TreatHSP Platform: Adaptive Natural History Platform for Ataxias, HSPs, and Spastic Ataxias

Ataxias, hereditary spastic paraplegias (HSP), and spastic ataxias (collectively referred to as SPAX diseases) are rare neurological conditions that cause progressive problems with walking, balance, coordination, and daily activities. Although many SPAX diseases are caused by specific genetic changes, there is still limited knowledge about how symptoms develop over time, how fast the diseases progress, and which clinical or biological measures best reflect meaningful changes for patients. The TreatHSP Master Protocol establishes an adaptive natural history study platform designed to improve the understanding of SPAX diseases across all ages and disease stages. Within this platform, the TreatHSP/SPAX study serves as the core natural history study, providing a shared framework for long-term clinical follow-up, standardized outcome assessments, and biosample collection. Participants enrolled in TreatHSP/SPAX are followed over time to document disease progression using clinical examinations, patient- and caregiver-reported outcomes, digital movement measures, imaging, and biological samples. In addition to this core dataset, the TreatHSP Platform allows optional, disease- or hypothesis-specific substudies to be added over time in selected participant groups. These additional assessments are introduced under the same master protocol, without creating separate stand-alone studies. The overall goal of the TreatHSP Master Protocol is to generate high-quality natural history data, identify sensitive and patient-relevant outcome measures, and support the development of future therapies for ataxias, hereditary spastic paraplegias, and spastic ataxias.

Inclusion Criteria: General inclusion criteria: \- Age 5 or older Cohort 1: Affected * Clinical diagnosis of neurodevelopmental or neurodegenerative ataxia, spastic ataxia, HSP or related phenotype AND * Alternative causes of phenotype excluded Cohort 2: Presymptomatic mutation carriers \- Premanifest mutation carrier of (likely) pathogenic variant(s) in a disease gene associated with ataxia, spastic ataxia, HSP or related phenotype Cohort 3: Family controls - 1st or 2nd degree relative of a person with a clinical or genetic diagnosis of ataxia, spastic ataxia, HSP or related phenotype Cohort 4: Community controls \- Healthy individual unrelated to a person with neurodevelopmental or neurodegenerative ataxia, spastic ataxia, HSP or related phenotype Exclusion Criteria: * Presence of an alternative neurological or systemic condition that sufficiently explains the phenotype and is incompatible with ataxia, spastic ataxia, hereditary spastic paraplegia, or a related disorder. * Severe comorbidity or unstable medical condition that substantially interferes with study participation or interpretation of neurological and functional assessments. * Inability to comply with study procedures or follow-up requirements. * Lack of informed consent, including absence of consent by a legally authorized representative where required. * Current participation in an interventional clinical trial that may interfere with the objectives or outcome assessments of this observational study.