Development of new outcome measures for adult SMA type III and IV: a multimodal longitudinal study

Objective The aim of this study was the comprehensive characterisation of longitudinal clinical, electrophysiological and neuroimaging measures in type III and IV adult spinal muscular atrophy (SMA) with a view to propose objective monitoring markers for future clinical trials. Methods Fourteen type III or IV SMA patients underwent standardised assessments including muscle strength testing, functional evaluation (SMAFRS and MFM), MUNIX (abductor pollicis brevis, APB; abductor digiti minimi, ADM; deltoid; tibialis anterior, TA; trapezius) and quantitative cervical spinal cord MRI to appraise segmental grey and white matter atrophy. Patients underwent a follow-up assessment with the same protocol 24 months later. Longitudinal comparisons were conducted using the Wilcoxon-test for matched data. Responsiveness was estimated using standardized response means (SRM) and a composite score was generated based on the three most significant variables. Results Significant functional decline was observed based on SMAFRS ( p = 0.019), pinch and knee flexion strength ( p = 0.030 and 0.027), MUNIX and MUSIX value in the ADM ( p = 0.0006 and 0.043) and in TA muscle ( p = 0.025). No significant differences were observed based on cervical MRI measures. A significant reduction was detected in the composite score ( p = 0.0005, SRM = −1.52), which was the most responsive variable and required a smaller number of patients than single variables in the estimation of sample size for clinical trials. Conclusions Quantitative strength testing, SMAFRS and MUNIX readily capture disease progression in adult SMA patients. Composite multimodal scores increase predictive value and may reduce sample size requirements in clinical trials.