Aim: Mucopolysaccharidosis type II (MPS II) is caused by variants in the iduronate-2-sulphatase gene (IDS). Patients can be either neuronopathic with intellectual disability, or non-neuronopathic. Few studies have reported on the IDS genotype–phenotype relationship and on the molecular effects involved. We addressed this in a cohort study of Dutch patients with MPS II. Method: Intellectual performance was assessed for school performance, behaviour, and intelligence. Urinary glycosaminoglycans were quantified by mass spectrometry. IDS variants were analysed in expression studies for enzymatic activity and processing by immunoblotting. Results: Six patients had a non-neuronopathic phenotype and 11 a neuronopathic phenotype, three of whom had epilepsy. Total deletion of IDS invariably resulted in the neuronopathic phenotype. Phenotypes of seven known IDS variants were consistent with the literature. Expression studies of nine variants were novel and showed impaired IDS enzymatic activity, aberrant intracellular processing, and elevated urinary excretion of heparan sulphate and dermatan sulphate irrespective of the MPS II phenotype. Interpretation: We speculate that very low or cell-type-specific IDS residual activity is sufficient to prevent the neuronal phenotype of MPS II. Whereas the molecular effects of IDS variants do not distinguish between MPS II phenotypes, the IDS genotype is a strong predictor.

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Journal Developmental Medicine and Child Neurology
Vollebregt, A.A.M, Hoogeveen-Westerveld, M, Kroos, M.A, Oussoren, E, Plug, I, Ruijter, G.J.G, … Pijnappel, W.W.M.P. (2017). Genotype–phenotype relationship in mucopolysaccharidosis II: predictive power of IDS variants for the neuronopathic phenotype. Developmental Medicine and Child Neurology, 59(10), 1063–1070. doi:10.1111/dmcn.13467