Neurofilament light protein as a biomarker for spinal muscular atrophy: a review and reference ranges.

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality, characterized by progressive neuromuscular degeneration resulting from mutations in the survival motor neuron (SMN1) gene. The availability of disease-modifying therapies for SMA therapies highlights the pressing need for easily accessible and cost-effective blood biomarkers to monitor treatment response and for better disease management. Additionally, the wide implementation of newborn genetic screening programs in Western countries enables presymptomatic diagnosis of SMA and immediate treatment administration. However, the absence of monitoring and prognostic blood biomarkers for neurodegeneration in SMA hinders effective disease management. Neurofilament light protein (NfL) is a promising biomarker of neuroaxonal damage in SMA and reflects disease progression in children with SMA undergoing treatment. Recently, the European Medicines Agency issued a letter of support endorsing the potential utilization of NfL as a biomarker of pediatric neurological diseases, including SMA. Within this review, we comprehensively assess the potential applications of NfL as a monitoring biomarker for disease severity and treatment response in pediatric-onset SMA. We provide reference ranges for normal levels of serum based NfL in neurologically healthy children aged 0-18 years. These reference ranges enable accurate interpretation of NfL levels in children and can accelerate the implementation of NfL into clinical practice.

Serum neurofilament light chain in pediatric spinal muscular atrophy patients and healthy children.

OBJECTIVE: The aim of this study was to evaluate neurofilament light chain as blood biomarker for disease activity in children and adolescents with different types of spinal muscular atrophy (SMA) and establish pediatric reference values. METHODS: We measured neurofilament light chain levels in serum (sNfL) and cerebral spinal fluid (cNfL) of 18 children with SMA and varying numbers of SMN2 copies receiving nusinersen by single-molecule array (SiMoA) assay and analyzed correlations with baseline characteristics and motor development. Additionally, we examined sNfL in 97 neurologically healthy children. RESULTS: Median sNfL levels in treatment-naïve SMA patients with 2 SMN2 copies are higher than in those with >2 SMN2 copies (P < 0.001) as well as age-matched controls (P = 0.010) and decline during treatment. The median sNfL concentration of healthy controls is 4.73 pg/mL with no differences in sex (P = 0.486) but age (P < 0.001). In all children with SMA, sNfL levels correlate strongly with cNfL levels (r = 0.7, P < 0.001). In children with SMA and 2 SMN2 copies, sNfL values correlate with motor function (r = -0.6, P = 0.134), in contrast to older SMA children with >2 SMN2 copies (r = -0.1, P = 0.744). INTERPRETATION: Reference sNfL values of our large pediatric control cohort may be applied for future studies. Strong correlations between sNfL and cNfL together with motor function suggest that sNfL may be a suitable biomarker for disease activity in children with 2 SMN2 copies and those with >2 SMN2 copies within their initial stages during early childhood.