Retrospective Natural History Study of neurodevelopment in neuronopathic Mucopolysaccharidosis Type II

Abstract

Mucopolysaccharidosis Type II (MPS II) is a X-linked lysosomal storage disease caused by deficiency of iduronate-2-sulfatase (I2S) leading to accumulation of glycosaminoglycans and in the neuronopathic form, results in irreversible neurocognitive decline. The objectives of this study were to better understand the developmental trajectories of patients with neuronopathic MPS II across multiple domains and to identify timepoints where patients deviate outside of typical development and where skill acquisition plateaus. This study presents a retrospective non-interventional medical records review of the neurodevelopmental natural history of patients with neuronopathic MPS II using the Mullen Scales of Early Learning (MSEL) Visual Reception, Expressive Language, Receptive Language, and Fine Motor scales. Function was characterized relative to MSEL normative ±1SD and ±2SD boundaries. MSEL natural history data was available for 32 patients. The majority of the children were on enzyme replacement therapy. Developmental trajectories deviated below –1SD from the normative mean at a mean chronological age range from 12.8 (Expressive Language) to 19.5 months (Visual Reception) and below -2SD from 24.0 (Fine Motor) to 29.3 months (Visual Reception). The mean chronological age where skill acquisition plateaued ranged from 66.1 to 74.6 months while the developmental age equivalence score where skill acquisition plateaued ranged from 25.7 to 29.9 months. Slowing in the rate of skill acquisition was present very early in development and varied by baseline function and chronological age. Visual Reception skill acquisition when developmental function was -1SD from the normative mean was 5.8 months/year, at -2SD was 4.7 months/year and, from -2SD to peak skill acquisition, the mean rate was 1.6 months/year. Results of this study support that developmental delay in patients with neuronopathic MPS II occurs across multiple domains very early in development and that the rate of skill acquisition varies by baseline function and chronological age. Although some children may acquire a small number of skills until they are 5–6 years old, function does not typically exceed the 2–3-year-old level and the rate of change per year is thereafter very small. Use of a multi-domain measure is important to understand disease impacts and developmental variability in neuronopathic MPS II.