A new study established associations between the levels of circulating neurofilaments (NFs) and spinal muscular atrophy (SMA) pathology and response to treatments, published in Molecular Therapy: Methods & Clinical Development.

“In the present study, in a real-world clinical setting, we demonstrate that circulating [phosphorylated neurofilament heavy chain] and [neurofilament light chain] concentrations are elevated in the first months of life in SMA patients,” the authors said. “These increased levels are inversely correlated to the number of SMN2 copies and to maximum ulnar [compound muscle action potential (CMAP)] negative peak amplitude values.”

Treatment initiation led to alterations in NF levels. For instance, the levels of NFs decreased more rapidly in the nusinersen (Spinraza®) cohort (n=9) than in the untreated cohort (n=68). In contrast, the levels of NFs increased in infants receiving onasemnogene abeparvovec-xioi (Zolgensma®) monotherapy (n=7), regardless of SMN2 copy number.

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The emergence of a later onset SMA phenotype in an infant with 2 SMA2 copies could be predicted by elevated NF levels in the setting of a declining ulnar CMAP following onasemnogene abeparvovec-xioi initiation.

On the other hand, the pretreatment of SMA infants with nusinersen might prevent or reduce the impact of elevated NFs observed after onasemnogene abeparvovec infusion.

Infants and children treated with either nusinersen or onasemnogene abeparvovec-xioi achieved important motor milestones not observed in the untreated group.

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“Timing for treatment intervention as early as possible in the neonatal period is critical to ensure the best possible clinical outcomes, especially for the SMN2 copy cohort but in all infants with borderline CMAP amplitudes or elevated NF levels,” the authors explained.

The study (NCT02831296) also showed that the baseline ulnar CMAP correlates with SMN2 copy number. Moreover, it reflects the overall status of denervation and is associated with the capacity for reinnervation in response to therapy. Since infants with >4 SMN2 copies can present with signs of denervation in early infancy, the use of ulnar CMAP and NFs can aid treatment decisions.

NFs are the main structural proteins of neurons. The detection of abnormal levels of NFs in biological fluids, such as cerebrospinal fluid, serum, or plasma, suggests neuronal damage. Therefore, they have been proposed as potential biomarkers in several pathological conditions.


Alves CRR, Petrillo M, Spellman R, et al. Implications of circulating neurofilaments for spinal muscular atrophy treatment early in life: a case series. Mol Ther Methods Clin Dev. Published online October 29, 2021. doi:10.1016/j.omtm.2021.10.011