Audrey A M Vollebregt1,2, Marianne Hoogeveen-Westerveld1,3, Marian A Kroos1,3, Esmee Oussoren1,2, Iris Plug1,2, George J Ruijter4, Ans T van der Ploeg1,2, W W M Pim Pijnappel1,2,3. 1. Center for Lysosomal and Metabolic Diseases, Erasmus Medical Center, Rotterdam, The Netherlands. 2. Department of Pediatrics, Division of Metabolic Diseases and Genetics, Erasmus Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands. 3. Molecular Stem Cell Biology, Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands. 4. Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
Abstract
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.
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.
Authors: Daniel C Julien; Kara Woolgar; Laura Pollard; Holly Miller; Ankit Desai; Kristin Lindstrom; Priya S Kishnani Journal: Front Immunol Date: 2020-05-21 Impact factor: 7.561
Authors: Audrey A M Vollebregt; Berendine J Ebbink; Dimitris Rizopoulos; Maarten H Lequin; Femke K Aarsen; Elsa G Shapiro; Ans T van der Ploeg; Johanna M P van den Hout Journal: J Inherit Metab Dis Date: 2021-01-25 Impact factor: 4.982