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 neurological 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

Study participants 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 participants.

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 of age, were captured to stratify cohorts by neurological severity.

Main Outcome and Measure

A primary outcome was not prespecified, as this was an observational study.

Results

In total, 1203 participants were identified across 42 leukodystrophies (age range of 9 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.