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

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.

Study Overview

• Status: Recruiting
• Conditions: Spastic Ataxia
• Intervention / Treatment: 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)

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.

• Study Type: Observational
• Enrollment (Anticipated): 250

Contacts and Locations

• Study Contact: Name: Rebecca Schüle, PD Dr.; Phone Number: 85653 +49 7071 29; Email: rebecca.schuele-freyer@uni-tuebingen.de
• Study Contact Backup: Name: Matthis Synofzik, Prof., Dr.; Phone Number: 82060 +49 7071 29; Email: matthis.synofzik@uni-tuebingen.de

Study Locations

• Canada
  • Quebec
    • Montreal,, Quebec, Canada, H3A 2B4
      • Recruiting
      • Montreal Neurological Institute of McGill University, Department of Neurology and Neurosurgery and Human Genetics
      • Contact: Bernard Brais, MD, PhD; Phone Number: 3334 +1-514-398; Email: bernard.brais@mcgill.ca
      • Principal Investigator: Bernard Brais, MD, PhD
    • Saguenay, Quebec, Canada, G7X 7X2
      • Recruiting
      • Université de Sherbrooke
      • Contact: Cynthia Gagnon, PhD; Phone Number: 1-418-695-7700; Email: cynthia.gagnon4@usherbrooke.ca
      • Contact: Isabelle Côté, M.Sc.; Phone Number: 1-418-695-7700; Email: Isabelle.Cote7@USherbrooke.ca
      • Principal Investigator: Cynthia Gagnon, PhD
• France
  • Paris, France, 75013
    • Recruiting
    • Département d'information médicale (DIM); Département de Biostatistique, Santn 3emé Publique et Information Médicale (BIOSPIM)- Bâtiment Mazarie étage; Hôpitaux Universitaires Pitié Salpêtrière
    • Contact: Hortense Hurmic; Phone Number: (33)1 57 27 42 22; Email: hortense.hurmic@icm-institute.org
    • Contact: Sophie Tezenas Du Montcel, MD, PhD; Phone Number: (33) 1 42 16 05 82; Email: sophie.tezenas@aphp.fr
    • Principal Investigator: Sophie Tezenas Du Montcel, MD, PhD
    • Sub-Investigator: Alexandra DURR, MD, PhD
• Germany
  • Essen, Germany, 45147
    • Recruiting
    • University Hospital Essen (AöR)
    • Contact: Stephan Klebe, Prof. Dr.; Phone Number: +49-201-723-6513; Email: Stephan.Klebe@uk-essen.de
    • Contact: Dagmar Timmann-braun, Prof. Dr.; Phone Number: (+)49 (0)201 7232180; Email: Dagmar.Timmann-braun@uk-essen.de
    • Principal Investigator: Stephan Klebe, Prof. Dr.
    • Sub-Investigator: Dagmar Timmann-braun, Prof. Dr.
  • Baden-Württemberg
    • Tübingen, Baden-Württemberg, Germany, 72076
      • Recruiting
      • Center for Neurology & Hertie-Institute for Clinical Brain Research, Dept. for Neurodegenerative Diseases
      • Contact: Selina Reich, M.Sc; Phone Number: 85548 +49 7071 29; Email: selina.reich@uni-tuebingen.de
      • Contact: Katrin Dillmann-Jehn; Phone Number: 85653 +49 7071 29; Email: katrin.dillmann@med.uni-tuebingen.de
      • Principal Investigator: Matthis Synofzik, Prof, Dr.
      • Principal Investigator: Rebecca Schüle, MD
• Italy
  • Pisa, Italy, 56128
    • Recruiting
    • IRCCS Fondazione Stella Maris
    • Contact: Filippo M. Santorelli, MD; Phone Number: +39 050 886275; Email: filippo.santorelli@fsm.unipi.it
    • Contact: Sirio Cocozza, MD; Phone Number: +39 081 7462560; Email: sirio.cocozza@unina.it
    • Principal Investigator: Filippo M. Santorelli, MD
    • Sub-Investigator: Sirio Cocozza, MD
• Netherlands
  • Nijmegen, Netherlands, 6525 GC
    • Recruiting
    • Radboud University Medical Center; Department of Neurology & Donders Institute for Brain, Cognition, and Behaviour
    • Contact: Bart van de Warrenburg, MD, PhD; Phone Number: 0031-24-3613396; Email: Bart.vandeWarrenburg@radboudumc.nl
    • Principal Investigator: Bart van de Warrenburg, MD, PhD
• Turkey
  • Istanbul, Turkey, 34010
    • Recruiting
    • Koç Univ. Hospital, KUTTAMNDAL
    • Contact: Nazli BAŞAK, PhD; Phone Number: +90-850-250825023811; Email: nbasak@ku.edu.tr
    • Contact: Atay Vural, MD, PhD; Phone Number: +90 850 250 8250; Email: atayvural@ku.edu.tr
    • Principal Investigator: Nazli BAŞAK, PhD
    • Sub-Investigator: Atay Vural, MD, PhD
• United Kingdom
  • Cambridge, United Kingdom, CB2 0PY
    • Recruiting
    • Department of Clinical Neurosciences, University of Cambridge; John Van Geest Cambridge Centre for Brain Repair
    • Contact: Rita Horvath, MD, PhD; Phone Number: +44 (0) 1223 331165; Email: rh732@medschl.cam.ac.uk
    • Principal Investigator: Rita Horvath, MD, PhD
    • Sub-Investigator: Evan Reid, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Probands with clinically manifest and genetically confirmed spastic ataxia (genetic subtypes: ARSACS, SPG7) will be enrolled in this study. Additionally, healthy unrelated controls will be enrolled; these are necessary to contrast unspecific, gender- or age-related findings to disease specific findings.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
ARSACS; 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; 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 Names: Scale for the Assessment and rating of Ataxia (SARA); 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 Names: Spastic Paraplegia Rating Scale (SPRS); 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.; Other Names: DSI-ARSACS; Diagnostic test: Next-Gen Sequencing (NGS); Whole Genome Sequencing, Whole Exome Sequencing, Transcriptomics, Proteomics, Metabolomics
SPG7; 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; 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 Names: Scale for the Assessment and rating of Ataxia (SARA); 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 Names: Spastic Paraplegia Rating Scale (SPRS); 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.; Other Names: DSI-ARSACS; Diagnostic test: Next-Gen Sequencing (NGS); Whole Genome Sequencing, Whole Exome Sequencing, Transcriptomics, Proteomics, Metabolomics
Unrelated healthy control; 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; 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 Names: Scale for the Assessment and rating of Ataxia (SARA); 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 Names: Spastic Paraplegia Rating Scale (SPRS); 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.; Other Names: DSI-ARSACS; Diagnostic test: Next-Gen Sequencing (NGS); Whole Genome Sequencing, Whole Exome Sequencing, Transcriptomics, Proteomics, Metabolomics

