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Mucopolysaccharidoses: Diagnosis, Treatment, and Management 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 35911

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Prof. Dr. Shunji Tomatsu

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Skeletal Dysplasia Lab Nemours Biomedical Research Nemours/Alfred I. du Pont Hospital for Children, 1600 Rockland Road., Wilmington, DE 19803, USA
Interests: lysosomal storage disease; mucopolysaccharidoses; newborn screening; bone targeting
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Prof. Dr. Roberto Giugliani

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1. Department of Genetics UFRGS, Medical Genetics Service, HCPA, DASA and Casa dos Raros, Porto Alegre 91501970, Brazil
2. Medical Genetics Service, HCPA, Porto Alegre 90035-903, Brazil
Interests: inborn errors of metabolism, particularly lysosomal disorders
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Prof. Dr. Grzegorz Wegrzyn

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Depratment of Molecular Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland
Interests: regulation of DNA replication; control of gene expression; oxidative stress in bacterial virulence; molecular mechanisms of mucopolysaccharidoses; development of novel therapeutic options
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Prof. Dr. Brian Bigger

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Division of Cell Matrix Biology and Regenerative Medicine, University of Manchester, Manchester M13 9PT, UK
Interests: mucopolysaccharidosis
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Dr. Julia B. Hennermann

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Department of Pediatric and Adolescent Medicine, University Medical Center Mainz, Villa Metabolica, Langenbeckstr. 1, 55131 Mainz, Germany
Interests: mucopolysaccharidoses
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mucopolysaccharidoses (MPS) are relatively frequent as a group among inborn errors of metabolism, with an overall incidence estimated around 1 of 20,000–25,000 births. If the clinical signs and symptoms appear, the excessive excretion of urinary glycosaminoglycans (GAGs) seen in MPS patients will provide a simple screening method with the identification of the specific enzyme deficiency. The development of therapeutic options for MPS, including hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT), has modified the natural history of many MPS types. In spite of the improvement in some tissues and organs, significant challenges remain unsolved, including blood–brain barrier, brain and avascular cartilage, heart valves, and cornea. Newer approaches, such as intrathecal ERT, ERT with fusion proteins to cross the blood–brain barrier, gene therapy, substrate reduction therapy, chaperone therapy, and combined strategies, may provide a better outcome for MPS in the near future.

Therapies should start at a very early stage prior to irreversible bone lesion, and damage due to the severity of CNS involvement and skeletal dysplasia is associated with level of activity during daily life. As early diagnosis and early treatment are imperative to improve therapeutic efficacy, the inclusion of MPS in newborn screening programs should reduce the morbidity associated with MPS diseases. Additionally, we will provide insights into primary storage materials on GAGs (“GAGnomics”), the measurement of GAGs, the pathogenesis pathway with the accumulation of GAGs, and GAGs’ role as a biomarker.

In this Special Issue, we will summarize diagnosis, treatment, and management of MPS and will evaluate available treatments such as ERT; HSCT; and future treatments including gene therapy, substrate reduction therapy, and chaperon therapy, and will describe their advantages and disadvantages. We will also assess the current clinical endpoints and biomarkers used in clinical trials.

Overall, this Special Issue illustrates an up-to-date overview of pathogenesis, diagnosis, biomarker, screening, and updated therapies and their impact in MPS. It comprehensively covers many areas in the MPS field and appeals to a broad range of readers including physicians, scientists, students, pharmaceutical companies, and MPS communities.

You may choose our Joint Special Issue in Diagnostics.

Related Special Issues:

"Mucopolysaccharidoses: Diagnosis, Treatment, and Management" in IJMS (25 Articles)

Characterization of Fluid Biomarkers Reveals Lysosome Dysfunction and Neurodegeneration in Neuronopathic MPS II Patients

High-Throughput Liquid Chromatography–Tandem Mass Spectrometry Quantification of Glycosaminoglycans as Biomarkers of Mucopolysaccharidosis II

Validation of Liquid Chromatography Tandem Mass Spectrometry-Based 5-Plex Assay for Mucopolysaccharidoses

Cathepsin B-associated Activation of Amyloidogenic Pathway in Murine Mucopolysaccharidosis Type I Brain Cortex

Genetic Base of Behavioral Disorders in Mucopolysaccharidoses: Transcriptomic Studies

Identification and Functional Characterization of IDS Gene Mutations Underlying Taiwanese Hunter Syndrome (Mucopolysaccharidosis Type II)

Autophagy in the Central Nervous System and Effects of Chloroquine in Mucopolysaccharidosis Type II Mice

Underestimated Aspect of Mucopolysaccharidosis Pathogenesis: Global Changes in Cellular Processes Revealed by Transcriptomic Studies

