Spinal Muscular Atrophy: An Evolving Scenario through New Perspectives in Diagnosis and Advances in Therapies

Abstract

Spinal muscular atrophy (SMA) linked to 5q is a recessive motor neuron disease characterized by progressive and diffuse weakness and muscular atrophy. SMA is the most common neurodegenerative disease in childhood with an incidence of approximately 1 in 6000-10,000 live births, being long considered a leading cause of hereditary mortality in infancy, worldwide. The classification of SMA is based on the natural history of the disease, with a wide clinical spectrum of onset and severity. We are currently in a new therapeutic era, that, thanks to the widespread use of the newly approved disease-modifying therapies and the possibility of an early administration, should lead to a deep change in the clinical scenario and, thus, in the history of SMA. With the aim to achieve a new view of SMA, in this review we consider different aspects of this neuromuscular disease: the historical perspective, the clinical features, the diagnostic process, the psychological outcome, innovation in treatments and therapies, the possibility of an early identification of affected infants in the pre-symptomatic phase through newborn screening programs.

Keywords: diagnosis; disease-modifying therapies; gene therapy; newborn screening; psychological adjustment; spinal muscular atrophy.

Figure 1

SMA timeline. SMA was first reported by Werdnig in 1891 and then by Hoffmann in 1893 [10]. In 1899 and 1903, Sylvestre and Beevor recognized variability of muscle weakness severity [11]. In the 1950s, Wolhfart, Fez, and Eliasson described a milder form of SMA [11] and in 1995 Melki discovered that 95% of SMA cases are caused by a homozygous deletion in SMN1 [13].

Figure 2

FDA-approved SMN-based therapies for SMA and their mechanism of action [19,67]. (a) The different actions of SMN2 splicing modifiers such as nusinersen (ASO) and risdiplam (small molecules in comparison to the absence of therapeutic intervention). Both SMN2-targeted therapies promote the inclusion of exon 7 in mature mRNA transcripts. (b) The mechanism of SMN1-targeted therapy, by non-replicating self-complementing AAV-9, compared to the homozygous loss of functional SMN1 gene. The onasemnogene abeparvovec gene therapy carries full-length human SMN cDNA to guarantee the production of SMN functional protein.

Figure 3

Two representative real-time PCR multicomponent plots obtained by the qualitative detection of exon 7 in SMN1 gene. Internal control (pink curve), SMN1 gene (purple curve): (a) a negative result with the amplification of the SMN1 gene is shown; (b) a positive result as determined by the absence of amplification of SMN1 gene is reported.

Figure 4

SMA NBS workflow [6,53,57].