Serum Neurofilament Light Chain Identifies Subclinical Axonal Injury in SMA Neonates

The clinical management of spinal muscular atrophy (SMA) has transitioned toward early intervention using disease-modifying therapies such as nusinersen, onasemnogene abeparvovec, and risdiplam [1, 2, 3, 4]. Data from the phase 3 DEVOTE trial (n=75) demonstrated that high-dose nusinersen (50-mg loading dose followed by 28-mg maintenance doses) achieved a 15.1-point improvement in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) scores at day 183, whereas sham-treated controls experienced an 11.1-point decline (difference 26.19; 95% CI 20.7 to 31.74; p < 0.0001) [5]. Early treatment remains a priority, as the SPR1NT trial (n=14) reported that infants with two copies of the survival motor neuron 2 (SMN2) gene reached 100% survival without permanent ventilation at 14 months after receiving onasemnogene abeparvovec [6, 7, 8]. However, the RESPOND trial (n=37) highlighted that some infants continue to show elevated neurofilament light chain (NfL) levels, a protein marker of axonal injury, and low compound muscle action potential (CMAP) amplitudes, which measure the electrical response of motor units, even after gene transfer therapy [9, 10]. These findings suggest that subclinical neurodegeneration may persist, requiring objective biomarkers to guide therapeutic adjustments before irreversible motor neuron loss occurs [3, 4].