Prospective 5-year natural history study of infantile PLA2G6-associated neurodegeneration.

Aim: To prospectively characterize the age of developmental milestone attainment and loss, disease milestone acquisition, and associations between a quality of life measure and age in 40 children with infantile PLA2G6-associated neurodegeneration (PLAN).

Method: We analysed developmental and disease milestones and health-related quality of life scores from the 97-item Infant Toddler Quality of Life Questionnaire (ITQOL-97) in a prospective, observational, longitudinal natural history study. Developmental and disease milestone attainments were visualized as histograms and Kaplan-Meier curves respectively. We used mixed-effects linear regression to assess the associations between ITQOL-97 domains and age and to compare marginal predictions to a US reference population.

Results: The study group was comprised of 19 males and 21 females with a mean age at enrollment of 5 years 1 month (SD 3 years; range 1 year 7 months-16 years 8 months). Over the course of the disease, children continued to vocalize, smile, and laugh, while other milestones like walking were rarely met at any time. ITQOL-97 domains differed significantly from a US reference population in all areas except for 'general behavior'. The 'physical abilities' domain had the greatest change with age (-6.24 per year).

Interpretation: In this first prospective natural history study of infantile PLAN, we characterize developmental and disease milestones, and longitudinal associations, with quality of life metrics. These data will provide valuable disease norms for use as clinical references and in the design of interventional trials.