Mucopolysaccharidosis Type VI, an Updated Overview of the Disease

Mucopolysaccharidosis type VI, or Maroteaux–Lamy syndrome, is a rare, autosomal recessive genetic disease, mainly affecting the pediatric age group. The disease is due to pathogenic variants of the ARSB gene, coding for the lysosomal hydrolase N-acetylgalactosamine 4-sulfatase (arylsulfatase B, ASB). The enzyme deficit causes a pathological accumulation of the undegraded glycosaminoglycans dermatan-sulphate and chondroitin-sulphate, natural substrates of ASB activity. Intracellular and extracellular deposits progressively take to a pathological scenario, often severe, involving most organ-systems and generally starting from the osteoarticular apparatus. Neurocognitive and behavioral abilities, commonly described as maintained, have been actually investigated by few studies. The disease, first described in 1963, has a reported prevalence between 0.36 and 1.3 per 100,000 live births across the continents. With this paper, we wish to contribute an updated overview of the disease from the clinical, diagnostic, and therapeutic sides. The numerous in vitro and in vivo preclinical studies conducted in the last 10–15 years to dissect the disease pathogenesis, the efficacy of the available therapeutic treatment (enzyme replacement therapy), as well as new therapies under study are here described. This review also highlights the need to identify new disease biomarkers, potentially speeding up the diagnostic process and the monitoring of therapeutic efficacy.

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Early Diagnosis and Results of Enzyme Replacement Therapy in the Patient with Mucopolysaccharidosis Type VI: Clinical Case

Вопросы современной педиатрии ◽

10.15690/vsp.v20i6s.2369 ◽

2021 ◽

Author(s):

Dmitry V. Ivanov ◽

Anna I. Ostrun ◽

Vladimir M. Kenis ◽

Tatiana V. Markova ◽

Ekaterina Yu. Zakharova

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Clinical Case ◽

Mucopolysaccharidosis Type ◽

Lysosomal Storage ◽

Enzyme Replacement ◽

Mucopolysaccharidosis Type Vi ◽

Mps Vi ◽

Arylsulfatase B ◽

Arsb Gene

Background. Mucopolysaccharidosis type VI (MPS VI, Maroteaux–Lamy syndrome) is rare autosomal-recessive multisystem disease, one of the group of lysosomal storage diseases. The MPS VI pathogenesis is determined by arylsulfatase B enzyme deficiency caused by mutations in the ARSB gene. There are only few published clinical examples of this disease that covers the results of early enzyme replacement therapy (ERT) onset.Clinical case description. The child was suspected to have lysosomal storage disease at the age of 1.5 months, it was based on microscopic analysis of blood smears: Alder abnormality was revealed (granulations and red-violet inclusions in neutrophils, monocytes, lymphocytes cytoplasm). The diagnosis was confirmed at the age of 3 months: increased glycosaminoglycans (GAGs) concentration in the urine, arylsulfatase B activity decrease in dried blood spots, and pathogenic variant c.943C>T (p. R315X) in the ARSB gene in homozygous state were revealed. ERT with galsulfase was started at the age of 7 months. There was decrease in excretion of GAGs in urine to normal level after 9 and 15 months of therapy. Normal growth and body proportions for the patient’s age were determined 3 years after continuous ERT. However, there was progression of multiple dysostosis and joint stiffness, as well as eyes lesion.Conclusion. Early ERT onset cannot completely stop MPS VI progression but it allows to reduce the severity of several symptoms and improves patient’s quality of life.

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Thrombocytopenia associated with galsulfase treatment

Human & Experimental Toxicology ◽

10.1177/0960327110379023 ◽

2010 ◽

Vol 30 (7) ◽

pp. 768-771 ◽

Cited By ~ 4

Author(s):

Murat Doğan ◽

Yasar Cesur ◽

Erdal Peker ◽

Ahmet F Oner ◽

Sekibe Zehra Dogan

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Lysosomal Storage Disorder ◽

