Spastic ataxias present an expanding group of >100 rare neurodegenerative diseases with joined damage of cerebellum and corticospinal tract (CST). While rapid genetic stratification facilitates current development of molecular therapies, effective trial-planning for SPAX is hampered by a lack of valid outcome measures and natural history studies. Uniting all major European ataxia and spastic paraplegia networks, and building on our prior networks and pilot data-sets, PROSPAX will establish a paradigmatic IRDiRC-guided integrated trial-ready model of disease progression and mechanistic evolution in SPAX. In a 2-year natural history study we will validate clinician- and patient-reported, digital and molecular outcomes. In addition, PROSPAX will improve existing and develop new outcome parameters that show superior sensitivity to change. These include a novel SPAX composite score, a smartphone mHealth toolbox combining remote assessment of daily living by wearable sensors with app- based patient-entered outcomes, and multimodal MRI radiomics with an innovative machine learning approach for multisite MRI analysis. Longitudinal validation of candidate biomarkers will be complemented by single-cell multi-omic studies in mouse By focusing on the two most prevalent recessive SPAX (SPG7, ARSACS), PROSPAX will create a paradigmatic trial-readiness pathway for charting disease progression and multimodal outcome measures that will be applicable to many of the >100 SPAX diseases alike.