Long-term outcomes of add-on risdiplam after nusinersen in pediatric spinal muscular atrophy: A three-year case report and literature review

Spinal muscular atrophy (SMA), caused by biallelic survival motor neuron 1 ( SMN 1) mutations, leads to progressive motor neuron degeneration. While nusinersen (intrathecal antisense oligonucleotide SMN 2 splicing modifier) and risdiplam (oral SMN 2 splicing modifier) have revolutionized SMA treatment, real-world evidence on add-on use remains limited. Two pediatric SMA type II cases (Case 1: age 9 years 4 months; Case 2: age 5 years 2 months) underwent 3-year follow-up. Both received nusinersen monotherapy add-on risdiplam therapy. Case 1 (treatment initiated at age 6 years 1 month) achieved sustained motor improvements (Hammersmith Functional Motor Scale–Expanded [HFMSE]: 30 → 42), including independent ambulation (10 m), while Case 2 (treatment initiated at age 2 years 0 month) progressed from no head control to assisted standing (HFMSE: 3 → 28). Transient thrombocytopenia (Case 1) and alanine aminotransferase (ALT) elevation (Case 2) resolved without intervention. Pulmonary function showed no clinically significant decline (FVC >70 % predicted throughout), despite motor gains. After risdiplam was added, both patients continued to gain motor function beyond the levels reached during nusinersen monotherapy. The safety profile aligned with prior trials, supporting its feasibility. Genetic modifiers (e.g., SMN 2 microduplications) influenced therapeutic responses, highlighting personalized strategies. Future studies should optimize pharmacokinetic sequencing and validate biomarkers (e.g., neurofilament light chain) to guide multimodal regimens.