RISCA : Prospective Study of Individuals at Risk for SCA1, SCA2, SCA3, SCA6, SCA7 (RISCA)

Prospective Study of Individuals at Risk for Spinocerebellar Ataxia Type 1, Type 2, Type 3, Type 6 and Type 7 (SCA1, SCA2, SCA3, SCA6, SCA7)

The spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of autosomal dominantly inherited progressive ataxia disorders. It is estimated that there are 30,000 individuals in the European Community that directly descend from individuals affected by a SCA disorder and thus carry a 50% risk of having inherited an SCA mutation. These at risk individuals provide a unique research opportunity to prospectively study the presymptomatic phase of SCA disorders and to identify the earliest and most sensitive clinical signs and biological markers that herald the onset of the illness. This information is of critical importance for the development of future therapeutic interventions aimed at postponing the clinical onset of ataxia.

We therefore propose to perform a prospective observational study of individuals at risk for the most common SCA disorders, SCA1, SCA2, SCA3 and SCA6 (RISCA). It is our aim to answer the following questions: (1) What is the incidence of disease manifestation in mutation carriers? (2) Which clinical signs precede the onset of manifest ataxia in SCA1, SCA2, SCA3 and SCA6? (3) What are the prevalence and incidence of preceding signs? (4) Are the prevalence and incidence of preceding signs affected by genotype, gender, age, estimated time until disease manifestation and repeat length? (5) Does the presence of certain preceding signs predict the manifestation of ataxia ? (6) Are there MRI alterations that precede the onset of ataxia? It is planned to enroll 480 study participants and to follow them at regular intervals over six years. At each visit, study participants are asked in a structured interview for a number of predefined clinical signs that potentially precede the onset of ataxia. In addition, the following self-assessment scales will be applied: Pittsburgh Sleep Quality Index (PSQI), Diagnostic Criteria for Restless Legs Syndrome, Patient´s Health Questionnaire (PHQ-9). All study participants will undergo a physical examination including the Scale for the Assessment and Rating of Ataxia (SARA). Study participants will further perform the SCA Functional Composite (SCA-FC) which is a comprehensive measure of functional capacity based on results in quantitative tests related to gait (8m timed walk), speech (PATA rate) and hand function (9 hole pegboard). In a subset of study participants, we will record eye movements and obtain volumetric MRIs. The study will also be used to collect and store blood and urine samples for proteomic and gene expression studies.

RISCA is conducted by the Ataxia Study Group (ASG). It relies on the network structure created by the EUROSCA project.

Study Overview

• Status: Completed
• Conditions: Spinocerebellar Ataxias

• Study Type: Observational
• Enrollment (Actual): 37

Contacts and Locations

Study Locations

• France
  • Paris, France, 75013
    • Pitié Salpetrière Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

French population

Description

Inclusion Criteria:

• individuals at risk for spinocerebellar ataxia type 1, type 2, type 3, type 6 and type 7 (SCA1, SCA2, SCA3, SCA6 and SCA7)
• age between 18 and 50 years old for SCA1, SCA2, SCA3 or SCA7
• age between 35 and 70 years old for SCA6
• no clinical sign of ataxia (SARA < 3)

Exclusion Criteria:

• no writing consent
• no family members affected
• presence of clinical sign of ataxia (SARA > 3)

Study Plan

How is the study designed?

Design Details

• Observational Models: Family-Based
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
presymptomatic carriers
non carrier relatives

