GNAO1-EU

GNAO1-associated disorders encompass a wide spectrum of neurological disorders featuring variable association with early-onset movement disorder, epilepsy, developmental delay and intellectual disability. GNAO1-associated disorder is an ultra-rare disease with an unknown prevalence. Approximately 150 patients have been described in the literature to date as case reports or included in small retrospective case studies. The full clinical spectrum, genotype-phenotype correlation and disease course still need to be delineated, as well as standard of care. The main objectives are: i A prospective natural history study combining a careful phenotyping with longitudinal quantitative assessment in a large cohort of patients, ii) the setting up and implementation of an international registry iii) the identification and validation of potential biomarkers, by exploring neuroinflammation and gut microbiome. The consortium consists of 8 partners representing the clinical and the basic research disciplines, including one underrepresented country and one early career researcher, 3 PAOs, and 8 collaborators. Each partner and collaborator is a national and international reference centre in its respective field with 4 partners being members of ERN network. The duration of the project will be 36 months; 90 to 96 patients are expected to be enrolled. The study design includes 2 distinct but highly interconnected Sub-projects. Subproject 1 will be involved in the prospective natural history study with standardized and quantitative assessments of several clinical aspects (movement disorder, cognition, sleep, epilepsy) and quality of life (WP1). In this regard, an international registry will be set up where data will be stored and analysed (WP2). Longitudinal brain MRI will be performed during the study (WP3). Subproject 2 will be dedicated to the identification of potential biomarkers ad subsequent validation in pre-clinical models. Samples (feces and plasma) will be collected at each visit from patients. The microbiome signature and the patient inflammatory profile will be analyzed and correlated to the GNAO1 mutation (WP4). On CSF available samples metabolomics analysis will also be performed (WP5). There are currently no disease-modifying treatments available for GNAO1-associated disorders, and identifying suitable biomarkers to assess disease phenotype, progression or therapeutic efficacy is consequently a main priority. The involved 3 national PAOs ensures transparency in the relationship between researchers and patients, a better recruitment strategy, dissemination and future sustainability of the registry.