Longitudinal Assessment of Cognitive Development in 23 Patients With Mucopolysaccharidosis (MPS) Type II: Results of up to 14 Years of Follow-Up.

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.