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Genotype–phenotype relationship in mucopolysaccharidosis II : predictive power of IDS variants for the neuronopathic phenotype
Author(s) -
Vollebregt Audrey A M,
HoogeveenWesterveld Marianne,
Kroos Marian A,
Oussoren Esmee,
Plug Iris,
Ruijter George J,
van der Ploeg Ans T,
Pijnappel W W M Pim
Publication year - 2017
Publication title -
developmental medicine and child neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.658
H-Index - 143
eISSN - 1469-8749
pISSN - 0012-1622
DOI - 10.1111/dmcn.13467
Subject(s) - phenotype , mucopolysaccharidosis type ii , hunter syndrome , genotype , mucopolysaccharidosis , biology , gene , microbiology and biotechnology , genetics , medicine , enzyme replacement therapy , biochemistry , disease
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.