Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias (SPAX-PBP)

Dr. Rebecca Schule

Status: Enrolling

Conditions: Spastic Ataxia

Treatments: Other: Clinical rating scale to measure spastic paraplegia disease severity and progression; Diagnostic Test: Next-Gen Sequencing (NGS); Other: Disease-specific severity index for adults with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS); Other: Clinical rating scale to measure Ataxia disease severity and progression

Study type: Observational

Funder types: Other

Identifiers

NCT04297891

SPAX-PBP

441409627 (Other Grant/Funding Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 250 estimated patients

Sex: All

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• ARSACS cohort: genetic diagnosis of ARSACS and clinically manifest disease
• SPG7 cohort: genetic diagnosis of SPG7 and clinically manifest disease
• Unrelated healthy controls: no signs or history of neurological or psychiatric disease

AND

• written informed consent provided

AND

• Participants are willing and able to comply with study procedures

Exclusion criteria

• Missing informed consent
• For controls: evidence of a neurodegenerative disease or movement disorders; inability to give informed consent

Trial design

250 participants in 3 patient groups

ARSACS

Description:

Participants with genetically confirmed ARSACS (ORPHA:98) will be recruited. Target sample size for the ARSACS cohort is 120.

Treatment:

Diagnostic Test: Next-Gen Sequencing (NGS)

Other: Clinical rating scale to measure Ataxia disease severity and progression

Other: Disease-specific severity index for adults with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)

Other: Clinical rating scale to measure spastic paraplegia disease severity and progression

SPG7

Description:

Participants with genetically confirmed SPG7 (ORPHA:99013) will be recruited. Target sample size for the SPG7 cohort is 72.

Treatment:

Diagnostic Test: Next-Gen Sequencing (NGS)

Other: Clinical rating scale to measure Ataxia disease severity and progression

Other: Disease-specific severity index for adults with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)

Other: Clinical rating scale to measure spastic paraplegia disease severity and progression

Unrelated healthy control

Description:

Unrelated healthy controls Healthy controls may undergo the same study procedures as the ARSACS and SPG7 cohort. Target sample size for the control cohort is 50.

Treatment:

Diagnostic Test: Next-Gen Sequencing (NGS)

Other: Clinical rating scale to measure Ataxia disease severity and progression

Other: Disease-specific severity index for adults with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)

Other: Clinical rating scale to measure spastic paraplegia disease severity and progression