Spinal muscular atrophy in the era of newborn screening: how the classification could change

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by deletions or mutations in the Survival Motor Neuron 1 gene, associated with high morbidity and mortality related to muscle weakness. In recent years, the availability of new disease-modifying therapies and the extension of newborn screening has brought radical changes in the natural history of SMA at all ages. Historically, the classification of SMA has been based on age of onset and achievement of maximum motor milestone. In this new era, the historical classification of SMA by typology is no longer adequate to define the prognosis and type of SMA, nor to guide clinical management and treatment choice. The aim of this work is to discuss the current status of SMA neonatal screening and access to therapies across Europe and propose a new updated nomenclature, more suitable to guide clinicians in the management of SMA patients in the era of newborn screening. In this perspective, we evaluate and analyze the genetic basis of the disease, the current therapeutic landscape, the possible genotypic/phenotypic scenarios and the related clinical management.

Keywords: gene replacement therapy; motor function; neuromuscular disorders; newborn screening; spinal muscular atrophy.

Figure 1

Simplified diagram of the 5q13.2 locus on chromosome 5 containing the SMN1, SMN2 and NAIP genes. (A) Screenshot of the chromosomal position of the three genes, according to the chromosome 5 reference GRCh38.p14 primary assembly (NC_000005.10; www.ncbi.nlm.nih.gov/gene; accessed on April 18, 2025). (B) Schematic representation of SMN1, SMN2 and NAIP, with the main nucleotide differences between SMN1 and SMN2. In SMN2, the c.840T nucleotide promotes skipping of exon 7 in about 90% of transcripts, thereby significantly reducing the overall SMN protein expression by this gene.

Figure 2

Classification of SMA patients identified by NBS based on genetic and clinical features. Therapeutic options and clinical menagement are also reported.

Figure 3

Historical classification of SMA based on age of symptoms onset and highest physical milestone achieved.

Figure 4

Diagram illustrating application of the proposed new classification to SMA patients identified by newborn screening (NBS). OA: onasemnogene abeparvovec.