Proteomic Analysis in Morquio A Cells Treated with Immobilized Enzymatic Replacement Therapy on Nanostructured Lipid Systems

Development of Substrate Degradation Enzyme Therapy for Mucopolysaccharidosis IVA Murine Model

Lower Exposure to Busulfan Allows for Stable Engraftment of Donor Hematopoietic Stem Cells in Children with Mucopolysaccharidosis Type I: A Case Report of Four Patients

A Case Report of a Japanese Boy with Morquio A Syndrome: Effects of Enzyme Replacement Therapy Initiated at the Age of 24 Months

First Report of a Patient with MPS Type VII, Due to Novel Mutations in GUSB, Who Underwent Enzyme Replacement and Then Hematopoietic Stem Cell Transplantation

Evading the AAV Immune Response in Mucopolysaccharidoses

Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations

Multiple Sulfatase Deficiency: A Disease Comprising Mucopolysaccharidosis, Sphingolipidosis, and More Caused by a Defect in Posttranslational Modification

Pathogenesis of Mucopolysaccharidoses, an Update

Mucopolysaccharidosis IVA: Diagnosis, Treatment, and Management

Mucopolysaccharidosis Type II: One Hundred Years of Research, Diagnosis, and Treatment

Targeting Macromolecules to CNS and Other Hard-to-Treat Organs Using Lectin-Mediated Delivery

Surgical Management of Spinal Disorders in People with Mucopolysaccharidoses

Mucopolysaccharidosis-Plus Syndrome

Genome Editing for Mucopolysaccharidoses

Novel Enzyme Replacement Therapies for Neuropathic Mucopolysaccharidoses

Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

"Mucopolysaccharidoses: Diagnosis, Treatment, and Management" in Diagnostics (20 Articles)

Pathophysiology of Hip Disorders in Patients with Mucopolysaccharidosis IVA

Modeling Morquio A Syndrome: An Anthropometric Study of Body Characteristics and Stature an anthropometric study of body characteristics and stature

Assessment of Activity of Daily Life in Mucopolysaccharidosis Type II Patients with Hematopoietic Stem Cell Transplantation

Elevated LysoGb3 Concentration in the Neuronopathic Forms of Mucopolysaccharidoses

Respiratory Dysfunction in Children and Adolescents with Mucopolysaccharidosis Types I, II, IVA, and VI

Cardiac Evaluation by Two-dimensional Speckle-Tracking Echocardiography and Conventional Echocardiography in Taiwanese Patients with Mucopolysaccharidoses

Safety Study of Sodium Pentosan Polysulfate for Adult Patients with Mucopolysaccharidosis Type II

Growth Plate Pathology in the Mucopolysaccharidosis Type VI Rat Model—An Experimental and Computational Approach

Neonatal Mass Urine Screening Approach for Early Detection of Mucopolysacharidoses by UPLC-MS/MS

Laryngeal, Tracheal, and Bronchial Disease in the Mucopolysaccharidoses: Endoscopic Study

Diagnosis and Management of Carpal Tunnel Syndrome in Children with Mucopolysaccharidosis: A 10 Year Experience

An At-risk Population Screening Program for Mucopolysaccharidoses by Measuring Urinary Glycosaminoglycans in Taiwan

Otolaryngologists and the Early Diagnosis of Mucopolysaccharidoses: A Cross-Sectional Study

Relationships among Height, Weight, Body Mass Index, and Age in Taiwanese Children with Different Types of Mucopolysaccharidoses

Long-term follow up post- Hematopoietic Stem Cell Transplantation in a Japanese patient with Mucopolysaccharidosis Type VII

Molecular Characterization of a Novel Splicing Mutation underlying Mucopolysaccharidosis (MPS) type VI – Proof of Principle on its Pathogenicity

Long-Term Outcomes of Early Enzyme Replacement Therapy for Mucopolysaccharidosis IV: Clinical Case Studies of Two Siblings

Emerging Approaches for Fluorescence Based Newborn Screening of Mucopolysaccharidoses

Mucopolysaccharidosis type I

Diagnosis of Mucopolysaccharidoses

Prof. Dr. Shunji Tomatsu
Prof. Dr. Roberto Giugliani
Prof. Dr. Grzegorz Wegrzyn
Prof. Dr. Brian Bigger
Dr. Julia B. Hennermann
Guest Editors

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Published Papers (6 papers)

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Review

24 pages, 1421 KiB

Open AccessReview

Mucopolysaccharidosis Type VI, an Updated Overview of the Disease

by Francesca D’Avanzo, Alessandra Zanetti, Concetta De Filippis and Rosella Tomanin

