NCT04297891

Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias

• Status: Unknown
• Phase: —
• Study type: Observational
• Enrollment: 250 (estimated)
• Sponsor: Dr. Rebecca Schule · Academic / Other
• Sex: All
• Age: —
• Healthy volunteers: Accepted

Summary

The aim of this study is to determine the clinical spectrum and natural progression of Spastic Ataxias (SPAX) and related disorders in a prospective multicenter natural history study, identify digital, imaging and molecular biomarkers that can assist in diagnosis and therapy development and study the genetic etiology and molecular mechanisms of these diseases.

Detailed description

The investigators will perform a registry-based standardized prospective Natural History Study (NHS) in SPAX and related disorders. Participants will be seen annually. At study visits a standardized clinical examination will be performed including application of clinical rating scales (selection of rating scales may vary depending on the individual phenotype and specific genotype); data will be entered into a clinical database (HSP Registry; https://www.hsp-registry.net and ARCA Registry; www.ARCA-registry.org). At all study visits, patients will be asked to donate biosamples; biomaterial collection is optional and participants can elect to participate in sampling of blood, urine, CSF, and/or a skin biopsy. Optionally, additional examinations may be performed including imaging, quantitative movement analysis, neuropsychological examinations, analysis of patient or observer reported outcomes and OMICS analysis to characterize molecular biomarkers. In participants without a genetic diagnosis, next generation sequencing may be performed. Thus this study will establish a model of disease progression and mechanistic evolution in SPAX, which will allow to track and understand selective as well as overlapping dysfunction of the cerebellum and corticospinal tract. In a transatlantic natural history study we will longitudinally validate clinician- and patient-reported, digital and molecular outcomes. In addition, we will improve on existing and develop new outcome parameters that show superior sensitivity to change. These include a novel clinical SPAX composite score, a smartphone mHealth toolbox combining remote assessment of daily living by wearable sensors with app-based patient-entered outcomes (SPAX.app), and multimodal MRI radiomics with an innovative machine learning approach for multisite MRI analysis, including in particular the infratentorial space. Longitudinal validation of targeted fluid biomarker candidates will aslo be an important part.

Conditions

• Spastic Ataxia

Interventions

Type	Name	Description
OTHER	Clinical rating scale to measure Ataxia disease severity and progression	SARA is a clinical scale developed by Schmitz-Hübsch et al which assesses a range of different impairments in cerebellar ataxia. The scale is made up of 8 items related to gait, stance, sitting, speech, finger-chase test, nose-finger test, fast alternating movements and heel-shin test.
OTHER	Clinical rating scale to measure spastic paraplegia disease severity and progression	A 13-item scale to rate functional impairment occurring in pure forms of spastic paraplegia (SP). Additional symptoms constituting a complicated form of SP are recorded in an inventory.
OTHER	Disease-specific severity index for adults with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)	The DSI-ARSACS is a valid measure of disease severity for the adult ARSACS population that is able to distinguish between patients with different clinical profiles. It considers the 3 components (pyramidal, cerebellar, neuropathic) of the disease, and documents its content validity, internal consistency, and construct validity.
DIAGNOSTIC_TEST	Next-Gen Sequencing (NGS)	Whole Genome Sequencing, Whole Exome Sequencing, Transcriptomics, Proteomics, Metabolomics

Timeline

• Start date: 2020-09-01
• Primary completion: 2024-06-01
• Completion: 2025-06-01
• First posted: 2020-03-06
• Last updated: 2022-05-18

Locations

9 sites across 7 countries: Canada, France, Germany, Italy, Netherlands, Turkey (Türkiye), United Kingdom