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Mucopolysaccharidoses: Diagnosis, Treatment, and Management 3.0

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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 (30 January 2023) | Viewed by 26027

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Dr. Shunji Tomatsu

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1. Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu 501-1193, Japan
2. Nemours Children's Health, Wilmington, DE 19803, USA
3. Faculty of Arts and Sciences, University of Delaware, Newark, DE 19716, USA
4. Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA 19144, USA
Interests: skeletal dysplasia; inactive project newborn screening; targeting therapy
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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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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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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
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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.

As volume 1 and 2 of special issue “Mucopolysaccharidoses: Diagnosis, Treatment, and Management” are successful, we reopen this issue again in the International Journal of Molecular Sciences (https://www.mdpi.com/journal/ijms, ISSN 1422-0067, IF 5.924, JCR Category Q1). In this third 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.

Related Special Issues:

https://www.mdpi.com/journal/ijms/special_issues/MPS

https://www.mdpi.com/journal/ijms/special_issues/MPS_v2

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

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Published Papers (8 papers)

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19 pages, 4851 KiB

Open AccessArticle

Sex Difference Leads to Differential Gene Expression Patterns and Therapeutic Efficacy in Mucopolysaccharidosis IVA Murine Model Receiving AAV8 Gene Therapy

by Matthew Piechnik, Paige C. Amendum, Kazuki Sawamoto, Molly Stapleton, Shaukat Khan, Nidhi Fnu, Victor Álvarez, Angelica Maria Herreño Pachon, Olivier Danos, Joseph T. Bruder, Subha Karumuthil-Melethil and Shunji Tomatsu

Int. J. Mol. Sci. 2022, 23(20), 12693; https://doi.org/10.3390/ijms232012693 - 21 Oct 2022

Cited by 7 | Viewed by 2719

Abstract

Adeno-associated virus (AAV) vector-based therapies can effectively correct some disease pathology in murine models with mucopolysaccharidoses. However, immunogenicity can limit therapeutic effect as immune responses target capsid proteins, transduced cells, and gene therapy products, ultimately resulting in loss of enzyme activity. Inherent differences in male versus female immune response can significantly impact AAV gene transfer. We aim to investigate sex differences in the immune response to AAV gene therapies in mice with mucopolysaccharidosis IVA (MPS IVA). MPS IVA mice, treated with different AAV vectors expressing human N-acetylgalactosamine 6-sulfate sulfatase (GALNS), demonstrated a more robust antibody response in female mice resulting in subsequent decreased GALNS enzyme activity and less therapeutic efficacy in tissue pathology relative to male mice. Under thyroxine-binding globulin promoter, neutralizing antibody titers in female mice were approximately 4.6-fold higher than in male mice, with GALNS enzyme activity levels approximately 6.8-fold lower. Overall, male mice treated with AAV-based gene therapy showed pathological improvement in the femur and tibial growth plates, ligaments, and articular cartilage as determined by contrasting differences in pathology scores compared to females. Cardiac histology revealed a failure to normalize vacuolation in females, in contrast, to complete correction in male mice. These findings promote the need for further determination of sex-based differences in response to AAV-mediated gene therapy related to developing treatments for MPS IVA. Full article

(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management 3.0)

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14 pages, 1248 KiB

Open AccessArticle

Mucopolysaccharidosis-Plus Syndrome: Report on a Polish Patient with a Novel VPS33A Variant with Comparison with Other Described Patients

by Patryk Lipiński, Krzysztof Szczałuba, Piotr Buda, Ekaterina Y. Zakharova, Galina Baydakova, Agnieszka Ługowska, Agnieszka Różdzyńska-Świątkowska, Zuzanna Cyske, Grzegorz Węgrzyn, Agnieszka Pollak, Rafał Płoski and Anna Tylki-Szymańska

Int. J. Mol. Sci. 2022, 23(19), 11424; https://doi.org/10.3390/ijms231911424 - 28 Sep 2022

