RFC1 Natural History Study

Study Overview
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Brief Summary
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This international, multi-center, multi-modal and prospective observational study aims to determine the phenotypic spectrum and the natural progression of the RFC1 repeat expansion disease, and to seek and validate digital, imaging, and molecular biomarkers that aid in diagnosis and serve as outcome measures in future clinical trials of this novel, but frequent ataxia with late adult-onset.

Detailed Description
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The investigators will perform an international, multi-center, multi-modal, and registry-based standardized prospective Natural History Study (NHS) in RFC1 repeat expansion disease. Participants will be assessed annually. Study visits with a standardized clinical examination will apply several clinical rating scales, and data will be entered into a clinical database (ARCA Registry; www.ARCA-registry.org) customized to the requirements of this specific study. 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, and depending on local availability at each participating site, additional examinations may be performed including imaging, quantitative movement and speech analysis, vestibular testing, a neuropsychological examination, or examination of swallowing function, all to fully capture the multisystemic presentation of the RFC1 repeat expansion disease. This study will delineate variable phenotypes of this relatively novel disease, and systematically characterize the longitudinal progression of multi-model biomarkers to determine the most sensitive, comprehensive, and reliable outcomes measures for future therapeutic trials. Here, longitudinal validation of targeted fluid biomarker candidates will be an important part. The multi-modal longitudinal design of the study and its comprehensive assessment will also provide mechanistic insights into the multisystemic evolution of the disease, which will especially allow to track and understand selective as well as overlapping dysfunction of the cerebellum, sensory peripheral nerves, the vestibular system, and additional systems known to be involved in RFC1 disease or 'CANVAS' as its related syndrome.

Official Title
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RFC1 Natural History Study

Conditions
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Ataxia

Intervention / Treatment
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* Other: Clinical rating scale to measure ataxia disease severity and progression


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: RFC1: genetic diagnosis of bi-allelic pathogenic repeat expansions in RFC1 Unrelated healthy controls: no signs or history of neurological or psychiatric disease AND Written informed consent AND Participants are willing and able to comply with study procedures Exclusion Criteria: RFC1: Missing informed consent Controls: evidence of neuropathy, neurodegenerative disease, or movement disorder; inability to give informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

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 |
| --- | --- |
| RFC1<br>Participants with genetically confirmed RFC1 repeat expansion disease (ORPHA: 504476; OMIM 102579) will be recruited. Target sample size for the RFC1 cohort is 100 participants. | 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);|
| Unrelated healthy controls<br>Unrelated healthy controls Healthy controls may undergo the same study procedures as the RFC1 cohort. Target sample size for the control cohort is 50. | |

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 ataxia in the RFC1 cohort 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 8 items, yielding a total score between 0 and 40. Hereby, higher SARA scores indicate more severe disease. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Friedreich Ataxia Rating Scale - Activities of Daily Living (FARS-ADL) from baseline to 2-year follow-up. | Impairment in activities of daily living by ataxia, neuropathy, vestibular impairment or other disease features will be assessed in the RFC1 cohort by application of the Activities of Daily Living part of the Friedreich Ataxia Rating Scale (FARS-ADL). The total score is calculated as the sum of 9 items, yielding a total score between 0 and 36. Hereby, higher FARS-ADL scores indicate more severe functional impairment. | 24 months | 
| Charcot-Marie-Tooth Examination Score Version 2 (CMTESv2) from baseline to 2-year follow-up. | Severity of neuropathy in the RFC1 cohort will be assessed by application of the Charcot-Marie-Tooth Examination Score Version 2 (CMTESv2). The total score is calculated as the sum of 7 items, yielding a total score between 0 and 28. Hereby, higher CMTESv2 scores indicate more severe neuropathy. | 24 months | 
| Nine-Hole Peg Test (9HPT) from baseline to 2-year follow-up. | Upper limb function in the RFC1 cohort will be quantified by application of the Nine-Hole Peg Test (9HPT). This performance measure yields the mean duration of 2 trials to complete the task with the dominant and non-dominant hand, respectively, with an upper limit of 5 minutes (300 seconds). | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RFC1, CANVAS, Natural History Study, Biomarker