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determination of the incidence rate of ataxia onset among mutation carriers	Blood sample for a genetic test. Identification of individuals carrying a mutation for SCA types 1, 2, 3, 6, and 7	Day 0
Confidence Rating for Ataxia Assessment	The invetigator must specify the degree of confidence in the presence of specific signs that may be associated with SCA ataxia . 90-100 % : investigator very confident in the diagnosis of ataxia, 70-89 % : high confidence, but with some uncertainty, 50-69 % : moderate confidence, <50 % : significant uncertainty.	Day 0, Month 24, Month 48, Month 72
INAS scoring in ataxia (Inventory of Non-Ataxia Signs)	Score range 0-16. 0 : No nonataxia signsdetected. Higher score : more non-ataxia neurological signs are present	Day 0, Month 24, Month 48, Month 72
Assessmet of sleep quality in ataxia : PSQI (Pittsburg Sleep Quality Index)	The global PSQI score ranges from 0 to 21. 0-5 : good sleep quality. >5 : Poor sleep quality / clinically significant slep disturbance. Higher scores : worse sleep quality	Day 0, Month 24, Month 48, Month 72
Restless Legs Syndrome (RLS) assessment in Ataxia	Total Score : 0-40 0 : No RLS symptoms, 1-10 : Mild, 11-20 : Moderate, 21-30 : Severe, 31-40 : Very severe.	Day 0, Month 24, Month 48, Month 72
Assessment of depression by Patient's Health Questionnaire PHQ-9	Used to evaluatethe severity of depressive symptoms, giving a total score rangong from 0 to 27. 0-4 : minimal or no deprssive symptoms, 5-9 : mild depression, 10-14 : moderate depression, 15-19 : moderately severe depression, 20-27 : severe depression	Day 0, Month 24, Month 48, Month 72
Assessment of the disease's impact on quality of life based on EQ-5D index (EuroQoL-5 Dimensions)	It generally ranges from less than 0 to 1 (perfect health). Higher scores indicate a better quality of life	Day 0, Month 24, Month 48, Month 72
Assessment and Rating of Ataxia	SARA (Scale of Assessment and Rating Ataxia) is an 8-item performance based scale, yielding a total score of 0 (no ataxia) to 40 (most severe ataxia).	Day 0, Month 24, Month 48, Month 72
Functional assessment of the severity of ataxia	Using CCFS (Composite Cerebellar Functional Severity Score) method for assessing cerebellar ataxia across a wide range of severity. =0,85 : average value in an individual without ataxia. 0,90-1,00 : very mild or early-stage cerebellar impairment. 1,00-1,20 : Mild to moderate cerebellar impairment. >1,2 : More pronounced cerebellar impairment.	Day 0, Month 24, Month 48, Month 72
Upper Limb motor coordination assessment	A device equipped with a pre-calibrated force sensor that measures grip strength and lifting capacity, and a Polhemus 3D position sensor that measures position along the -x, -y, and -z axes and the object's orientation to assess movement. Grip force variability coefficient is calculated : Lowe % (more stable greap force control) - Higher % (greater variability and poorer motor coordination)	Day 0, Month 24, Month 48, Month 72
Finger tapping assessment	Number of taps within 10 seconds (higher = better)	Day 0, Month 24, Month 48, Month 72
GAITRite in an ataxia assessment	The participant walks along a carpet equipped with sensors that record the time it takes to make a step as well as the position of the feet.	Day 0, Month 24, Month 48, Month 72

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional performance assessment by 8MW test (8 meters walking time)	Measure in seconds, the time needed to cover a distance of 8 meters as quickly and safely as possible	Day 0, Month 24, Month 48, Month 72
Functional performance assessment by 9HPT : Nine Hole Peg Test	The test consists of insertingand removing 9 wooden pegs from a board as quickly as possible, using only one hand. A healthy adult completes the test in about 10 to 20 seconds.	Day 0, Month 24, Month 48, Month 72
Functional performance assessment by by PATA	It involves counting the number of clear répétitions of the syllable or sentence " pa-ta " that a patient can produce in 10 seconds	Day 0, Month 24, Month 48, Month 72
Assessment of retinal thickness	By using Optical Coherence Tomography (OCT) scan	Day 0, Month 24, Month 48, Month 72
Identification of slow saccades during eye tracking	By recording of eye movements	Day 0, Month 24, Month 48, Month 72
Evaluation of the functional connectivity	Brain imaging will help determine whether functional connectivity between the cortex and the cerebellum is impaired	Day 0, Month 72

