Genotype–phenotype relationship in mucopolysaccharidosis II: predictive power of IDS variants for the neuronopathic phenotype

• Published in: Developmental medicine and child neurology 2017-10, Vol.59 (10), p.1063-1070
• Main Authors: Vollebregt, Audrey A M, Hoogeveen‐Westerveld, Marianne, Kroos, Marian A, Oussoren, Esmee, Plug, Iris, Ruijter, George J, van der Ploeg, Ans T, Pijnappel, W W M Pim
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Child; Child, Preschool; Cohort Studies; Educational Status; Epilepsy - enzymology; Epilepsy - genetics; Epilepsy - psychology; Genetic Association Studies; Genetic Variation; Glycoproteins - genetics; Glycoproteins - metabolism; Glycosaminoglycans - urine; Humans; Immunoblotting; Intelligence; Mass Spectrometry; Middle Aged; Mucopolysaccharidosis II - drug therapy; Mucopolysaccharidosis II - genetics; Mucopolysaccharidosis II - metabolism; Mucopolysaccharidosis II - psychology; Netherlands; Phenotype; Young Adult
• ISSN: 0012-1622; 1469-8749
• DOI: 10.1111/dmcn.13467

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. Resumen Relación genotipo – fenotipo en mucopolisacaridosis tipo II: Poder predictivo de las variantes del gen de la Iduronato‐2‐ sulfatasa en el fenotipo neuropático Objetivos La Mucopolisacaridosis tipo II (MPS II) es causada por variantes en el gen de la Iduronato‐2‐ sulfatasa (IDS). Los pacientes pueden presentar un perfil con discapacidad intelectual, o un perfil no‐neuropático del genotipo de IDS y el fenotipo y en los efectos moleculares involucrados. En este estudio abordamos este tema en una cohorte en pacientes Holandeses con MPS II. Método Se evaluó el desempeño intelectual en el rendimiento escolar, la conducta, y la inteligencia. Se cuantificaron los glicosaminoglicanos por espectrometría de masas. Las variantes de IDS se analizaron en estudios de expresión para la actividad enzimática y el procesamiento por inmunotransferencia. Resultados Seis pacientes tuvieron un fenotipo no‐neuropático y 11 un fenotipo neuropático, tres de los cuales tenían epilepsia. La deleción total del gen IDS resultó consistentemente con el fenotipo neuropático. El fenotipo