Longitudinal Assessment of Cognitive Development in 23 Patients With Mucopolysaccharidosis (MPS) Type II: Results of up to 14 Years of Follow-Up.
Holdorp JJ, Kruijshaar MEM, Vollebregt AAMA, Rietman ABA, Dijkstra MRKM, Klees CC, Wagenmakers MM, Nguyen AHPA, Oussoren EE, van der Ploeg ATA, van den Hout JMPH
Journal of inherited metabolic disease, 2026 Sep
Abstract
This study investigated long-term cognitive development and genotype-phenotype relationships in patients with Mucopolysaccharidosis Type II (MPS II). A nationwide prospective cohort study was conducted in the Netherlands with cognitive follow-up since 2007. Patients were classified as neuronopathic or non-neuronopathic based on iduronate-2-sulphatase (IDS) genotype; novel variants based on age and intelligence quotient (IQ). IQ and Mental Age (MA) were analysed individually and, using linear mixed-effect models, at group level to compare trajectories by genotype and phenotype. Twenty-three male patients (22 children, 1 adult) underwent 136 cognitive assessments, beginning at a median age of 2.9 years with a median follow-up of 6.3 (range 0-13.5) years. IQ and MA trajectories significantly differed between neuronopathic and non-neuronopathic patients (p < 0.001). Non-neuronopathic patients (n = 5) showed normal or mildly impaired cognition. Neuronopathic patients (n = 18) initially developed normally, then stagnated, plateaued, and declined; IQ fell below 70 at a median age of 4 years. Patients with deletions (n = 3) experienced the earliest, most severe impairment (p < 0.001), while those with other IDS variants showed more variable trajectories. Neurocognitive patterns diverge early in MPS II, highlighting the importance of understanding genotype-specific developmental trajectories. This insight is essential for guiding timely brain-targeted interventions, ideally initiated before neurocognitive decline begins.