Mucopolysaccharidosis Type ◽

Lysosomal Storage ◽

Cultured Fibroblasts ◽

Enzyme Replacement ◽

Mucopolysaccharidosis Type Vi ◽

Mps Vi ◽

Arylsulfatase B

Mucopolysaccharidosis type VI (MPS VI), or Maroteaux-Lamy syndrome, is a lysosomal storage disorder that results from a deficiency of the enzyme N-acetylgalactosamine-4-sulfatase or arylsulfatase B (ASB). It is a relatively rare disorder, with an estimated incidence of 1 in 248,000 to 1 in 300,000. The diagnosis is made on the basis of findings of elevated urine glycosaminoglycans and a deficiency of ASB activity in leukocytes or cultured fibroblasts. In treatment of MPS VI, enzyme replacement therapy (galsulfase; human recombinant ASB enzyme) became available. Infusions of galsulfase were generally well tolerated. But in some patients, infusion-associated reactions including rash, urticaria, headache, hypotension, nausea, and vomiting were documented and were managed successfully by interrupting or slowing the rate of infusion and/or by the administration of antihistamines, antipyretics, corticosteroids, or oxygen. Here, we report a case with MPS VI who developed thrombocytopenia after third dose of therapy. To the best of our knowledge, this is the first report about thrombocytopenia associated with galsulfase therapy in the literature. Additionally, with this report, we want to share our approach for this case.

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Galsulfase: enzyme-replacement therapy for mucopolysaccharidosis Type VI (Maroteaux-Lamy syndrome)

Therapy ◽

10.1586/14750708.3.1.9 ◽

2006 ◽

Vol 3 (1) ◽

pp. 9-17 ◽

Cited By ~ 1

Author(s):

Michael Beck

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Mucopolysaccharidosis Type ◽

Enzyme Replacement ◽

Mucopolysaccharidosis Type Vi

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Mucopolysaccharidosis type VI enzyme replacement therapy initiated in adulthood: Findings from the MPS VI clinical surveillance program

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2017.12.141 ◽

2018 ◽

Vol 123 (2) ◽

pp. S59

Author(s):

Paul Harmatz ◽

Christina Lampe ◽

Rossella Parini ◽

Reena Sharma ◽

Elisa Leão Teles ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Surveillance Program ◽

Mucopolysaccharidosis Type ◽

Enzyme Replacement ◽

Mucopolysaccharidosis Type Vi ◽

Mps Vi ◽

Clinical Surveillance

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The extracellular matrix of the developing cornea: diversity, deposition and function*

Development ◽

10.1242/dev.103.supplement.195 ◽

1988 ◽

Vol 103 (Supplement) ◽

pp. 195-205

Author(s):

J. B. L. Bard ◽

M. K. Bansal ◽

A. S. A. Ross

Keyword(s):

Extracellular Matrix ◽

Chondroitin Sulphate ◽

Corneal Stroma ◽

Experimental System ◽

Collagen I ◽

And Function ◽

20 Nm

This paper examines the role of the extracellular matrix (ECM) in the development of the cornea. After a brief summary of the corneal structure and ECM, we describe evidence suggesting that the differentiation of neural crest (NC) cells into endothelium and fibroblasts is under the control of ocular ECM. We then examine the role of collagen I in stromal morphogenesis by comparing normal corneas with those of homozygous Movl3 mice which do not make collagen I. We report that, in spite of this absence, the cellular morphology of the Movl3 eye is indistinguishable from that of the wild type. In the 16-day mutant stroma, however, the remaining collagens form small amounts of disorganized, thin fibrils rather than orthogonally organized 20 nm-diameter fibrils; a result implying that collagen I plays only a structural role and that its absence is not compensated for. It also suggests that, because these remaining collagens will not form the normal fibrils that they will in vitro, fibrillogenesis in the corneal stroma differs from that elsewhere. The latter part of the paper describes our current work on chick stromal deposition using corneal epithelia isolated with an intact basal lamina that lay down in vitro ∼3μm-thick stromas of organized fibrils similar to that seen in vivo. This experimental system has yielded two unexpected results. First, the amount of collagen and proteoglycans produced by such epithelia is not dependent on whether its substratum is collagenous and we therefore conclude that stromal production by the intact epithelium is more autonomous than hitherto thought. Second, chondroitin sulphate (CS), the predominant proteoglycan, appears to play no role in stromal morphogenesis: epithelia cultured in testicular hyaluronidase, which degrades CS, lay down stromas whose organization and fibrildiameter distribution are indistinguishable from controls. One possible role for CS, however, is as a lubricant which facilitates corneal growth: it could allow fibrils to move over one another without deforming their orthogonal organization. Finally, we have examined the processes of fibrillogenesis in the corneal stroma and conclude that they are different from those elsewhere in the embryo and in vitro, perhaps because there is in the primary stroma an unidentified, highly hydrated ECM macromolecule that embeds the fibrils and that may mediate their morphogenesis.

