Neurodevelopmental status and adaptive behavior of pediatric patients with mucopolysaccharidosis II: a longitudinal observational study

Abstract

Background: Mucopolysaccharidosis (MPS) II is a rare, X-linked lysosomal storage disease. Approximately two-thirds of patients have central nervous system involvement with some demonstrating progressive cognitive impairment (neuronopathic disease). The natural history of cognitive and adaptive function in patients with MPS II is not well-defined. This 2-year, prospective, observational study evaluated the neurodevelopmental trajectories of boys with MPS II aged ≥ 2 years and < 18 years.

Results: Overall, 55 patients were enrolled. At baseline, mean (standard deviation [SD]) age was 5.60 (3.32) years; all patients were receiving intravenous idursulfase. Cognitive and adaptive function were assessed using the Differential Ability Scales, Second Edition (DAS-II) General Conceptual Ability (GCA) and the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Adaptive Behavior Composite (ABC) scores, respectively. Baseline mean (SD) DAS-II GCA and VABS-II ABC scores were 78.4 (19.11) and 83.7 (14.22), respectively, indicating low cognitive function and moderately low adaptive behavior. Over 24 months, modest deteriorations in mean (SD) scores were observed for DAS-II GCA (-3.8 [12.7]) and VABS-II ABC (-2.0 [8.07]). Changes in DAS-II GCA scores varied considerably, and data suggested the existence of four potential patient subgroups: (1) patients with marked early impairment and rapid subsequent decline, (2) patients with marked early impairment then stabilization, (3) patients with mild early impairment then stabilization, and (4) patients without impairment who remained stable. Subgroup analyses revealed numerically greater DAS-II GCA score reductions from baseline in patients aged < 7 years at baseline (vs. those aged ≥ 7 years) and in patients with DAS-II GCA scores ≤ 70 at baseline (vs. those with scores > 70); between-group differences were nonsignificant. No clear subgroups or patterns were identified for individual changes in VABS-II ABC scores. In total, 49 patients (89.1%) reported ≥ 1 adverse event (AE) and nine patients (16.4%) reported serious AEs.

Conclusions: Some patients with MPS II had rapid declines in cognitive ability, whereas others remained relatively stable after an initial decline. These insights provide a basis for more detailed analyses of different patient subgroups, which may enhance the definition and understanding of factors that influence cognitive and adaptive function in MPS II.

Trial registration: ClinicalTrials.gov, NCT01822184. Registered retrospectively: April 2, 2013.

Keywords: Adaptive; Behavior; Cognitive; Decline; Function; Impairment; Mucopolysaccharidosis II; Neurodevelopment; Observational; Pediatric.

Fig. 1

Study design. ^aIn addition to the assessments also performed at baseline, the screening period includes: obtaining/evaluating informed consent/assent; inclusion/exclusion criteria; genotyping; demographic information; medical history; and assessment of medications/therapies. ^bHeight and weight were measured at baseline and at months 12 and 24 only. AE, adverse event; BSID-III, Bayley Scales of Infant Development, Third Edition; DAS-II, Differential Ability Scales, Second Edition; HRQoL, health-related quality of life; HS-FOCUS, Hunter Syndrome Functional Outcomes for Clinical Understanding Scale; VABS-II, Vineland Adaptive Behavior Scales, Second Edition

Fig. 2

Individual DAS-II GCA scores^a for the overall study population by chronological age. ^aThe horizontal and vertical lines show the upper limits of the subgroup analyses for baseline DAS-II GCA score and age, respectively. The only subgroup that showed a clear decline in cognitive function were younger patients (aged < 7 years) who had a lower DAS-II GCA score at baseline (≤ 70), as depicted in the left-hand lower quadrant. Decline in cognitive function decline was less clear in the other baseline age/DAS-II GCA score subgroups, which may have been due to patients having non-neuronopathic disease (and therefore not experiencing a decline in cognitive function) or neuronopathic disease that was in the plateau stage of cognitive impairment. DAS-II, Differential Ability Scales, Second Edition; GCA, General Conceptual Ability

Fig. 3

Individual DAS-II GCA scores by baseline DAS-II GCA score (a) ≤ 70 and (b) > 70. DAS-II, Differential Ability Scales, Second Edition; GCA, General Conceptual Ability

Fig. 4

Individual VABS-II ABC scores (a) overall and by baseline DAS-II GCA scores (b) ≤ 70 and (c) > 70. ABC, Adaptive Behavior Composite; DAS-II, Differential Ability Scales, Second Edition; GCA, General Conceptual Ability; VABS-II, Vineland Adaptive Behavior Scales, Second Edition

Fig. 5

Individual VABS-II (a) communication domain standard scores and V-scale scores for (b) expressive and (c) receptive communication. VABS-II, Vineland Adaptive Behavior Scales, Second Edition