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nusinersen therapy for pediatric spinal muscular atrophy

nusinersen therapy for pediatric spinal muscular atrophy

Study Background 

Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by the degeneration of anterior horn cells of the spinal cord and brainstem. SMA primarily affects babies and young children and has an incidence of 1:10,000. It is caused by a homozygous deletion at 5q13, the coding region for the survival of the motor neuron 1 (SMN1) gene. The SMN1 gene encodes the SMN protein, which is essential for the health and normal function of motor neurons. Insufficient levels of the SMN protein lead to motor neuron loss.

Neurophysiological studies have shed light on the pathogenesis of infantile-onset SMA with electrophysiological markers such as motor unit number estimation (MUNE) and compound muscle action potentials (CMAP). SMA patients typically have lower CMAPs. Weng et al. showed that the CMAP values were lower and decreased faster in children with two SMN2 copies compared to those with three or four copies. This was consistent with Swoboda et al.’s findings, who also reported an age-dependent decline in motor unit number estimation (MUNE) in both SMA 1 and SMA 2. Axonal excitability studies have revealed a mixed pathology of axonal degeneration and regeneration.

Nusinersen, a modified 2’-O-methoxyethyl antisense oligonucleotide, is the first disease-modifying drug approved to treat SMA in pediatric and adult patients. It acts as a splicing modifier of the SMN2 gene and increases full-length SMN protein synthesis when delivered intrathecally. Though there is emerging data supporting the efficacy of nusinersen in type 1 and 2 SMA populations, its therapeutic effect on patients with SMA type 3 is limited.

This prospective cohort study investigated axonal changes during neurodevelopment in children treated with nusinersen.


After ethics committee approval, 24 children (median age: 82 months; R = 4–193), all with genetically verified SMA types I–III and treated with nusinersen, were included in a 3-year (June 2017–February 2020) prospective cohort study. Children with comorbidities, secondary diagnoses, or acute illnesses that affect nerve excitability indices were excluded; as were children on medications. 

Gender, age at diagnosis, SMA type, number of copies of the SMN2 gene, disease duration, and functional status at the start of therapy were collected from medical records. 

Axonal excitability of the median nerve in participants was recorded using Qtrac threshold tracking software. An isolated linear bipolar constant-current stimulator was used to deliver electrical stimulation of the median nerve. The CMAP recordings from the abductor pollicis brevis (APB) muscle were then amplified and filtered through a purpose-built low-noise amplifier. The mean wrist temperature was maintained at>32°C in subjects with and without controls and measured with a surface probe. 

Multiple nerve excitability measures recorded include stimulus-response curves, the strength–duration time constant (τSD), threshold electrotonus, and the current–threshold (I-V) relationship. The last part of the nerve excitability study protocol recorded the recovery of nerve excitability following supramaximal activation. The changes were recorded at intervals between 2 and 20 ms. For all recovery cycles, the relative refractory period, super excitability, and late subexcitability were measured. 

 Data analysis 

SPSS Statistics Version 25 was used to describe numerical summaries of clinical and demographic data. A student’s t-test was then used to estimate the probability of the mean axonal excitability between children with SMA and age-matched healthy controls. Data that were log-normally distributed were presented as geometric mean, while data that were normally distributed were presented as mean. Pearson’s product-moment coefficient was used to analyze the correlation between excitability measures and age. The differences in means for each axonal excitability parameter were compared between induction and maintenance dosing, and the statistical significance level was set at P < 0.05.


  • For investigating axonal change during neurodevelopment, an SMA group of 24 children and 71 controls of the same age were recruited. The median age was 82 (range: 4 -193) and the median disease duration was 61 months (range: 2-141) for the children with SMA. Of the total cohort, 75% (n = 18) participated in the longitudinal study.   
  • The results showed that in children with SMA, axonal threshold (R = -0.66; p = 0.005) and rheobase (R = -0.66; = 0.005) decreased with increasing age. The authors also reported fanning-in of threshold electrotonus and an increase in resting current-threshold slope (R = 0.59; P = 0.020) and a reduction in subexcitability (R = 0.33); P = 0.226).  
  • There was a drop in CMAP amplitude with increasing age. In early childhood, axonal threshold ((5.75 [1.17] mA; P = 0.016) and rheobase (4.63 [1.21] mA; p = 0.012) were significantly higher in children with SMA. 
  • With a decrease in age, the threshold for electrotonus fanned out in children with SMA. However, the change was greater in subjects in their early childhood compared to controls. Though the accommodation to depolarisation was significantly lower in SMA patients in early childhood compared to healthy controls (SMA 14.36 ± 1.91% vs. controls 21.95 ± 1.43%), it increased gradually in late childhood (SMA 25.11 ± 0.89% vs. controls 22.49 ± 0.64%). 
  • The relative refractory period (the period after an action potential during which threshold is elevated) was significantly longer in subjects with SMA (SMA 3.04 [1.2] ms vs. controls 2.35 [1.03] ms; P = 0.020). 
  • Subexcitability changes in subjects and controls were measured and found to persist with development (late childhood subexcitability SMA: 19.47 ± 0.93% vs controls: 12.58 ±0.67%; P < 0.0001). 
  • With treatment, CMAP increased (induction 1.47 [1.31] mV; maintenance 4.06 [1.22] mV; p = 0.021) and axonal threshold reduced (threshold induction 5.01 [1.08] mA; maintenance 3.27 [1.26] mA; P = 0.181) in early age group children. 


The present study investigates the in vitro effects of low levels of SMN protein in children with SMA. The results are important for deciding the best intervention to adopt early in the developmental stage. 

Of the currently approved disease-modifying modalities for SMA, nusinersen and risdiplam increase SMN protein synthesis in patients with SMA via modified splicing of the SMN2 gene. A phase 1 study,  and a phase II study reported statistically and clinically significant improvements in motor function in children with SMA.

In this cross-sectional clinical study, nusinersen therapy was found to restore the developmental trajectory of motor neurons even in the youngest subjects with SMA. The age-dependent decline in axonal threshold and rheobase has been previously described. Extensive changes in nerve excitability measures with SMN deficiency as reported in this study indicate strong evidence for SMN’s role in the growth and maintenance of motor neurons. Literature shows that the difference in nerve excitability measures is greater during early childhood, and this study supports that. Also, this study provided in vivo insights into the relationship between low levels of SMN protein and cytoskeletal defects. The authors also observed a fanning in of threshold electrotonus and a reduction in sub-excitabilities. According to Kanai et al. and Farrar et al., the fanning of threshold electrotonus and reduced subexcitability could be an indicator of fast and slow potassium conductance. This also signifies the role of axonal degeneration as a novel therapeutic target in SMA. Myelination affects Na+ and K+ channel expression and function. The changes in nerve excitability with SMN deficiency seen in this study may be a secondary effect of axonal developmental changes, where remyelinated axons facilitate juxtaparanodal clustering of potassium channels. This study supports previous clinical trial findings by indicating an age-dependent optimal therapeutic window for maximum disease modification effects.

Axonal excitability techniques are reliable for recovering motor neurons to some extent in children with SMA. For the implementation of these data in the pathogenesis and treatment of SMA further research is needed.


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