Biomarkers for spinal muscular atrophy are needed to further analyze treatment efficacy, and a recent study points to serum neurofilament light chain levels as a possible option.
Spinal muscular atrophy (SMA) management has evolved in recent years, with disease-modifying treatments and genetic testing for the disease becoming more common. A recent study published in Annals of Clinical and Translational Neurology aimed to evaluate neurofilament light chain (NfL) levels as a blood biomarker for SMA, which is lacking in biomarkers to assess disease activity in patients.
Deleterious variants in the SMN1 gene are known to cause SMA by causing survival motor neuron deficiency in patients. The SMN2 gene can partially compensate for the deficiency, but not entirely, making SMN2 a key phenotype modifier in SMA.
The levels of SMA are based on age of onset and a patient’s motor capacity. They range from 0 to 4, with 0 encompassing severe prenatal onset. In type 1, the most common, patients are unable to sit independently. Patients with type 2 can sit but not stand or walk, those with type 3 are able to walk but typically require wheelchair assistance eventually, and type 4 is adult-onset SMA, which presents at age 30 years or older.
There are 3 disease-modifying treatments currently approved for SMA (the antisense oligonucleotide nusinersen, the gene therapy onasemnogene abeparvovec, and the small molecule splicing modifier risdiplam). However, there is a lack of objectively measured molecular biomarkers to reflect pathologic processes and their response to therapy.
Neurofilaments, structural constituents of the axoskeleton, have multiple components, one of which is NfL. Neurofilaments are released into interstitial fluid, cerebral spinal fluid (CSF), and blood when neuroaxonal damage is done. Ultra-sensitive single-molecule array (SiMoA) assays can detect serum proteins at very low blood concentrations. Serum NfL (sNfL) levels and NfL levels in CSF (cNfL) were the main targets of the current study.
A total of 18 children undergoing treatment for SMA (nusinersen) with varying SMN2 copies were included in the study and had an age range of 18 days to 17.2 years at time of inclusion. Serum and CSF samples were collected prior to each nusinersen treatment. One-time serum samples were also taken from an age-matched control group of 97 healthy children. Serum from peripheral blood was taken, centrifuged, and stored at –112 °F. Researchers used a SiMoA assay to analyze the samples.
The median sNfL level in the overall control group was 4.73 pg/mL, with higher levels in infants and children under 4 years old (7.12 pg/mL) vs those between 5 and 18 years old (4.07 pg/mL). In untreated SMA patients under 1 year old with 2 SMN2 copies, the median sNfL was 529 pg/mL, which was 50 times what healthy age-matched controls showed in serum samples (10.53 pg/mL).
In treatment-naïve patients with 2 SMN2 copies, median sNfL levels were higher than in those with fewer than 2 copies (P < 0.001). The same was true in untreated patients vs age-matched controls (P = 0.010). Patients between ages 1 and 17 years with more than 2 SMN2 copies had a mean sNfL level of 10.42 pg/mL, or twice that of the healthy children.
In children with SMA, sNfL levels correlated strongly with cNfL levels and with motor function. Over the course of treatment, nusinersen was associated with a steady improvement in motor function and a decline of sNfL concentrations. Patients’ cNfL levels declined steadily between treatment doses 1 and 7 and plateaued afterward. The same was seen in sNfL from doses 2 and 5.
The small sample size was one notable study limitation, so more studies are needed to validate the findings. Even so, the authors conclude that sNfL levels reliably reflect cNfL values in SMA patients with varying SMN2 copies regardless of subtype. sNfL levels also correlated with motor function changes in patients with 2 SMN2 copies and in the first 2 years for a patient who had more than 2 SMN2 copies.
“With regard to the availability of different disease-modifying therapies, monitoring of sNfL in these children may serve as a complementary early indicator of treatment response and help to stratify disease management,” the authors concluded.
They encouraged further research and noted that the data gleaned from the control group may be useful as a reference for further studies on sNfL in pediatric neurodegenerative diseases.
Nitz E, Smitka M, Schallner J, et al. Serum neurofilament light chain in pediatric spinal muscular atrophy patients and healthy children. Ann Clin Transl Neurol. Published online September 4, 2021. doi:10.1002/acn3.51449