Int. J. Mol. Sci. 2021, 22(24), 13456; https://doi.org/10.3390/ijms222413456 - 15 Dec 2021

Cited by 21 | Viewed by 8568

Abstract

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. Full article

(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management 2.0)

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10 pages, 652 KiB

Open AccessReview

Bone Biomarkers in Mucopolysaccharidoses

by Akari Nakamura-Utsunomiya

Int. J. Mol. Sci. 2021, 22(23), 12651; https://doi.org/10.3390/ijms222312651 - 23 Nov 2021

Cited by 9 | Viewed by 2671

Abstract

The accumulation of glycosaminoglycans (GAGs) in bone and cartilage leads to progressive damage in cartilage that, in turn, reduces bone growth by the destruction of the growth plate, incomplete ossification, and growth imbalance. The mechanisms of pathophysiology related to bone metabolism in mucopolysaccharidoses (MPS) include impaired chondrocyte function and the failure of endochondral ossification, which leads to the release of inflammatory cytokines via the activation of Toll-like receptors by GAGs. Although improvements in the daily living of patients with MPS have been achieved with enzyme replacement, treatment for the bone disorder is limited. There is an increasing need to identify biomarkers related to bone and cartilage to evaluate the progressive status and to monitor the treatment of MPS. Recently, new analysis methods, such as proteomic analysis, have identified new biomarkers in MPS. This review summarizes advances in clinical bone metabolism and bone biomarkers. Full article

(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management 2.0)

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17 pages, 960 KiB

Open AccessReview

Gene Therapy for Neuronopathic Mucopolysaccharidoses: State of the Art

by María José de Castro, Mireia del Toro, Roberto Giugliani and María Luz Couce

Int. J. Mol. Sci. 2021, 22(17), 9200; https://doi.org/10.3390/ijms22179200 - 25 Aug 2021

Cited by 11 | Viewed by 5683

Abstract

The need for long-lasting and transformative therapies for mucopolysaccharidoses (MPS) cannot be understated. Currently, many forms of MPS lack a specific treatment and in other cases available therapies, such as enzyme replacement therapy (ERT), do not reach important areas such as the central nervous system (CNS). The advent of newborn screening procedures represents a major step forward in early identification and treatment of individuals with MPS. However, the treatment of brain disease in neuronopathic MPS has been a major challenge to date, mainly because the blood brain barrier (BBB) prevents penetration of the brain by large molecules, including enzymes. Over the last years several novel experimental therapies for neuronopathic MPS have been investigated. Gene therapy and gene editing constitute potentially curative treatments. However, despite recent progress in the field, several considerations should be taken into account. This review focuses on the state of the art of in vivo and ex vivo gene therapy-based approaches targeting the CNS in neuronopathic MPS, discusses clinical trials conducted to date, and provides a vision for the future implications of these therapies for the medical community. Recent advances in the field, as well as limitations relating to efficacy, potential toxicity, and immunogenicity, are also discussed. Full article

(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management 2.0)

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25 pages, 5887 KiB

Open AccessReview

Differences in MPS I and MPS II Disease Manifestations

by Christiane S. Hampe, Brianna D. Yund, Paul J. Orchard, Troy C. Lund, Jacob Wesley and R. Scott McIvor

Int. J. Mol. Sci. 2021, 22(15), 7888; https://doi.org/10.3390/ijms22157888 - 23 Jul 2021

Cited by 26 | Viewed by 5398

Abstract

Mucopolysaccharidosis (MPS) type I and II are two closely related lysosomal storage diseases associated with disrupted glycosaminoglycan catabolism. In MPS II, the first step of degradation of heparan sulfate (HS) and dermatan sulfate (DS) is blocked by a deficiency in the lysosomal enzyme iduronate 2-sulfatase (IDS), while, in MPS I, blockage of the second step is caused by a deficiency in iduronidase (IDUA). The subsequent accumulation of HS and DS causes lysosomal hypertrophy and an increase in the number of lysosomes in cells, and impacts cellular functions, like cell adhesion, endocytosis, intracellular trafficking of different molecules, intracellular ionic balance, and inflammation. Characteristic phenotypical manifestations of both MPS I and II include skeletal disease, reflected in short stature, inguinal and umbilical hernias, hydrocephalus, hearing loss, coarse facial features, protruded abdomen with hepatosplenomegaly, and neurological involvement with varying functional concerns. However, a few manifestations are disease-specific, including corneal clouding in MPS I, epidermal manifestations in MPS II, and differences in the severity and nature of behavioral concerns. These phenotypic differences appear to be related to different ratios between DS and HS, and their sulfation levels. MPS I is characterized by higher DS/HS levels and lower sulfation levels, while HS levels dominate over DS levels in MPS II and sulfation levels are higher. The high presence of DS in the cornea and its involvement in the arrangement of collagen fibrils potentially causes corneal clouding to be prevalent in MPS I, but not in MPS II. The differences in neurological involvement may be due to the increased HS levels in MPS II, because of the involvement of HS in neuronal development. Current treatment options for patients with MPS II are often restricted to enzyme replacement therapy (ERT). While ERT has beneficial effects on respiratory and cardiopulmonary function and extends the lifespan of the patients, it does not significantly affect CNS manifestations, probably because the enzyme cannot pass the blood–brain barrier at sufficient levels. Many experimental therapies, therefore, aim at delivery of IDS to the CNS in an attempt to prevent neurocognitive decline in the patients. Full article

