Abstract
ObjectiveThe 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.MethodsWe 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.ResultsMedian 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).InterpretationReference 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.
Highlights
As the most common genetic cause of infant mortality, spinal muscular atrophy (SMA) results from deleterious variants in SMN1, which lead to deficiency of survival motor neuron protein (SMN)
Baseline neurofilament light chain (NfL) values in both body fluids, cerebral spinal fluid (CSF) and serum, of the 18 SMA patients before the initiation of nusinersen treatment were significantly higher within the group of patients with 2 SMN2 copies than in those with >2 SMN2 copies
To assess the value of NfL as a diagnostic and monitoring biomarker in pediatric SMA patients of different ages, we investigated whether NfL values in serum and CSF reflect changes of disease activity and treatment response in children and adolescents with SMA and different SMN2 copies over an extended period of up to 34 months
Summary
As the most common genetic cause of infant mortality, spinal muscular atrophy (SMA) results from deleterious variants in SMN1, which lead to deficiency of survival motor neuron protein (SMN). This deficiency of SMN is followed by degeneration of motor neurons and associated with progressive atrophy of skeletal and respiratory muscles.[1] An SMN1 paralog, SMN2, is considered the most important phenotype modifier in a copy-dependent manner and partially compensates the deficit of SMN1.2. In SMA III, most individuals carry 4 SMN2 copies and are able to walk, but require wheelchair assistance later in life.[4]
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