Systematic Multimodal Approach for Biomarkers And Bulbar assessments In Early-diagnosed SMA

SMA is a monogenetic disease based on a homozygous deletion of SMN1 which
results in motor neuron degeneration with progressive muscle weakness. Despite
the monogentic background, SMA shows a wide clinical variability with 60% of
children never able to sit if untreated (SMA type 1) and 10% learning to walk
and only having milde proximal muscle weakness through life. (SMA type 3).
The perspective of infants with spinal muscular atrophy(SMA) has changed
dramatically with the discovery and implementation of gene-targeting therapies
and the inclusion of SMA in the Dutch newborn screening program. Treatment is
effective and timing is key (=earlier treatment is better), but still, outcome
is quite variable and cure incomplete.
Diagnosis of SMA through newborn screening results in a diagnosis in
asymptomatic children. There are currently no markers to predict the clinical
phenotype of SMA, and prediction of treatment effect is limited. Counseling of
parents is therefor quite difficult.
CMAP scan determines the number of (viable) motor units. Motor unit estimation
in previous studies in symptomatic patients have shown dramatic changes in the
first weeks of live in severely affected (type 1) patients, with already
altered motor unit number early on. Motor unit number is correlated with
disease severity in SMA types 1, 2 and 3. CMAP scan analysis is feasible in
infants, but was not tested before in newborns with SMA.
We hypothesis that motor unit number at time of diagnose coudl differentiate
between asymptomatic patients at the wide ends of the disease severity
spectrum: severe SMA (50% of all patients) and late-onset SMA (10% of
patients). In these particular cases treatment perspectives and follow up might
be significantly different, and prediction of these patients will improve
counselling and might alter treatment discissions.

The goal of this research project comprises two important components
1) To determine the motor unit number from the CMAP scan at time of diagnosis
correlates with treatment efficacy
2) To establish the usefulness of the changes in motor unit number and CMAP
scan parameters over time as a therapeutic biomarker for treatment efficacy

We will perform a longitudinal study:
Part One: search of therapeutic biomarker at time of diagnosis c.q. at start of
treatment
• Determine the motor unit number, size or pattern (large cs small) by CMAP
scan at time of diagnosis and its relation to treatment efficacy
Part Two: search of therapeutic biomarker over time after treatment
• Determine the change of motor unit number, size or pattern (large cs small)
by CMAP scan during treatment in relation to treatment effect.
Assessments will be done at diagnosis c.q. at start of treatment (age 7-14
days), age 4-6 months (4 months after treatment) and age 18 months

Minimal burden and risks