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.

Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study

“…Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease associated with progressive and often severe muscle weakness and atrophy and is a leading cause of death in infants [1][2][3][4] . SMA is caused by homozygous deletions ( ∼95% of SMA patients) or compound heterozygous mutations ( ∼5% of SMA patients) in the survival motor neuron 1 ( SMN1 ) gene that prevent production of full-length functional SMN protein [5] .…”

Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies

“…In both disease groups, SMA and HMN, autosomal recessive (AR), autosomal dominant (AD), and X-linked inheritance have been described (Wee, Kong, & Sumner, 2010). However, while the majority of SMA patients show an AR mode of inheritance, individuals with HMN are predominantly presenting an AD mode of inheritance (Farrar & Kiernan, 2015). In the era of novel therapeutic options for 5q-SMA patients (Finkel, et al, 2017;Mendell et al, 2017), a correct genetic diagnosis is important.…”

Identification of a homozygous VRK1 mutation in two patients with adult‐onset distal hereditary motor neuropathy

“…Hereditary motor neuropathies include a group of heterogeneous disorders, caused by mutations in a large number of genes with autosomal dominant, autosomal recessive or X‐linked models of inheritance . Adult‐onset patients usually present with a slowly progressive, predominantly distal, muscle weakness and atrophy as the main manifestation, termed distal hereditary motor neuropathy (dHMN) or distal spinal muscular atrophy (dSMA) . However, additional clinical signs have also been described …”