The Genetics of Spinal Muscular Atrophy: Progress and Challenges

Abstract

Spinal muscular atrophies (SMAs) are a group of inherited disorders characterized by motor neuron loss in the spinal cord and lower brainstem, muscle weakness, and atrophy. The clinical and genetic phenotypes incorporate a wide spectrum that is differentiated based on age of onset, pattern of muscle involvement, and inheritance pattern. Over the past several years, rapid advances in genetic technology have accelerated the identification of causative genes and provided important advances in understanding the molecular and biological basis of SMA and insights into the selective vulnerability of the motor neuron. Common pathophysiological themes include defects in RNA metabolism and splicing, axonal transport, and motor neuron development and connectivity. Together these have revealed potential novel treatment strategies, and extensive efforts are being undertaken towards expedited therapeutics. While a number of promising therapies for SMA are emerging, defining therapeutic windows and developing sensitive and relevant biomarkers are critical to facilitate potential success in clinical trials. This review incorporates an overview of the clinical manifestations and genetics of SMA, and describes recent advances in the understanding of mechanisms of disease pathogenesis and development of novel treatment strategies.

Fig. 1

Clinical features of spinal muscular atrophies (SMAs). (a) Infant with SMA type 1 with severe weakness, bell-shaped chest, and respiratory insufficiency. (b) Thoracolumbar radiograph of patient with SMA type 2 demonstrating thoracolumbar scoliosis. (c–g) A 36-year-old patient with distal hereditary motor neuropathy type 5C and mutation in BSCL2 demonstrating (c) distal wasting of the legs, (d–f) early and marked weakness and atrophy in the hands with finger contractures, and (g) pes cavus. (h) Chest radiograph of infant with SMA with respiratory distress type 1 demonstrating eventration of the right hemidiaphragm

Fig. 2

Proposed mechanisms underlying spinal muscular atrophies (SMAs). Most of these genes associated with SMA encode for ubiquitously expressed proteins with diverse cellular functions: protein translation and synthesis (glycyl-tRNA synthetase, Bernardinelli-Seip congenital lipodystrophy 2), RNA/DNA metabolism (senataxin, immunoglobulin μ-binding protein 2), axonal guidance and trafficking [heat shock protein (HSP)27, dynactin 1, pleckstrin homology domain containing, family G (with RhoGef domain) member 5], cellular protection (HSP22, HSP27), and apoptosis (HSP27). snRNP = small nuclear ribonucleic particles; SMN = survival motor neuron