The Dynamics of Neurofilament Light Chain in Spinal Muscular Atrophy

OBJECTIVE: Newborn screening (NBS) for spinal muscular atrophy (SMA) facilitates early diagnosis and treatment for affected individuals. However, fluid biomarkers that provide early insights into disease activity and outcomes in a neonatal cohort and those unable to access (due to reimbursement criteria) or deferring immediate treatment are lacking. This study evaluated neurofilament light chain (NfL) levels to provide insights into disease activity and outcomes in newborns and children with SMA. METHODS: This study correlated pretreatment NfL levels in the serum and cerebrospinal fluid (CSF) in a cross-sectional cohort of individuals with SMA against clinical, neurophysiological, molecular genetic variables, and treatment characteristics. Longitudinal NfL levels were evaluated in individuals that did not immediately commence treatment (governed by Australian reimbursement policies) and in those treated with nusinersen monotherapy. RESULTS: Participants included 45 individuals with SMA (age range = 4 days to 42 years). Pretreatment serum NfL (sNfL) in 2 SMN2 copy neonates were significantly higher (2 SMN2, mean[SE] 680.9 [163.7]; ≥ 3 SMN2 146.9 [59.8] pg/ml, p = 0.01), correlating with increasing post-natal age (2 SMN2 r[12] = 0.75, p = 0.005). Combining sNfL and compound muscle action potential (CMAP) with pretreatment CHOP-INTEND in a regression model provided a stronger prediction of motor outcomes for neonates at 2 years (p = 0.02). Pretreatment sNfL in infants with ≥3 SMN2 copies who did not initiate immediate treatment increased despite motor function remaining stable. INTERPRETATION: There is a malignant disease course with active denervation in children with 2 SMN2 copies within the neonatal period. sNfL gives early insights into underlying pathophysiology prior to a clinical phenotype and may expedite access to the initiation of treatment. ANN NEUROL 2026;100:109-122.