Cited by 4 | Viewed by 2000

Abstract

Eleven patients from Yakutia with a new lysosomal disease assumed then as mucopolysaccharidosis-plus syndrome (MPS-PS) were reported by Gurinova et al. in 2014. Up to now, a total number of 39 patients have been reported; in all of them, the c.1492C>T (p.Arg498Trp) variant of the VPS33A gene was detected. Here, we describe the first Polish MPS-PS patient with a novel homozygous c.599G>C (p.Arg200Pro) VPS33A variant presenting over 12 years of follow-up with some novel clinical features, including fetal ascites (resolved spontaneously), recurrent joint effusion and peripheral edemas, normal growth, and visceral obesity. Functional analyses revealed a slight presence of chondroitin sulphate (only) in urine glycosaminoglycan electrophoresis, presence of sialooligosaccharides in urine by thin-layer chromatography, and normal results of lysosomal enzymes activity and lysosphingolipids concentration in dried blood spot. The comparison with other MPS-PS described cases was also provided. The presented description of the natural history of MPS-PS in our patient may broaden the spectrum of phenotypes in this disease. Full article

(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management 3.0)

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17 pages, 2765 KiB

Open AccessArticle

Updated Confirmatory Diagnosis for Mucopolysaccharidoses in Taiwanese Infants and the Application of Gene Variants

by Chih-Kuang Chuang, Yuan-Rong Tu, Chung-Lin Lee, Yun-Ting Lo, Ya-Hui Chang, Mei-Ying Liu, Hsin-Yun Liu, Hsiao-Jan Chen, Shu-Min Kao, Li-Yun Wang, Huey-Jane Ho, Hsiang-Yu Lin and Shuan-Pei Lin

Int. J. Mol. Sci. 2022, 23(17), 9979; https://doi.org/10.3390/ijms23179979 - 1 Sep 2022

Cited by 7 | Viewed by 2358

Abstract

Mucopolysaccharidosis (MPS) is a lysosomal storage disease caused by genetic defects that result in deficiency of one specific enzyme activity, consequently impairing the stepwise degradation of glycosaminoglycans (GAGs). Except for MPS II, the other types of MPS have autosomal recessive inheritance in which two copies of an abnormal allele must be present in order for the disease to develop. In this study, we present the status of variant alleles and biochemistry results found in infants suspected of having MPS I, II, IVA, and VI. A total of 324 suspected infants, including 12 for MPS I, 223 for MPS II, 72 for MPS IVA, and 17 for MPS VI, who were referred for MPS confirmation from newborn screening centers in Taiwan, were enrolled. In all of these infants, one specific enzyme activity in dried blood spot filter paper was lower than the cut-off value in the first blood sample, as well asin a second follow-up sample. The confirmatory methods used in this study included Sanger sequencing, next-generation sequencing, leukocyte enzyme fluorometric assay, and GAG-derived disaccharides in urine using tandem mass spectrometry assays. The results showed that five, nine, and six infants had MPS I, II, and IVA, respectively, and all of them were asymptomatic. Thus, a laboratory diagnosis is extremely important to confirm the diagnosis of MPS. The other infants with identified nucleotide variations and reductions in leukocyte enzyme activities were categorized as being highly suspected cases requiring long-term and intensive follow-up examinations. In summary, the final confirmation of MPS depends on the most powerful biomarkers found in urine, i.e., the quantification of GAG-derived disaccharides including dermatan sulfate, heparan sulfate, and keratan sulfate, and analysis of genetic variants can help predict outcomes and guide treatment. Full article

(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management 3.0)

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10 pages, 4159 KiB

Open AccessArticle

Hematopoietic Disorders, Renal Impairment and Growth in Mucopolysaccharidosis-Plus Syndrome

by Viktoriia Sofronova, Rina Iwata, Takuya Moriya, Kiunniai Loskutova, Elizaveta Gurinova, Mairanush Chernova, Anastasia Timofeeva, Anna Shvedova, Filipp Vasilev, Saina Novgorodova, Seigo Terawaki, Takahito Moriwaki, Aitalina Sukhomyasova, Nadezhda Maksimova and Takanobu Otomo

