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Enzyme-Replacement Therapy in Mucopolysaccharidoses with A Enzyme-replacement Therapy in Mucopolysaccharidoses with a Specific Focus on MPS VI Enzym vervangende therapie in de mucopolysaccharidosen met specifieke aandacht voor MPS VI proefschrift.indb 1 27-8-2013 16:01:52 Financial support for this project was obtained from ZonMw (the Netherlands Organisation for Health Research and Development), the Dutch TI Pharma initiative “Sustainable Orphan Drug Development through Registries and Monitoring”, European Union, 7th Framework programme EUCLYD – European Consortium for Lysosomal Storage Disorders. Printing of this thesis was financially supported by: BioMarin Pharmaceutical Shire International Licensing BV ISBN: 978-90-6464-700-0 Lay-out: Chris Bor Medical Photography and Illustration, Academic Medical Center, Amsterdam, the Netherlands Cover design: Anne Bonthuis Druk: GVO | Ponsen & Looijen, Ede © Marion Brands, 2013 All rights reserved. No part of this thesis may be reproduced, stored in a retrieval system or transmitted in any form or means without permission of the author, or, when appropriate, of the publishers of the publications. proefschrift.indb 2 27-8-2013 16:01:53 Enzyme-replacement Therapy in Mucopolysaccharidoses with a Specific Focus on MPS VI Enzym vervangende therapie in de mucopolysaccharidosen met specifieke aandacht voor MPS VI Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof.dr. H.G. Schmidt en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op dinsdag 15 oktober 2013 om 15:30 uur. Marion Maria Mathilde Geertruida Brands geboren te Heerlen proefschrift.indb 3 27-8-2013 16:01:53 Promotiecommissie Promotor: Prof.dr. A.T. van der Ploeg Overige leden: Prof.dr. A.J. van der Heijden Prof.dr. W.A. Helbing Prof.dr. F.A. Wijburg Copromotor: Dr. A.J.J. Reuser proefschrift.indb 4 27-8-2013 16:01:53 Inhoudsopgave Chapter 1: General Introduction 7 Chapter 2: Enzyme-replacement therapy for mucopolysaccharidosis type VI 19 (Maroteaux-Lamy): A systematic review of the literature Ready for Submission Chapter 3: MPS and Cardiology 39 Paragraph 3.1: Mucopolysaccharidosis: Cardiologic features and 39 effects of enzyme-replacement therapy in 24 children with MPS I, II and VI J Inherit Metab Dis. 2013 Mar;36(2):227-34. Paragraph 3.2 Macrophage involvement in mitral valve 55 pathology in mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome) Accepted for publication in American Journal of Medical Genetics Part A Chapter 4: Up to five years experience with 11 mucopolysaccharidosis type 65 VI patients Mol Genet Metab. 2013 May;109(1):70-6. Chapter 5: Mucopolysaccharidosis type VI phenotypes-genotypes and 83 antibody response to galsulfase Orphanet J Rare Dis. 2013 Apr 4;8(1):51. [Epub ahead of print] Chapter 6: Long-term cognitive follow-up in children treated for 101 Maroteaux-Lamy syndrome In preparation Chapter 7: Pain: a prevalent feature in patients with mucopolysaccharidosis 123 Results of a cross-sectional national survey Submitted Chapter 8: Discussion 141 Addendum Summary 155 Samenvatting 159 Dankwoord 165 Portfolio 171 Curriculum vitae 175 List of Publications 179 proefschrift.indb 5 27-8-2013 16:01:53 proefschrift.indb 6 27-8-2013 16:01:53 Chapter 1 General introduction proefschrift.indb 7 27-8-2013 16:01:53 proefschrift.indb 8 27-8-2013 16:01:53 General introduction General introduction Chapter History of MPS Before the discovery of the lysosome, already three out of the seven currently known 1 mucopolysaccharidoses (MPSs) were described in medical literature. In 1917, Hunter syndrome was the first to be described in two brothers (“they are as alike as two peas”) by Charles Hunter 1. Gertrud Hurler published her two case reports about MPS I in 1919, and MPS IV was outlined in 1929 by the Uruguayan dr. Morquio 2, 3. All described young children with or without mental impairment, with profound bone abnormalities. In 1955, the Belgian scientist Christian de Duve discovered a new intra-cellular organelle that he named the lysosome. Eventually, this brought light to more than 50 inherited diseases all concerning a defect in the lysosomal system. The group of mucopolysaccharidoses belonged to these lysosomal disorders and all types proved to be characterized by the deficiency of a lysosomal enzyme. New types of MPSs were discovered since then. In 1963 two French physicians described a new form of dysostosis mupltiplex, MPS VI, and the syndrome was named after them: Maroteaux-Lamy’s syndrome 4. In the same year dr. Sanfilippo described for the first time a MPS III patient with mental impairment and excretion of heparan sulphate 5. Later, Sanfillippo disease was subdivided in type A, B, C, and D because between 1972 and 1980 different enzyme deficiencies were discovered