RFC1 Natural History Study

Prof. Dr. Matthis Synofzik150 enrolled

Overview

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.

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.

Study Type

OBSERVATIONAL

Enrollment

150

Conditions

Ataxia

Interventions

Clinical rating scale to measure ataxia disease severity and progressionOTHER

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.

Eligibility

Sex: ALLMin age: 18 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (10)

Department of Neuroscience, Central Clinical School, Monash University

Melbourne, Victoria, Australia

RECRUITING

Department of Neurology, Ataxia Unit, Universidade Federal de São Paulo

São Paulo, State of São Paulo, Brazil

Outcomes

Primary Outcomes

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.

Time frame: 24 months

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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).

Time frame: 24 months

Central Contacts

Matthis Synofzik, Prof. Dr.

CONTACT

+49 7071 29 matthis.synofzik@uni-tuebingen.de

Andreas Traschütz, Dr. Dr.

CONTACT

+49 7071 29 andreas.traschuetz@uni-tuebingen.de

Data from ClinicalTrials.gov

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