Interim analysis of an international multi-site prospective natural history study evaluating the clinical presentation and progression of Leigh syndrome spectrum disorders

Background Leigh Syndrome Spectrum (LSS) is the most common pediatric mitochondrial disease syndromic presentation. However, its natural history has not been well-characterized, particularly across diverse populations. Objectives Information obtained through robust, prospective natural history studies (NHSs) in LSS will be foundational to accurately counsel newly diagnosed families, develop effective therapeutics, and identify outcome measures for future clinical trials. Design We describe an ongoing multi-site, international, patient advocacy group funded, observational NHS in LSS. We employed a multi-site international federated design with local regulatory review coupled with central regulatory and coordinator support. To date, NHS outcome measures have been collected on LSS participants across 5 sites every 3 to 6 months for up to 3.8 years. Methods Objective and subjective outcome measures were carefully selected by the international LSS outcome measure working group. Study data across sites were anonymized and combined for cleaning and analysis at the Data Coordinating Center (Children’s Hospital of Philadelphia). Descriptive statistics of the study cohort and inter-measure correlations were analyzed across NHS assessments. Results Preliminary analysis of the first 74 participants was completed to characterize demographics, symptomatology, and clinical history. The average age at enrollment was 10.7 years, ranging from 0 to 50 years. The most common gene disorders were MT-ATP6 (22%, n=16), MT-ND5 (8%, n=6) and SURF1 (8%, n=6). No statistically significant between-group differences were detected by sex or genetic etiology. High inter-measure correlation between all the outcome measures and “gold standard” outcomes provides justification for future use of these assessments in both NHSs and clinical trials. Conclusion We have demonstrated the feasibility of prospectively collecting robust international-site LSS NHS data through multi-site collaboration. These LSS community data will be critical for informing therapeutic development, outcome measure selection and clinical trial design, and providing baseline comparator evidence for development of future therapeutic interventions.