Multimodal Analysis of Biomarkers for SMA - Data from the First Six-Month Nusinersen Follow-Up

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by mutations in the SMN1 gene, with disease severity modulated by the number of SMN2 gene copies. Nusinersen, the first approved disease-modifying therapy, has significantly improved survival and motor outcomes, yet treatment response remains heterogeneous, underscoring the need for sensitive biomarkers. This retrospective study analyzed 53 pediatric patients with SMA types 1–3 treated with nusinersen at the CNCRNC “Dr. N. Robănescu” between October 2018 and May 2022. Clinical (CHOP-INTEND, HFMSE), electrophysiological (CMAP), biochemical (CSF and serum pNF-H, serum creatinine), and genetic (SMN2 copy number) parameters were assessed at baseline and after 6 months (end of the loading period). Statistical analyses included normality testing and correlation analysis (Pearson or Spearman). In the first 6 month of treatment, a decrease in motor neuron degradation due to insufficient SMN2 protein synthesis was observed, which led to a decrease in CSF pNF-H levels and an increase in CMAP values, concomitant with an increase in serum creatinine concentration and better scores on motor scales due to increased muscle activity. Results showed that younger age, fewer SMN2 copies, and more severe disease were associated with lower CMAP amplitudes, higher CSF pNF-H concentrations, poorer motor scores, and lower serum creatinine levels. Strong correlations were observed between CMAP and motor scale scores, and between pNF-H levels and disease severity, with distinct patterns across SMA types. Nusinersen treatment conferred functional benefits in all patient groups, most pronounced in those with greater initial disease burden. These findings highlight the complementary predictive value of multimodal biomarkers for early monitoring of therapeutic response