Developmental delay can precede neurologic regression in early onset metachromatic leukodystrophy

Abstract

Objective: 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.

Methods: 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.

Results: 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).

Interpretation: 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.

Keywords: Development; Lysosomal storage disorder; Metachromatic Leukodystrophy; Neurodegeneration.

Fig. 1.

Spectrum of age at symptom onset and developmental milestone acquisition in MLD. A. Frequency distribution of age at presentation of MLD-related symptomatology (n = 351). The age at first clinical symptom was collected across the MLD cohort (median 2.0 years; mean 4.9 years). B-C. Distribution of developmental milestone acquisition in MLD. B represents the LI-MLD cohort, (onset before 2.5 years), while C represents the non-LI-MLD cohort. The acquisition of 17 developmental milestones was collected and designated as attained on time (light grey), attained delayed (dark grey; age at attainment was ≥ P90 + 2SD), plateau (skill never attained; black), and attained unknown (UK) timing (light blue) as detailed in Supplemental Table 2. Graphs represent individuals with a minimum of age of 2 years at the time of last data collection. D. Early developmental trajectories in LI-MLD. Milestones were binned into expected attainment groups by P50 of the normative dataset as 3-, 6-, 9-, 12-, and 15- months skills. Within a cohort of subjects who presented within 2.5 years (n = 127) with a minimum of 2 years of data, subjects were sorted into 3 categories for each age-based milestone skills: on time, delayed, and plateau. Delayed was defined as a gain of new skills at ages later than typical development; plateau was defined as a failure to gain new developmental milestones prior to regression.

Fig. 2.

Association between milestone acquisition and age at presentation. From the medical records, the age at presentation and acquisition of each milestone were obtained. For each subject, the milestone was designated as attained (solid shape) or never attained (the age in last available medical record designated with open shape). The developmental delay (DD) threshold ages are shown for each milestone. A: rolling (blue grey) and pull-to stand (black); B: independent sitting (blue grey) and walking (black); C: speaking 1 word (blue grey) and 6 words (black).

Fig. 3.

Gross motor developmental milestones acquisition in MLD. Kaplan Meier curves were used to assess the rates of acquisition of developmental milestones in late infantile (LI; red line) versus non-late infantile (non-LI; black line) MLD. On each graph, the P50 and delay (P90 + 2SD) ages for each milestone are shown: independent sitting (A), pulling to stand (B), standing independently (C), and walking independently (D).

Fig. 4.

Comparison of acquisition of cognitive developmental milestones in MLD. Kaplan Meier curves were used to assess the rates of acquisition of developmental milestones in late infantile (LI; grey solid line) versus non-late infantile (non-LI; black line) MLD. On each graph, the P50 and delay (P90 + 2SD) ages for each milestone are shown: A. non-specific speech, B. single word, C. 2 words, D. 6 words.

Fig. 5.

Developmental delay is associated with early age at disease onset and earlier regression. A. The age at onset of MLD was compared between cohorts by a history of developmental delay or plateau (Mann-Whitney 2-tailed p value: <0.0001). B. Comparison of regression onset in MLD by history of delay. The age at first milestone loss was compared by history of developmental delay irrespective of age at onset (Log-rank Mantel-Cox test p value <0.0001). [No history developmental delay (-DD): black line; history of developmental delay (+DD: red line).