The ARCA Registry: A Collaborative Global Platform for Advancing Trial Readiness in Autosomal Recessive Cerebellar Ataxias

Abstract

Autosomal recessive cerebellar ataxias (ARCAs) form an ultrarare yet expanding group of neurodegenerative multisystemic diseases affecting the cerebellum and other neurological or non-neurological systems. With the advent of targeted therapies for ARCAs, disease registries have become a precious source of real-world quantitative and qualitative data complementing knowledge from preclinical studies and clinical trials. Here, we review the ARCA Registry, a global collaborative multicenter platform (>15 countries, >30 sites) with the overarching goal to advance trial readiness in ARCAs. It presents a good clinical practice (GCP)- and general data protection regulation (GDPR)-compliant professional-reported registry for multicenter web-based capture of cross-center standardized longitudinal data. Modular electronic case report forms (eCRFs) with core, extended, and optional datasets allow data capture tailored to the participating site's variable interests and resources. The eCRFs cover all key data elements required by regulatory authorities [European Medicines Agency (EMA)] and the European Rare Disease (ERD) platform. They capture genotype, phenotype, and progression and include demographic data, biomarkers, comorbidity, medication, magnetic resonance imaging (MRI), and longitudinal clinician- or patient-reported ratings of ataxia severity, non-ataxia features, disease stage, activities of daily living, and (mental) health status. Moreover, they are aligned to major autosomal-dominant spinocerebellar ataxia (SCA) and sporadic ataxia (SPORTAX) registries in the field, thus allowing for joint and comparative analyses not only across ARCAs but also with SCAs and sporadic ataxias. The registry is at the core of a systematic multi-component ARCA database cluster with a linked biobank and an evolving study database for digital outcome measures. Currently, the registry contains more than 800 patients with almost 1,500 visits representing all ages and disease stages; 65% of patients with established genetic diagnoses capture all the main ARCA genes, and 35% with unsolved diagnoses are targets for advanced next-generation sequencing. The ARCA Registry serves as the backbone of many major European and transatlantic consortia, such as PREPARE, PROSPAX, and the Ataxia Global Initiative, with additional data input from SPORTAX. It has thus become the largest global trial-readiness registry in the ARCA field.

Capturing clinical progression in multisystemic genetic ataxias: lessons from a prospective study of 884 patients with autosomal recessive or early-onset ataxia

“…Prevalence and influence of non-ataxia features. The presence of multisystemic non-ataxia features was determined from each patient's last available INAS and the registry's systematic history for a priori recurrent features of ARCAs (e.g., epilepsy or mitochondrial features such as hearing loss or diabetes; case report form "Clinical Features" 20 ). Their respective impact on the SARA as a measure of ataxia severity was analyzed by generalized linear modeling (GLM), using the last SARA score of each patient as dependent variable; selecting age of onset, ataxia duration, ataxia duration squared, and genotype as independent variables 25 ; and adding non-ataxia features in the corresponding assessment that occurred in at least 40 patients (i.e.…”

“…Prospective cross-sectional and longitudinal data from all 948 consecutive patients enrolled between 2013 and August 4th 2021 were retrieved from the global multicenter ARCA Registry 20 . Datasets included (i) genotypic and demographic data, (ii) assessments of ataxia severity (SARA 1 ) and non-ataxia features (including the Inventory of Non-Ataxia Signs (INAS) 21 ), and (iii) the functional staging (FARS-FS) and activities of daily living (FARS-ADL) scales of the Friedreich Ataxia Rating Scale (FARS) 22 as patient-focused outcomes.…”

Consensus Recommendations for Clinical Outcome Assessments and Registry Development in Ataxias: Ataxia Global Initiative (AGI) Working Group Expert Guidance

“…Information on performed tests and negative results needs to be included. For this purpose, the genetic case report form (CRF) from autosomal recessive cerebellar ataxias (ARCA) registry can be used [8]. • Disability status: FARS functional staging for ataxia (FARS part I) [19] (http:// www.…”

Genetische Diagnostik zerebellärer Ataxien

“…Jahre; early-onset ataxias, EOA), bei denen die autosomal-rezessiven Ataxien gegenüber den sporadischen Ataxien mit spätem Beginn angereichert sind, und kombiniert diese mit den Patienten, bei denen die Ataxie wiederholt, aber nur in einer Generation vorkommt, so findet sich auch in dieser Gruppe bei ca. 65 % eine klare monogenetische Ursache 9 . Bei dieser Gruppe der genetisch gelösten früh beginnenden/autosomal-rezessiven Ataxien bleibt die häufigste genetische Ursache mit 50 % die Friedreich-Ataxie, mit deutlichem Abstand (alle jeweils < 10 %) gefolgt von RFC1, SPG7, autosomal-rezessive Ataxie Charlevoix Saguenay (ARSACS) und Ataxia teleangiectasia (AT) 10 .…”