Study Evaluates Potential Cerebrospinal Fluid Biomarkers in SMA Treatment

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The single-center study explored cerebrospinal fluid neurofilament and protein levels in patients with spinal muscular atrophy (SMA) undergoing treatment with nusinersen in an effort to identify useful biomarkers as treatment options expand.

As the number of therapies available and being researched for spinal muscular atrophy (SMA) expands, the importance of biomarkers to gauge therapy response in individual patients grows.A study published in the Journal of Cellular and Molecular Medicine assessed phosphorylated heavy chain neurofilaments (pNf-H), light-chain neurofilaments (NfL), and total tau protein (T-Tau) as potential cerebrospinal fluid (CSF) biomarkers.

Neurofilaments are found in neurons, and elevated neurofilament levels in CSF or plasma indicate neuronal injury and/or neuron degeneration. In amyotrophic lateral sclerosis, for example, high neurofilament concentrations correlate with disease severity and progression. In SMA1, past research has shown higher baseline pNf-H levels in plasma to correlate with more severe disease, and pNf-H levels were found to decline more quickly in nusinersen-treated patients, although any correlation in regard to motor function was not reported.

Tau protein plays a role in intracellular trafficking and signal transduction. In some neurodegenerative disease such as Alzheimer disease, hyperphosphorylation of Tau occurs. Tau hyperphosphorylation has also been suggested as a contributor to motor neuron degeneration in SMA.


The current, single-center study at the University Medical Center Hamburg-Eppendorf in Germany initially included 193 CSF samples from 44 SMA patients in total. The final analysis included 15 patients with type 1 SMA (SMA1), 15 patents with type 2 SMA (SMA2), and 10 patients with type 3 SMA (SMA3).

All of the patients received nusinersen, the first approved therapy for SMA, intrathecally on the recommended dosing schedule. Patients with SMA1, the most severe form in the group, initiated treatment under an early access program in January 2017. Patients with SMA2 and SMA3 were included starting in July 2017, when the drug was approved by the European Medicines Agency. CSF samples were taken before treatment and throughout at the site of intrathecal injection.

Researchers analyzed motor function in patients using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) in patients with SMA1. The Hammersmith Functional Motor Scale Expanded (HFMSE) and revised upper limb module (RULM) were both used in patients with types 2 and 3 SMA. The correlation between biomarkers and motor function was therefore assessed separately for SMA1 patients versus for SMA2/3 patients.

In SMA1, there was a significant inverse correlation between motor function scores and T-Tau and pNf-H concentrations after nusinersen treatment. There was a significant inverse correlation between motor function scores and pNf-H levels in SMA2 and SMA3 patients. Neurogranin, another CSF protein, and RULM scores also had a significant correlation in SMA2/3 patients.

Overall, the analysis suggests that pNf-H and NfL should be explored as biomarkers for neuronal loss and clinical outcome in SMA, and that T-Tau may may be a marker for treatment response.

The small patient population and lack of a control group are notable limitations in the study, and the authors encourage the interpretation of the findings as explorative results that warrant additional studies.


Johannsen J, Weiss D, Daubmann A, et al. Evaluation of putative CSF biomarkers in paediatric spinal muscular atrophy (SMA) patients before and during treatment with nusinersen. J Cell Mol Med. Published online Jul 27, 2021. doi:10.1111/jcmm.16802