Int. J. Mol. Sci. 2022, 23(10), 5851; https://doi.org/10.3390/ijms23105851 - 23 May 2022

Cited by 6 | Viewed by 2802

Abstract

Mucopolysaccharidoses (MPS) are rare lysosomal storage disorders (LSD) characterized by the excessive accumulation of glycosaminoglycans (GAG). Conventional MPS, caused by inborn deficiencies of lysosomal enzymes involved in GAG degradation, display various multisystemic symptoms—including progressive neurological complications, ophthalmological disorders, hearing loss, gastrointestinal and hepatobiliary issues, cardiorespiratory problems, bone and joint abnormalities, dwarfism, and coarse facial features. Mucopolysaccharidosis-Plus Syndrome (MPSPS), an autosomal recessive disease caused by a mutation in the endo-lysosomal tethering protein VPS33A, shows additional renal and hematopoietic abnormalities (“Plus symptoms”) uncommon in conventional MPS. Here, we analyze data from biochemical, histological, and physical examinations—particularly of blood counts and kidney function—to further characterize the clinical phenotype of MPSPS. A series of blood tests indicate hematopoietic symptoms including progressive anemia and thrombocytopenia, which correlate with histological observations of hypoplastic bone marrow. High urinary excretion of protein (caused by impairments in renal filtration), hypoalbuminemia, and elevated levels of creatinine, cholesterol, and uric acid indicate renal dysfunction. Histological analyses of MPSPS kidneys similarly suggest the extensive destruction of glomerular structures by foamy podocytes. Height and weight did not significantly deviate from the average, but in some cases, growth began to decline at around six months or one year of age. Full article

(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management 3.0)

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Review

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21 pages, 2999 KiB

Open AccessReview

Mucopolysaccharidoses: Cellular Consequences of Glycosaminoglycans Accumulation and Potential Targets

by Andrés Felipe Leal, Eliana Benincore-Flórez, Estera Rintz, Angélica María Herreño-Pachón, Betul Celik, Yasuhiko Ago, Carlos Javier Alméciga-Díaz and Shunji Tomatsu

Int. J. Mol. Sci. 2023, 24(1), 477; https://doi.org/10.3390/ijms24010477 - 28 Dec 2022

Cited by 21 | Viewed by 5049

Abstract

Mucopolysaccharidoses (MPSs) constitute a heterogeneous group of lysosomal storage disorders characterized by the lysosomal accumulation of glycosaminoglycans (GAGs). Although lysosomal dysfunction is mainly affected, several cellular organelles such as mitochondria, endoplasmic reticulum, Golgi apparatus, and their related process are also impaired, leading to the activation of pathophysiological cascades. While supplying missing enzymes is the mainstream for the treatment of MPS, including enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), or gene therapy (GT), the use of modulators available to restore affected organelles for recovering cell homeostasis may be a simultaneous approach. This review summarizes the current knowledge about the cellular consequences of the lysosomal GAGs accumulation and discusses the use of potential modulators that can reestablish normal cell function beyond ERT-, HSCT-, or GT-based alternatives. Full article

(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management 3.0)

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18 pages, 994 KiB

Open AccessReview

Current and Future Treatment of Mucopolysaccharidosis (MPS) Type II: Is Brain-Targeted Stem Cell Gene Therapy the Solution for This Devastating Disorder?

by Claire Horgan, Simon A. Jones, Brian W. Bigger and Robert Wynn

Int. J. Mol. Sci. 2022, 23(9), 4854; https://doi.org/10.3390/ijms23094854 - 27 Apr 2022