(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management 2.0)

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7 pages, 409 KiB

Open AccessReview

Morquio B Disease. Disease Characteristics and Treatment Options of a Distinct GLB1-Related Dysostosis Multiplex

by Nataliya Yuskiv, Katsumi Higaki and Sylvia Stockler-Ipsiroglu

Int. J. Mol. Sci. 2020, 21(23), 9121; https://doi.org/10.3390/ijms21239121 - 30 Nov 2020

Cited by 15 | Viewed by 2990

Abstract

Morquio B disease (MBD) is an autosomal recessive GLB1-gene-related lysosomal storage disease, presenting with a peculiar type of dysostosis multiplex which is also observed in GALNS-related Morquio A disease. MBD may present as pure skeletal phenotype (pure MBD) or in combination with the neuronopathic manifestations seen in type 2 (juvenile) or type 3 (late onset) GM1 gangliosidosis (MBD plus). The main skeletal features are progressive growth impairment, kyphoscoliosis, coxa/genua valga, joint laxity, platyspondyly and odontoid hypoplasia. The main neuronopathic features are dystonia, ataxia, and intellectual/developmental/speech delay. Spinal cord compression occurs as a complication of spinal dysostosis. Chronic pain is reported, along with mobility issues and challenges with daily living and self-care activities, as the most common health concern. The most commonly reported orthopedic surgeries are hip and knee replacements. Keratan sulphate-derived oligosaccharides are characteristic biomarkers. Residual β-galactosidase activities measured against synthetic substrates do not correlate with the phenotype. W273 L and T500A are the most frequently observed GLB1 variants in MBD, W273L being invariably associated with pure MBD. Cytokines play a role in joint destruction and pain, providing a promising treatment target. In the future, patients may benefit from small molecule therapies, and gene and enzyme replacement therapies, which are currently being developed for GM1 gangliosidosis. Full article

(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management 2.0)

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20 pages, 2579 KiB

Open AccessReview

Mucolipidoses Overview: Past, Present, and Future

by Shaukat A. Khan and Saori C. Tomatsu

Int. J. Mol. Sci. 2020, 21(18), 6812; https://doi.org/10.3390/ijms21186812 - 17 Sep 2020

Cited by 35 | Viewed by 9177

Abstract

Mucolipidosis II and III (ML II/III) are caused by a deficiency of uridine-diphosphate N-acetylglucosamine: lysosomal-enzyme-N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase, EC2.7.8.17), which tags lysosomal enzymes with a mannose 6-phosphate (M6P) marker for transport to the lysosome. The process is performed by a sequential two-step process: first, GlcNAc-1-phosphotransferase catalyzes the transfer of GlcNAc-1-phosphate to the selected mannose residues on lysosomal enzymes in the cis-Golgi network. The second step removes GlcNAc from lysosomal enzymes by N-acetylglucosamine-1-phosphodiester α-N-acetylglucosaminidase (uncovering enzyme) and exposes the mannose 6-phosphate (M6P) residues in the trans-Golgi network, in which the enzymes are targeted to the lysosomes by M6Preceptors. A deficiency of GlcNAc-1-phosphotransferase causes the hypersecretion of lysosomal enzymes out of cells, resulting in a shortage of multiple lysosomal enzymes within lysosomes. Due to a lack of GlcNAc-1-phosphotransferase, the accumulation of cholesterol, phospholipids, glycosaminoglycans (GAGs), and other undegraded substrates occurs in the lysosomes. Clinically, ML II and ML III exhibit quite similar manifestations to mucopolysaccharidoses (MPSs), including specific skeletal deformities known as dysostosis multiplex and gingival hyperplasia. The life expectancy is less than 10 years in the severe type, and there is no definitive treatment for this disease. In this review, we have described the updated diagnosis and therapy on ML II/III. Full article

(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management 2.0)

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