Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias

Conditions
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Spastic Ataxia

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


Participation Criteria
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Eligibility Criteria
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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
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| ARSACS<br>Participants with genetically confirmed ARSACS (ORPHA:98) will be recruited. Target sample size for the ARSACS cohort is 120. | Other: Clinical rating scale to measure Ataxia disease severity and progression<br>* 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.<br>* Other names: Scale for the Assessment and rating of Ataxia (SARA);Other: Clinical rating scale to measure spastic paraplegia disease severity and progression<br>* 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.<br>* Other names: Spastic Paraplegia Rating Scale (SPRS);Other: Disease-specific severity index for adults with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)<br>* 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.<br>* Other names: DSI-ARSACS;Diagnostic Test: Next-Gen Sequencing (NGS)<br>* Whole Genome Sequencing, Whole Exome Sequencing, Transcriptomics, Proteomics, Metabolomics<br>|
| SPG7<br>Participants with genetically confirmed SPG7 (ORPHA:99013) will be recruited. Target sample size for the SPG7 cohort is 72. | Other: Clinical rating scale to measure Ataxia disease severity and progression<br>* 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.<br>* Other names: Scale for the Assessment and rating of Ataxia (SARA);Other: Clinical rating scale to measure spastic paraplegia disease severity and progression<br>* 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.<br>* Other names: Spastic Paraplegia Rating Scale (SPRS);Other: Disease-specific severity index for adults with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)<br>* 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.<br>* Other names: DSI-ARSACS;Diagnostic Test: Next-Gen Sequencing (NGS)<br>* Whole Genome Sequencing, Whole Exome Sequencing, Transcriptomics, Proteomics, Metabolomics<br>|
| Unrelated healthy control<br>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. | Other: Clinical rating scale to measure Ataxia disease severity and progression<br>* 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.<br>* Other names: Scale for the Assessment and rating of Ataxia (SARA);Other: Clinical rating scale to measure spastic paraplegia disease severity and progression<br>* 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.<br>* Other names: Spastic Paraplegia Rating Scale (SPRS);Other: Disease-specific severity index for adults with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)<br>* 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.<br>* Other names: DSI-ARSACS;Diagnostic Test: Next-Gen Sequencing (NGS)<br>* Whole Genome Sequencing, Whole Exome Sequencing, Transcriptomics, Proteomics, Metabolomics<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Scale for the Assessment and Rating of Ataxia (SARA) from baseline to 2-year follow-up | Severity of the ataxia component of the disease will be assessed by application of the Scale for the Assessment and Rating of Ataxia (SARA). The total score is calculated as the sum of al items, yielding a total score between 0 and 38. Hereby, higher SARA scores indicate more severe disease. | 24 months | 
| Change of Spastic Paraplegia Rating Scale (SPRS) from baseline to 2-year follow-up | Severity of the spasticity component of the disease will be assessed by application of the Spastic Paraplegia Rating Scale. The total score is calculated as the sum of al items, yielding a total score between 0 and 52. Hereby, higher SPRS scores indicate more severe disease. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Disease severity index - Autosomal recessive spastic ataxia of Charlevoix-Saguenay(DSI-ARSACS) from baseline to 2-year follow-up | The DSI-ARSACS is a clinical rating scale consisting of 8 items reflecting the 3 main components of the disease (pyramidal, cerebellar, and neuropath systems) specifically developed to measure disease progression in ARSACs. The DSI-ARSACS total score can range from 0 to 38. Hereby, higher DSI-ARSACS scores indicate more severe disease. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Spastic Ataxia, Biomarker, Genetic etiology, Molecular mechanisms, Natural History Study