Developmental delay can precede neurologic regression in early onset metachromatic leukodystrophy

Area of Science:

• Neuroscience
• Genetics
• Pediatrics

Background:

• Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disorder.
• Emerging therapies for MLD are most effective during the presymptomatic phase.
• Defining the onset of neurologic disease is critical for timely therapeutic intervention.

Purpose of the Study:

• To determine if early developmental delay precedes developmental plateau or regression in children with late infantile MLD (LI-MLD).
• To establish the window for presymptomatic intervention in LI-MLD.
• To identify early indicators of neurologic dysfunction in LI-MLD.

Main Methods:

• Retrospective analysis of medical records from an international cohort of 351 MLD subjects, including 194 with LI-MLD.
• Characterization of milestone acquisition as on target, delayed, or plateaued.
• Definition of regression as the age skills were lost; LI-MLD defined by onset before 2.5 years.

Main Results:

• In the LI-MLD cohort (n=194), 39% exhibited developmental delay or plateau before clinical presentation.
• Among LI-MLD subjects with follow-up (n=187), 39% never achieved independent ambulation.
• The median time from first missed milestone to MLD decline was 0.60 years in the LI-MLD + delay subgroup.

Conclusions:

• Early developmental delay precedes regression in a subset of LI-MLD patients, indicating an earlier onset of neurologic dysfunction than previously recognized.
• Real-world data reveal early deviations from typical development prior to diagnosis.
• Close monitoring for early developmental delays in presymptomatic individuals is crucial for earlier diagnosis and treatment decisions in LI-MLD.