European Cystinosis Cohort 2

Cystinosis is a rare autosomal recessive lysosomal storage disorder caused by pathogenic variants in the CTNS gene encoding cystinosin, the lysosomal cystine transporter. The resulting defect leads to progressive intralysosomal cystine accumulation, causing multisystem cellular dysfunction and progressive organ involvement. The disease typically presents in infancy with renal Fanconi syndrome and progresses to chronic kidney disease and, without cystine-depleting therapy, end-stage kidney disease in childhood. With advances in cysteamine therapy, renal replacement therapy, and kidney transplantation, survival has improved significantly, resulting in a chronic multisystem disease affecting both pediatric and adult populations.

At the cellular level, cystinosis involves lysosomal dysfunction, impaired autophagy, oxidative stress, dysregulated endolysosomal trafficking, and chronic inflammatory activation. Macrophage activation and inflammatory pathways are increasingly recognized as contributors to disease progression.

This study is conducted within the RaDiCo-ECYSCO platform, a European rare disease cohort designed for standardized longitudinal data collection in patients with cystinosis followed in expert reference centers. ECYSCO2 is the continuation of the original ECYSCO cohort and extends long-term follow-up and harmonized clinico-biological data collection.

The cohort is multicentric and includes specialized centers across Europe. It is embedded in routine clinical care, and data collection is non-interventional and based on standard follow-up procedures without modification of patient management.

Data are collected using standardized electronic case report forms (eCRFs) within the REDCap® platform of the RaDiCo information system. The system supports full data lifecycle management including data capture, validation, monitoring, and statistical analysis. Source data are defined as medical records, laboratory reports, imaging data, and patient questionnaires (paper or electronic). Investigators are responsible for ensuring consistency between source documents and eCRF entries.

Data quality is ensured through predefined validation rules, including range checks, logical consistency checks, and cross-variable verification. Monitoring procedures are implemented according to a predefined monitoring plan, and source data verification may be performed by comparing registry data with original medical records to ensure accuracy and completeness. Completed eCRF forms are validated and locked after quality review. Database freeze is performed prior to statistical analysis under joint agreement of investigators, data managers, statisticians, and study sponsor.

The RaDiCo information system complies with GDPR requirements and ISO 27001-based security standards. Data are hosted by an authorized health data hosting provider. Access is restricted through individual credentials, secure authentication, and audit trails ensuring traceability of all modifications. Regular backups are performed, and data are stored securely for the duration of the study followed by regulatory archiving.

A study data dictionary is maintained describing all collected variables, including definitions, data sources, and coding standards where applicable. It ensures harmonized interpretation of clinical, biological, and patient-reported data across centers and supports data consistency and statistical analysis.

The study includes structured quality oversight procedures. In addition to internal monitoring, the study may be subject to audits or inspections by competent authorities or independent bodies to ensure data quality, regulatory compliance, and adherence to study procedures.

Collected data include demographic, clinical, genetic, biological, and treatment-related information, as well as patient-reported outcomes. Data are collected longitudinally across repeated visits in both pediatric and adult populations.

Missing data are documented and described. Their extent and pattern are evaluated during analysis, and appropriate statistical approaches may be applied depending on the level and mechanism of missingness.

Statistical analyses are performed by the Inserm-RaDiCo biostatistics team using validated software (R, SAS or equivalent). A statistical analysis plan consistent with ICH E6 guidelines is developed prior to database lock. Analyses include descriptive statistics, longitudinal analyses, and survival methods where appropriate.

Given the rarity of cystinosis, all eligible patients willing to participate are included. The expected cohort size is approximately 250 patients across European centers.

A biobank is established including serum, plasma, blood-derived cells, and urine samples collected under informed consent. Samples are stored in certified facilities and linked to longitudinal clinical data to support biomarker research, including inflammatory and macrophage-related markers such as chitotriosidase and galectin-3.

No transfer of data outside the European Union is planned.

• Quality of life in patients with cystinosis (adults) [Time frame: Through study completion, an average of 6 years]
• Quality of life in patients with cystinosis (children) [Time frame: Through study completion, an average of 6 years]
• Treatment adherence in patients with cystinosis [Time frame: Through study completion, an average of 6 years]
• Renal function assessment in patients with cystinosis [Time frame: Through study completion, an average of 6 years]
• Ocular manifestations assessment in patients with cystinosis [Time frame: Through study completion, an average of 6 years]
• Endocrine manifestations assessment in patients with cystinosis [Time frame: Through study completion, an average of 6 years]
• Neurological, gastrointestinal, muscular and dermatological manifestations assessment in patients with cystinosis [Time frame: Through study completion, an average of 6 years]
• Cystinosis treatment exposure [Time frame: Through study completion, an average of 6 years]
• Long-term safety and adverse events of treatments [Time frame: Through study completion, an average of 6 years]
• Biological sample collection and biomarker analysis [Time frame: Baseline and every 2 years during follow-up, and at disease events]