Cited by 8 | Viewed by 4027

Abstract

Mucopolysaccharidosis type II (Hunter Syndrome) is a rare, x-linked recessive, progressive, multi-system, lysosomal storage disease caused by the deficiency of iduronate-2-sulfatase (IDS), which leads to the pathological storage of glycosaminoglycans in nearly all cell types, tissues and organs. The condition is clinically heterogeneous, and most patients present with a progressive, multi-system disease in their early years. This article outlines the pathology of the disorder and current treatment strategies, including a detailed review of haematopoietic stem cell transplant outcomes for MPSII. We then discuss haematopoietic stem cell gene therapy and how this can be employed for treatment of the disorder. We consider how preclinical innovations, including novel brain-targeted techniques, can be incorporated into stem cell gene therapy approaches to mitigate the neuropathological consequences of the condition. Full article

(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management 3.0)

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20 pages, 800 KiB

Open AccessReview

Innate Immunity in Mucopolysaccharide Diseases

by Oriana Mandolfo, Helen Parker and Brian Bigger

Int. J. Mol. Sci. 2022, 23(4), 1999; https://doi.org/10.3390/ijms23041999 - 11 Feb 2022

Cited by 22 | Viewed by 3647

Abstract

Mucopolysaccharidoses are rare paediatric lysosomal storage disorders, characterised by accumulation of glycosaminoglycans within lysosomes. This is caused by deficiencies in lysosomal enzymes involved in degradation of these molecules. Dependent on disease, progressive build-up of sugars may lead to musculoskeletal abnormalities and multi-organ failure, and in others, to cognitive decline, which is still a challenge for current therapies. The worsening of neuropathology, observed in patients following recovery from flu-like infections, suggests that inflammation is highly implicated in disease progression. This review provides an overview of the pathological features associated with the mucopolysaccharidoses and summarises current knowledge regarding the inflammatory responses observed in the central nervous system and periphery. We propose a model whereby progressive accumulation of glycosaminoglycans elicits an innate immune response, initiated by the Toll-like receptor 4 pathway, but also precipitated by secondary storage components. Its activation induces cells of the immune system to release pro-inflammatory cytokines, such as TNF-α and IL-1, which induce progression through chronic neuroinflammation. While TNF-α is mostly associated with bone and joint disease in mucopolysaccharidoses, increasing evidence implicates IL-1 as a main effector of innate immunity in the central nervous system. The (NOD)-like receptor protein 3 inflammasome is therefore implicated in chronic neuroinflammation and should be investigated further to identify novel anti-inflammatory treatments. Full article

(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management 3.0)

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Other

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9 pages, 1621 KiB

Open AccessCase Report

A Case of Mucopolysaccharidosis II Caused by a Novel Variant with Skin Linear Hyperpigmented Streaks along Blaschko’s Lines

by Viktoriia Sofronova, Elizaveta Gurinova, Diana Petukhova, Hiroko Fukamatsu, Takenobu Yamamoto, Yumi Aoyama, Polina Golikova, Gavril Moskvitin, Roza Ivanova, Mira Savvina, Filipp Vasilev, Takahito Moriwaki, Seigo Terawaki, Aitalina Sukhomyasova, Nadezhda Maksimova and Takanobu Otomo

Int. J. Mol. Sci. 2023, 24(6), 5647; https://doi.org/10.3390/ijms24065647 - 15 Mar 2023

Viewed by 2104

Abstract

We report a case of an eight-year-old boy with mucopolysaccharidosis (MPS) II with atypical skin lesions of hyperpigmented streaks along Blaschko’s lines. This case presented with mild symptoms of MPS such as hepatosplenomegaly, joint stiffness, and quite mild bone deformity, which was the reason for the delay in diagnosis until the age of seven years. However, he showed an intellectual disability that did not meet the diagnostic criteria for an attenuated form of MPS II. Iduronate 2-sulfatase activity was reduced. Clinical exome sequencing of DNA from peripheral blood revealed a novel pathogenic missense variant (NM_000202.8(IDS_v001):c.703C>A, p.(Pro235Thr)) in the IDS gene, which was confirmed in the mother with a heterozygous state. His brownish skin lesions differed from the Mongolian blue spots or “pebbling” of the skin that are observed in MPS II. Full article

(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management 3.0)

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