Clinically Important Endpoints in Individuals With Leukodystrophy: A Multisite Study.

Importance: Leukodystrophies are a diverse group of rare disorders that disrupt central myelination. These disorders present with a broad spectrum of neurologic severity and are associated with a range of potential secondary complications, such as scoliosis and failure of independent feeding. Objective: we explore real-world data of leukodystrophy complications to inform future evidence-based care guidelines across these rare diseases. Design: In a cross-sectional observational study, we use a leukodystrophy-specific research consortium and the availability of electronic health records (EHR) to capture a cross-section of real-world data. Setting: Subjects were identified using EHR data from five hospital systems with established expertise in leukodystrophies. Participants: Principal investigators or genetic counselors confirmed leukodystrophy diagnoses in all subjects. Exposures: Time-to-event measures were collected, including orthopedic complications (scoliosis, hip subluxation/dislocation), loss of ambulation, artificial ventilation, gastrostomy tube placement, and urinary tract infections (UTIs). Maximum motor milestones, including gain of ambulation by 2 years old, were captured to stratify cohorts by neurologic severity. Main Outcome and Measure: A primary outcome was not prespecified as this was an observational study. Results: In total, 1203 subjects were identified across 42 leukodystrophies (age range of nine days to 89 years at last encounter). The most common event was feeding tube placement, and the median time to any first complication varied between disorders (Fleming-Harrington weighted log-rank test). The specific diagnosis correlated with maximum gross motor milestone attainment (Chi-square test of independence). When all disorders were stratified by maximum motor milestone attainment (not specific diagnosis), the median time to adverse events was significantly associated with function (Fleming-Harrington weighted log-rank test). Conclusions: This cross-sectional, retrospective observational study demonstrated that key medical events could be identified across institutions using EHR capture. Rates of health events and attainment of maximum motor milestones varied by specific leukodystrophy type. However, when the overall cohort was stratified by severity of motor impairment rather than individual diagnoses, the frequency of health events was associated with motor function. Our findings suggest utility for development of comprehensive care models for leukodystrophies as stratified by motor function, and demonstrate the utility of integrated EHR review for real-world data analyses.