Motor function score changes in severe 5q spinal muscular atrophy during risdiplam treatment: an observational longitudinal nationwide cohort study

Background: Spinal muscular atrophy (SMA) is caused by the loss of function of the SMN1 gene resulting in deficiency of intracellular survival motor neuron (SMN) protein and is characterised by progressive motor function loss. Motor function changes during treatment with SMN2 splicing modifiers (i.e., nusinersen and risdiplam) have been shown in randomised clinical trials in infants, children and young adults with SMA, but not in severely affected adult patients, for whom risdiplam is often the only treatment option. Methods: Patients were screened for eligibility for risdiplam treatment between January and July 2021. We longitudinally evaluated motor scores during treatment up to 36 months using the Revised Upper Limb Module (RULM), the Adapted Test of Neuromuscular Disorders (ATEND), and hand strength tests. We assessed patient-reported Global Impression of Change (PGIC) after long-term treatment. Additionally, we investigated construct validity and responsiveness of ATEND as an additional outcome measure for severely affected patients. Findings: In this nationwide observational study, we analysed 72 patients with SMA types 1c and 2 (median age 29, IQR 23–42 years). We observed stabilised or improved RULM scores in 26 (43%) and increased ATEND scores in 33 (60%) patients after a median of 36 months of treatment. Eleven patients (18%) had a RULM score of 0 throughout treatment. ATEND score correlated strongly with RULM score supporting construct validity. After more than 3 years of treatment, 50 (89%) patients self-reported stability or improvement in overall wellbeing on the PGIC scale. Interpretation: Patients with SMA types 1 and 2 and severe motor impairment treated with risdiplam showed a deviation of the natural disease course of progressive motor score decline. The ATEND score is useful to monitor motor function change in severely affected patients. The majority of patients report improvement or stabilisation in motor function and overall wellbeing. Funding: None.