SMA Motor Map - an extensive neurophysiologic protocol to assess (dys)function of the peripheral motor circuits in SMA

Spinal muscular atrophy (SMA) is a monogenetic neuromuscular disorder in
children and adults with a wide range in severity but a high degree of
morbidity and impairment across the spectrum. SMA is a motor neuron disorder,
with evidence for additional abnormal function of the axon and the
neuromuscular junction (NMJ). The relative contributions of dysfunction of the
different parts of the motor circuit to the clinical phenotype are unknown. The
variability of dysfunction of the different parts of the motor unit might
explain (parts of) the clinical variability between SMA types and individual
patients.
The introduction of the intrathecally injected and high-cost drug
*nusinersen* (Spinraza) that showed efficacy in survival and motor function in
patients with SMA types 1 and 2 younger than 13 years, represents a major
breakthrough. Followed by introduction of Risdiplam, which showed effacacy in
survival and motor function as well. Important remaining questions are whether
this treatment is efficacious in older patients and how to identify patients
non-responsive to treatment. The relatively slow disease progression and
insensitivity of clinical scales to detect subtle functional changes underlines
the urgent need for new biomarkers.

The goal of this research project comprises two important components that are
intricately related:
1) To define the pathophysiological state of the peripheral motor pathway in
patients with SMA and to determine the contribution of the constituting parts
to disease severity and variability by means of the SMA Motor Map (SMM) (Part I)
2) To establish the usefulness of the targeted SMA Motor Map (tSMM) as a
therapeutic biomarker in patients treated with SMN modulators (e.g. nusinersen
or risdiplam) (Part II)

We will perform 2 parallel, observational studies:
Part One: Cross-sectional study
• Analyse the different parts of the motor circuit by use of the SMA Motor Map
Part Two: Longitudinal study
• Analyse the motor neuron status and its changes to treatment
• Analyse the biomarker function of the targeted SMA Motor Map for the efficacy
on motor neuron function of the SMN modulating drug longitudinally (baseline,
two and 14 months) in 100 patients treated with nusinersen. Children and adults
who recently have started (<1 month) or will start nusinersen treatment will be
enrolled in the sec-ond arm of the study.
SMA Motor Map and clinical scores will be performed and correlated with SMA
type, disease duration, age and SMN2 copy number. Objective and
patient-reported outcomes will be cor-related to the SMA Motor Map in order
detect neurophysiologic biomarkers for (non-) re-sponse on therapy.

This research will be done in children and adults with SMA. The burden of
participation con-sists of undergoing the (targeted) SMA Motor Map.
Overall, the burden and risk associated with participation in the study will be
minor using the correct equipment and protocols. All study personal will be
trained to perform the investigations safely.
The criteria of the Nederlandse Vereniging voor Kindergeneeskunde (Dutch
association of Paediatrics) concerning research involving children will be
strictly applied.