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The Rise of Retinal Organoids for Vision Research

International Journal of Molecular Sciences ◽

10.3390/ijms21228484 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8484 ◽

Cited By ~ 1

Author(s):

Kritika Sharma ◽

Tim U. Krohne ◽

Volker Busskamp

Keyword(s):

Molecular Mechanisms ◽

Cell Types ◽

Therapeutic Interventions ◽

Retinal Cell ◽

Retinal Diseases ◽

Organ Systems ◽

Cell Sources ◽

Retinal Degenerative Diseases

Retinal degenerative diseases lead to irreversible blindness. Decades of research into the cellular and molecular mechanisms of retinal diseases, using either animal models or human cell-derived 2D systems, facilitated the development of several therapeutic interventions. Recently, human stem cell-derived 3D retinal organoids have been developed. These self-organizing 3D organ systems have shown to recapitulate the in vivo human retinogenesis resulting in morphological and functionally similar retinal cell types in vitro. In less than a decade, retinal organoids have assisted in modeling several retinal diseases that were rather difficult to mimic in rodent models. Retinal organoids are also considered as a photoreceptor source for cell transplantation therapies to counteract blindness. Here, we highlight the development and field’s improvements of retinal organoids and discuss their application aspects as human disease models, pharmaceutical testbeds, and cell sources for transplantations.

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The Pax6 master control gene initiates spontaneous retinal development via a self-organising Turing network

Development ◽

10.1242/dev.185827 ◽

2020 ◽

Vol 147 (24) ◽

pp. dev185827

Author(s):

Timothy Grocott ◽

Estefania Lozano-Velasco ◽

Gi Fay Mok ◽

Andrea E. Münsterberg

Keyword(s):

Model Organism ◽

Control Gene ◽

Tissue Interactions ◽

Organ Systems ◽

Necessary And Sufficient ◽

Regenerative Therapies ◽

Further Development ◽

Master Control

ABSTRACTUnderstanding how complex organ systems are assembled from simple embryonic tissues is a major challenge. Across the animal kingdom a great diversity of visual organs are initiated by a ‘master control gene’ called Pax6, which is both necessary and sufficient for eye development. Yet precisely how Pax6 achieves this deeply homologous function is poorly understood. Using the chick as a model organism, we show that vertebrate Pax6 interacts with a pair of morphogen-coding genes, Tgfb2 and Fst, to form a putative Turing network, which we have computationally modelled. Computer simulations suggest that this gene network is sufficient to spontaneously polarise the developing retina, establishing the first organisational axis of the eye and prefiguring its further development. Our findings reveal how retinal self-organisation may be initiated independently of the highly ordered tissue interactions that help to assemble the eye in vivo. These results help to explain how stem cell aggregates spontaneously self-organise into functional eye-cups in vitro. We anticipate these findings will help to underpin retinal organoid technology, which holds much promise as a platform for disease modelling, drug development and regenerative therapies.

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ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency

Blood ◽

10.1182/blood-2009-03-209221 ◽

2009 ◽

Vol 114 (15) ◽

pp. 3216-3226 ◽

Cited By ~ 45

Author(s):

Aisha V. Sauer ◽

Emanuela Mrak ◽

Raisa Jofra Hernandez ◽

Elena Zacchi ◽

Francesco Cavani ◽

...

Keyword(s):

Gene Therapy ◽

Bone Marrow ◽

Severe Combined Immunodeficiency ◽

Intrinsic Defect ◽

Combined Immunodeficiency ◽

Hematopoietic Stem ◽

Enzyme Replacement ◽

Bone Phenotype

Abstract Adenosine deaminase (ADA) deficiency is a disorder of the purine metabolism leading to combined immunodeficiency and systemic alterations, including skeletal abnormalities. We report that ADA deficiency in mice causes a specific bone phenotype characterized by alterations of structural properties and impaired mechanical competence. These alterations are the combined result of an imbalanced receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin axis, causing decreased osteoclastogenesis and an intrinsic defect of osteoblast function with subsequent low bone formation. In vitro, osteoblasts lacking ADA displayed an altered transcriptional profile and growth reduction. Furthermore, the bone marrow microenvironment of ADA-deficient mice showed a reduced capacity to support in vitro and in vivo hematopoiesis. Treatment of ADA-deficient neonatal mice with enzyme replacement therapy, bone marrow transplantation, or gene therapy resulted in full recovery of the altered bone parameters. Remarkably, untreated ADA–severe combined immunodeficiency patients showed a similar imbalance in RANKL/osteoprotegerin levels alongside severe growth retardation. Gene therapy with ADA-transduced hematopoietic stem cells increased serum RANKL levels and children's growth. Our results indicate that the ADA metabolism represents a crucial modulatory factor of bone cell activities and remodeling. The trials were registered at www.clinicaltrials.gov as #NCT00598481 and #NCT00599781.

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