Spinal muscular atrophy: journeying from bench to bedside

Abstract

Spinal muscular atrophy (SMA) is a frequently fatal neuromuscular disorder and the most common inherited cause of infant mortality. SMA results from reduced levels of the survival of motor neuron (SMN) protein. Although the disease was first described more than a century ago, a precise understanding of its genetics was not obtained until the SMA genes were cloned in 1995. This was followed in rapid succession by experiments that assigned a role to the SMN protein in the proper splicing of genes, novel animal models of the disease, and the eventual use of the models in the pre clinical development of rational therapies for SMA. These successes have led the scientific and clinical communities to the cusp of what are expected to be the first truly promising treatments for the human disorder. Yet, important questions remain, not the least of which is how SMN paucity triggers a predominantly neuromuscular phenotype. Here we review how our understanding of the disease has evolved since the SMA genes were identified. We begin with a brief description of the genetics of SMA and the proposed roles of the SMN protein. We follow with an examination of how the genetics of the disease was exploited to develop genetically faithful animal models, and highlight the insights gained from their analysis. We end with a discussion of ongoing debates, future challenges, and the most promising treatments to have emerged from our current knowledge of the disease.

Fig. 1

Distal motor unit defects in spinal muscular atrophy (SMA). (A) Neuromuscular synapses in the diaphragms of a 10-year-old SMA patient and a 4-year-old control individual. Despite the greater age of the SMA patient, his neuromuscular junctions appear smaller, less complex in structure, and relatively immature as evidenced by persistent expression of the fetal (γ) isoform of the acetylcholine receptor (AChR) (scale bar = 30 μm). (b) Distal axons of an SMA mouse and its control littermate depicting defects in the form of neurofilament-filled swellings in the former (arrows) (scale bar = 5 μm)

Fig. 2

Genetic basis of spinal muscular atrophy (SMA). The cartoon depicts the two survival of motorneuron (SMN) genes and the proportions of the full-length (FL)-SMN and SMNΔ7 transcripts/protein expressed by them. SMN1 but not SMN2 is lost in SMA patients. Ex = exon; ESS = exonic splicing silencer