Collaborators and Investigators

• Sponsor: Institut National de la Santé Et de la Recherche Médicale, France

Publications and helpful links

General Publications

• Wilke C, Haas E, Reetz K, Faber J, Garcia-Moreno H, Santana MM, van de Warrenburg B, Hengel H, Lima M, Filla A, Durr A, Melegh B, Masciullo M, Infante J, Giunti P, Neumann M, de Vries J, Pereira de Almeida L, Rakowicz M, Jacobi H, Schule R, Kaeser SA, Kuhle J, Klockgether T, Schols L; SCA3 neurofilament study group; Barro C, Hubener-Schmid J, Synofzik M. Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice. EMBO Mol Med. 2020 Jul 7;12(7):e11803. doi: 10.15252/emmm.201911803. Epub 2020 Jun 8.
• Jacobi H, du Montcel ST, Romanzetti S, Harmuth F, Mariotti C, Nanetti L, Rakowicz M, Makowicz G, Durr A, Monin ML, Filla A, Roca A, Schols L, Hengel H, Infante J, Kang JS, Timmann D, Casali C, Masciullo M, Baliko L, Melegh B, Nachbauer W, Burk-Gergs K, Schulz JB, Riess O, Reetz K, Klockgether T. Conversion of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 to manifest ataxia (RISCA): a longitudinal cohort study. Lancet Neurol. 2020 Sep;19(9):738-747. doi: 10.1016/S1474-4422(20)30235-0.
• Wilke C, Mengel D, Schols L, Hengel H, Rakowicz M, Klockgether T, Durr A, Filla A, Melegh B, Schule R, Reetz K, Jacobi H, Synofzik M. Levels of Neurofilament Light at the Preataxic and Ataxic Stages of Spinocerebellar Ataxia Type 1. Neurology. 2022 May 17;98(20):e1985-e1996. doi: 10.1212/WNL.0000000000200257. Epub 2022 Mar 9.
• Jacobi H, Reetz K, du Montcel ST, Bauer P, Mariotti C, Nanetti L, Rakowicz M, Sulek A, Durr A, Charles P, Filla A, Antenora A, Schols L, Schicks J, Infante J, Kang JS, Timmann D, Di Fabio R, Masciullo M, Baliko L, Melegh B, Boesch S, Burk K, Peltz A, Schulz JB, Dufaure-Gare I, Klockgether T. Biological and clinical characteristics of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 in the longitudinal RISCA study: analysis of baseline data. Lancet Neurol. 2013 Jul;12(7):650-8. doi: 10.1016/S1474-4422(13)70104-2. Epub 2013 May 22.
• Tezenas du Montcel S, Durr A, Rakowicz M, Nanetti L, Charles P, Sulek A, Mariotti C, Rola R, Schols L, Bauer P, Dufaure-Gare I, Jacobi H, Forlani S, Schmitz-Hubsch T, Filla A, Timmann D, van de Warrenburg BP, Marelli C, Kang JS, Giunti P, Cook A, Baliko L, Melegh B, Boesch S, Szymanski S, Berciano J, Infante J, Buerk K, Masciullo M, Di Fabio R, Depondt C, Ratka S, Stevanin G, Klockgether T, Brice A, Golmard JL. Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6. J Med Genet. 2014 Jul;51(7):479-86. doi: 10.1136/jmedgenet-2013-102200. Epub 2014 Apr 29.

Study record dates

Study Major Dates

• Study Start (Actual): May 7, 2009
• Primary Completion (Actual): December 1, 2017
• Study Completion (Actual): December 14, 2017

Study Registration Dates

• First Submitted: December 21, 2009
• First Submitted That Met QC Criteria: December 22, 2009
• First Posted (Estimated): December 23, 2009

Study Record Updates

• Last Update Posted (Actual): August 19, 2026
• Last Update Submitted That Met QC Criteria: August 17, 2026
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: individuals at risk for SCA1, SCA2, SCA3, SCA6 and SCA7
• Additional Relevant MeSH Terms: Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Spinal Cord Diseases; Dyskinesias; Cerebellar Diseases; Cerebellar Ataxia; Spinocerebellar Degenerations; Ataxia; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Spinocerebellar Ataxias
• Other Study ID Numbers: C08-37