Characterizing Diagnostic Delays in Metachromatic Leukodystrophy: A Real‐World Data Approach

Neurodegeneration in metachromatic leukodystrophy (MLD) may be preceded by systemic complications. Characterization of these features is critical to define barriers to early diagnosis and treatment eligibility for gene therapy. We utilized medical billing (claims) datasets and a natural history study to capture pre-diagnosis MLD-related events. MLD-related events (ICD-10-CM codes) were aggregated into system-based diagnosis clusters, and time to MLD diagnosis (TTD) computed for each organ-system diagnosis cluster. Differences in TTD distribution, instantaneous diagnosis hazard, and survival to MLD diagnosis were compared by sex and payor type. TTD and regression from onset of first symptoms were described using median and inter-quartile range. The claims dataset identified 174 MLD cases (diagnosis ≤ 6 years old) with 14 diagnosed within the first year of life. General neurologic concerns (n = 138; median 257 days pre-diagnosis), gastrointestinal (n = 137; 231 days), seizures (n = 48; 236 days), ophthalmologic (n = 46; 362 days), and language-related events (n = 41; 267 days) were common. Time to MLD diagnosis from onset of prodromal clusters was longer for children with non-commercial insurance: most prominent with seizures (survival logrank p value < 0.02) and non-degenerative neurological symptoms (survival logrank p value < 0.04). Similar findings were noted in our analysis of a second claims dataset. The natural history cohort demonstrated a similar pattern of prodromal disease features and delayed diagnosis. This study defines barriers to MLD diagnosis and highlights prodromal periods of pre-regression symptomatology, further supporting the need for early screening in this fatal disorder of childhood.