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of the Patient-Reported Outcomes Measurement Information System (PROMIS) short form "physical function" 12a from baseline to 2-year follow-up	Self-report questionnaire comprising 12 questions. All PROMIS scores are standardized (item-level calibration) and expressed as T-scores with a population mean of 50 and a Standard Deviation (SD) of 10. Higher T-scores hereby indicate a higher physical function level.	24 months
Change of the Patient-Reported Outcomes Measurement Information System (PROMIS) short form "social roles and activities" 8a from baseline to 2-year follow-up	Self-report questionnaire comprising 8 questions. All PROMIS scores are standardized (item-level calibration) and expressed as T-scores with a population mean of 50 and a Standard Deviation (SD) of 10. Higher T-scores hereby indicate a higher degree of social participation.	24 months

Collaborators and Investigators

• Sponsor: Dr. Rebecca Schule
• Collaborators: German Research Foundation; German Center for Neurodegenerative Diseases (DZNE)
• Investigators: Principal Investigator: Rebecca Schüle, PD Dr., University Hospital Tübingen; Principal Investigator: Matthis Synofzik, Prof., Dr., University Hospital Tübingen

Publications and helpful links

Helpful Links

• Website of the HSP Registry
• Website of the ARCA Registry

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2020
• Primary Completion (Anticipated): June 1, 2024
• Study Completion (Anticipated): June 1, 2025

Study Registration Dates

• First Submitted: February 27, 2020
• First Submitted That Met QC Criteria: March 3, 2020
• First Posted (Actual): March 6, 2020

Study Record Updates

• Last Update Posted (Actual): May 18, 2022
• Last Update Submitted That Met QC Criteria: May 17, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Biomarker; Natural History Study; Spastic Ataxia; Genetic etiology; Molecular mechanisms
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Eye Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Genetic Diseases, Inborn; Musculoskeletal Diseases; Muscular Diseases; Neurodegenerative Diseases; Neuromuscular Manifestations; Dyskinesias; Spinal Cord Diseases; Heredodegenerative Disorders, Nervous System; Optic Nerve Diseases; Cranial Nerve Diseases; Neurodevelopmental Disorders; Muscle Hypertonia; Cerebellar Diseases; Spinocerebellar Degenerations; Ataxia; Muscle Spasticity; Intellectual Disability; Cerebellar Ataxia; Spinocerebellar Ataxias; Optic Atrophy
• Other Study ID Numbers: SPAX-PBP; 441409627 (Other Grant/Funding Number: Deutsche Forschungsgemeinschaft (DFG))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No