Developmental delay can precede neurologic regression in early onset metachromatic leukodystrophy

• DOI: 10.1016/j.ymgme.2024.108521
• Publication Date: 2024-06-29T16:03:45Z
• Authors: Laura Ann Adang; Samuel Groeschel; Chloe Grzyb; Russell D'Aiello; Francesco Gavazzi; Omar Sherbini; Nowa Bronner; Akshilkumar Patel; Ariel Vincent; Anjana Sevagamoorthy; Sylvia Mutua; Kayla Muirhead; Johanna Schmidt; Amy Pizzino; Emily Yu; Danielle Jin; Florian Eichler; Jamie L. Fraser; Lisa Emrick; Keith Van Haren; Jean-Martin Boula...; Maura Ruzhnikov; Michel Sylvain; Cam-Tu Émilie Nguyen; Ana Potic; Stephanie Keller; Ali Fatemi; Eloise Uebergang; Michele Poe; Pouneh Amir Yazdani; John Bernat; Kristen Lindstrom; Joshua L. Bonkowsky; Genevieve Bernard; Chloe A. Stutterd; Paul Orchard; Ashish O. Gupta; Merete Ljungberg; Sabine Groenborg; Alberto Zambon; Sara Locatelli; Francesca Fumagalli; Saskia Elguen; Christiane Kehrer; Ingeborg Krägeloh...; Justine Shults; Adeline Vanderver; Maria L. Escolar
• Keywords: Male; 570; Adolescent; Developmental Disabilities; Infant; 610; Leukodystrophy, Metachromatic; Cohort Studies; Child, Preschool; Disease Progression; Humans; Female; Age of Onset; Child

Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disorder. Emerging therapies are most effective in the presymptomatic phase, and thus defining this window is critical. We hypothesize that early development delay may precede developmental plateau. With the advent of presymptomatic screening platforms and transformative therapies, it is essential to define the onset of neurologic disease.The specific ages of gain and loss of developmental milestones were captured from the medical records of individuals affected by MLD. Milestone acquisition was characterized as: on target (obtained before the age limit of 90th percentile plus 2 standard deviations compared to a normative dataset), delayed (obtained after 90th percentile plus 2 standard deviations), or plateau (skills never gained). Regression was defined as the age at which skills were lost. LI-MLD was defined by age at onset before 2.5 years.Across an international cohort, 351 subjects were included (n = 194 LI-MLD subcohort). The median age at presentation of the LI-MLD cohort was 1.4 years (25th-75th %ile: 1.0-1.5). Within the LI-MLD cohort, 75/194 (39%) had developmental delay (or plateau) prior to MLD clinical presentation. Among the LI-MLD cohort with a minimum of 1.5 years of follow-up (n = 187), 73 (39.0%) subjects never attained independent ambulation. Within LI-MLD + delay subcohort, the median time between first missed milestone target to MLD decline was 0.60 years (maximum distance from delay to onset: 1.9 years).Early developmental delay precedes regression in a subset of children affected by LI-MLD, defining the onset of neurologic dysfunction earlier than previously appreciated. The use of realworld data prior to diagnosis revealed an early deviation from typical development. Close monitoring for early developmental delay in presymptomatic individuals may help in earlier diagnosis with important consequences for treatment decisions.