Spinal Muscular Atrophy in the Era of Precision Medicine: Pathophysiology, Therapeutic Advances, and Future Perspectives

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by biallelic loss-of-function mutations in the survival motor neuron 1 (SMN1) gene, resulting in progressive degeneration of anterior horn cells and consequent proximal muscle weakness. Historically one of the leading monogenic causes of infant mortality, SMA has undergone a paradigm shift in its clinical outlook over the past decade, driven by the development and regulatory approval of three disease-modifying therapies: nusinersen, an antisense oligonucleotide targeting SMN2 pre-mRNA splicing; onasemnogene abeparvovec, an adeno-associated virus serotype 9 (AAV9)-mediated gene replacement therapy; and risdiplam, an orally bioavailable small-molecule SMN2 splicing modifier. These advances have transformed SMA from a uniformly fatal or severely debilitating condition into one amenable to substantial clinical stabilization and, in presymptomatic cases, near-normal neurodevelopmental trajectories. This review provides a comprehensive synthesis of the current understanding of SMA, encompassing its molecular genetics, pathophysiological mechanisms, clinical classification, diagnostic approaches, and the evolving therapeutic landscape. Particular emphasis is placed on recently approved and investigational agents, the role of newborn screening in enabling presymptomatic intervention, and outstanding challenges including treatment access, long-term efficacy, combinatorial strategies, and the management of non-responders. By integrating recent evidence from high-impact clinical trials and translational studies, this review aims to serve as an authoritative reference for clinicians and researchers engaged in the care and study of SMA.