Caprine mucopolysaccharidosis IIID - Fetal and neonatal brain and liver glycosaminoglycan and morphological perturbations

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dc.contributor.authorJones, M.
dc.contributor.authorAlroy, J.
dc.contributor.authorDowns-Kelly, E.
dc.contributor.authorLucas, R.
dc.contributor.authorKraemer, S.
dc.contributor.authorCavanagh, K.
dc.contributor.authorKing, B.
dc.contributor.authorHopwood, J.
dc.date.issued2004
dc.description.abstractMucopolysaccharidosis IIID (MPS IIID) is a lysosomal storage disease associated with deficient activity of the enzyme N-acetylglucosamine 6-sulfatase (EC 3.1.6.14), a lysosomal hydrolase in the heparan sulfate glycosaminoglycan (HS-GAG) degradation pathway. In caprine MPS IIID, enzyme replacement therapy reversed early postnatal systemic but not primary or secondary central nervous system (CNS) substrate accumulations. The caprine MPS IIID large animal model system was used in this investigation to define the developmental profile of morphological and biochemical perturbations to estimate a time frame for therapeutic intervention. Light and electron microscopy were used to compare the CNS, liver, and kidney of normal +/+, MPS IIID carrier +/-, and MPS IIID-affected -/- goat kids (kids), at 60, 113-114, 128-129, and 135 d gestation (dg) of a 150-d gestational period, at birth, and at 59-64 d of postnatal (d-pn) age. In the CNS of -/- kids, morphological correlations of HS-GAG and glycolipid accumulations were evident in early differentiating neurons at 60 dg. CNS and systemic developmental, regional, and cellular differences in -/-kids at all time points included more prominent and earlier accumulation of lucent, putative HS-GAG substrates in lysosomes of meningeal and perivascular macrophages and hepatic sinusoidal cells than in CNS, hepatic, or renal parenchymal cells. The amounts and compositions of HS-GAG substrates in the brain and liver of +/+, +/-, and -/- kids were determined at 60, 65, 113-114, and 128-135 dg, at birth, and 53-78 d-pn. In the CNS of -/- kids, HS-GAG concentrations were variable and exceeded those of age-matched control tissue samples in the third but not the second trimester. In contrast, hepatic HS-GAG levels in -/- kids exceeded control values at all time points evaluated and paralleled the progressive morphological alterations. CNS and hepatic HS-GAG compositions in -/- kids were similar to each other and were more complex at all pre- and postnatal ages than those from control kids. Based on the time frame of development of CNS lesions and biochemical perturbations, prenatal therapeutic intervention in caprine MPS IIID is likely to be necessary to prevent or ameliorate substantive CNS and systemic lesions
dc.description.statementofresponsibilityJones Margaret, Alroy Joseph, Downs-Kelly Erinn, Lucas Rebecca, Kraemer Stacey, Cavanagh Kevin, King Barbara and Hopwood John
dc.identifier.citationJournal of Molecular Neuroscience, 2004; 24(2):277-291
dc.identifier.doi10.1385/JMN:24:2:277
dc.identifier.issn0895-8696
dc.identifier.issn1559-1166
dc.identifier.urihttp://hdl.handle.net/2440/54793
dc.language.isoen
dc.publisherHumana Press Inc
dc.source.urihttps://doi.org/10.1385/jmn:24:2:277
dc.subjectMucopolysaccharidosis IIID (MPS IIID)
dc.subjectSanfilippo syndrome
dc.subjectN-acetylglucosamine 6-sulfatase
dc.subjectdevelopment
dc.subjectbrain
dc.subjectCNS
dc.subjectliver
dc.subjectlysosomal storage diseases
dc.subjectheparan sulfate
dc.subjectglycosaminoglycans
dc.subjectglycolipids
dc.titleCaprine mucopolysaccharidosis IIID - Fetal and neonatal brain and liver glycosaminoglycan and morphological perturbations
dc.typeJournal article
pubs.publication-statusPublished

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