic, progressive motor neuron disorder caused by deletion or mutation in the SMN1 gene. A broad range of phenotypic severity, from very weak infants (Type 1) to ambulant children (type 3), is modified mainly by the number of copies of the "backup" SMN2 gene. Since the discovery of the role of both genes, basic research into the pathobiology of SMA, with in vitro and animal model studies, has identified therapeutic targets. Development of clinical outcome measures, natural history studies and standard of care guidelines have contributed to the development of protocols for therapeutic drugs now under clinical investigation. Following regulatory approval of the first drug treatment for SMA in the US (December, 2016) and marketing authorization in Europe (June, 2017), the prospects for care of these patients have changed. The evolution of the phenotype of SMA now needs to be considered beyond the clinical trials. This perspective review discusses potential new trajectories in the phenotype of SMA and the need for multidisciplinary teams to prepare for this changing landscape.

Keywords: Changing epidemiology; Combinatorial therapies; Evolving phenotypes; SMN1 and SMN2 genes; Spinal muscular atrophy; Standard of care; Therapeutic approaches.