in each of the four subtypes. Finally, in 1973, MPS VII was described by the American dr. Sly 6. MPS V and MPS VIII, first thought to be novel diseases, later turned out to be already known types of MPS and are not separate entities anymore. In 1996 Natowicz et al reported the first patient with MPS IX 7. Till now, only one other family has been reported with this disease 8. Pathophysiology and clinical features The word mucopolysaccharidosis (MPS) literally means “a disease in which viscous polysaccharides are being stored” 9. Mucopolysaccharides are nowadays termed glyco- saminoglycans (GAGs). GAGs are essential constituents of the extracellular matrix of connective tissues. They are composed of long sugar chains, containing highly sulfated, repeating units of disaccharides with alternating uronic acid and hexosamine residues. The polysaccharide chains are linked to a specific core protein thereby forming complex macromolecular structures called proteoglycans (Figure 1). Depending on the composition of the repeating units, several glycosaminoglycans are known. GAG degradation takes place inside the lysosomes and requires concerted action of several acid hydrolases. Deficiencies of these enzymes are responsible for the different types of MPSs 10. There are seven major clinical types of MPSs, involving eleven enzyme deficiencies (Table 1). The types of MPSs share many clinical features, varying from dysostosis multiplex, hepatosplenomegaly, neurological abnormalities, cardiac abnormalities, and 9 proefschrift.indb 9 27-8-2013 16:01:53 Chapter 1 Figure 1: Aggrecan is the complex of proteoglycans that all are connected to a central long chain of hyaluronic acid via link proteins. The proteoglycans in the large aggrecan complex are feather-like structures composed of a number of regularly spaced glycosaminoglycan chains, such as keratin sulfate and chondroitin sulfate, which are covalently linked to a protein core. From: Alberts et al., Essential Cell Biology (2003 2nd ed.). Table 1: Different types of mucopolysaccharidoses Eponym Missing enzyme Current therapy Mental retardation options MPS I Hurler/ Hurler- alpha-L-iduronidase - Enzyme replacement Hurler: Yes Scheie/ Scheie therapy (ERT) Scheie: No - Bone marrow transplantation (HSCT; for Hurler phenotype <2.5 years) MPS II Hunter iduronate-2-sulfatase ERT Often, but not always MPS III Sanfilippo A: heparin N-sulfatase No ltreatment available Often, but not always type: A-B-C-D B: a-N-acetylglucosaminidase C: acetyl coenzyme A: a-glucosaminide acetyltransferase D: N-acetylglucosamine-6- sulfatase MPS IV Morquio A: N-acetylgalactosamine-6- No licensed treatment No sulfate sulfatase, available yet B: β-galactosidase MPS VI Maroteaux-Lamy N-acetylgalactosamine ERT No 4-sulfatase MPS VII Sly β-glucuronidase No treatment available Often, but not always MPS IX hyaluronoglucosaminidase 1 No treatment available No 10 proefschrift.indb 10 27-8-2013 16:01:54 General introduction developmental delay. All represent a clinical spectrum, with on one end the severely Chapter affected patient with a substantially reduced lifespan and neurodegenerative disease, and on the other end the patient with an attenuated type of disease, presenting primarily with bone and cartilage disease. 1 All MPSs are caused by genetic deficiency of a different lysosomal enzyme involved in the degradation of these polysaccharides or glycosaminoglycans (GAGs). All genes involved in the pathophysiology of the different types of MPSs are known and hundreds of mutations have already been described. Fenotype-genotype correlations are under close investigation in all types of MPSs, but are not fully elucidated for any type of MPS. Pathophysiology of Mucopolysaccharidosis type VI Mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome, OMIM #253200) is an autosomal recessive disorder caused by mutations in the ARSB (arylsulfatase B) gene located on chromosome 5q13-q14. The mutation causes a deficiency of the lysosomal enzyme arylsulfate B (also called N-acetylgalactosamine 4-sulfatase) and leads to accumulation of the glycosaminoglycan dermatan sulfate. The storage of dermatan sulphate disrupts normal cellular and extra-cellular matrix functions which eventually causes the clinical symptoms (Figure 2). The ARSB protein composed of 533 amino acids is synthesized on membrane-bound ribosomes. The nascent polypeptide is translocated into the lumen of the endosplasmatic reticulum (ER) where the 39 amino acid long signal peptide is cleaved off. The 55.8 kDa ARSB polypeptide is glycosylated and the lysosomal targeting signal mannose 6-phophatase is acquired. During transport through the ER and the Golgi complex, ARSB attains a molecular mass of 66 kDa, but is subsequently processed to
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