Research

17 pages, 1117 KiB

Open AccessArticle

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

by Junhua Wang, Akhil Bhalla, Julie C. Ullman, Meng Fang, Ritesh Ravi, Annie Arguello, Elliot Thomsen, Buyankhishig Tsogtbaatar, Jing L. Guo, Lukas L. Skuja, Jason C. Dugas, Sonnet S. Davis, Suresh B. Poda, Kannan Gunasekaran, Simona Costanzo, Zachary K. Sweeney, Anastasia G. Henry, Jeffrey M. Harris, Kirk R. Henne and Giuseppe Astarita

Int. J. Mol. Sci. 2020, 21(15), 5449; https://doi.org/10.3390/ijms21155449 - 30 Jul 2020

Cited by 8 | Viewed by 4963

Abstract

We recently developed a blood–brain barrier (BBB)-penetrating enzyme transport vehicle (ETV) fused to the lysosomal enzyme iduronate 2-sulfatase (ETV:IDS) and demonstrated its ability to reduce glycosaminoglycan (GAG) accumulation in the brains of a mouse model of mucopolysaccharidosis (MPS) II. To accurately quantify GAGs, [...] Read more.

We recently developed a blood–brain barrier (BBB)-penetrating enzyme transport vehicle (ETV) fused to the lysosomal enzyme iduronate 2-sulfatase (ETV:IDS) and demonstrated its ability to reduce glycosaminoglycan (GAG) accumulation in the brains of a mouse model of mucopolysaccharidosis (MPS) II. To accurately quantify GAGs, we developed a plate-based high-throughput enzymatic digestion assay coupled with liquid chromatography–tandem mass spectrometry (LC-MS/MS) to simultaneously measure heparan sulfate and dermatan sulfate derived disaccharides in tissue, cerebrospinal fluid (CSF) and individual cell populations isolated from mouse brain. The method offers ultra-high sensitivity enabling quantitation of specific GAG species in as low as 100,000 isolated neurons and a low volume of CSF. With an LOD at 3 ng/mL and LLOQs at 5–10 ng/mL, this method is at least five times more sensitive than previously reported approaches. Our analysis demonstrated that the accumulation of CSF and brain GAGs are in good correlation, supporting the potential use of CSF GAGs as a surrogate biomarker for brain GAGs. The bioanalytical method was qualified through the generation of standard curves in matrix for preclinical studies of CSF, demonstrating the feasibility of this assay for evaluating therapeutic effects of ETV:IDS in future studies and applications in a wide variety of MPS disorders. Full article

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

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20 pages, 3468 KiB

Open AccessArticle

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

by Akhil Bhalla, Ritesh Ravi, Meng Fang, Annie Arguello, Sonnet S. Davis, Chi-Lu Chiu, Jessica R. Blumenfeld, Hoang N. Nguyen, Timothy K. Earr, Junhua Wang, Giuseppe Astarita, Yuda Zhu, Damian Fiore, Kimberly Scearce-Levie, Dolores Diaz, Heather Cahan, Matthew D. Troyer, Jeffrey M. Harris and Maria L. Escolar

Int. J. Mol. Sci. 2020, 21(15), 5188; https://doi.org/10.3390/ijms21155188 - 22 Jul 2020

Cited by 13 | Viewed by 6285

Abstract

Mucopolysaccharidosis type II is a lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS) and characterized by the accumulation of the primary storage substrate, glycosaminoglycans (GAGs). Understanding central nervous system (CNS) pathophysiology in neuronopathic MPS II (nMPS II) has been hindered by [...] Read more.

Mucopolysaccharidosis type II is a lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS) and characterized by the accumulation of the primary storage substrate, glycosaminoglycans (GAGs). Understanding central nervous system (CNS) pathophysiology in neuronopathic MPS II (nMPS II) has been hindered by the lack of CNS biomarkers. Characterization of fluid biomarkers has been largely focused on evaluating GAGs in cerebrospinal fluid (CSF) and the periphery; however, GAG levels alone do not accurately reflect the broad cellular dysfunction in the brains of MPS II patients. We utilized a preclinical mouse model of MPS II, treated with a brain penetrant form of IDS (ETV:IDS) to establish the relationship between markers of primary storage and downstream pathway biomarkers in the brain and CSF. We extended the characterization of pathway and neurodegeneration biomarkers to nMPS II patient samples. In addition to the accumulation of CSF GAGs, nMPS II patients show elevated levels of lysosomal lipids, neurofilament light chain, and other biomarkers of neuronal damage and degeneration. Furthermore, we find that these biomarkers of downstream pathology are tightly correlated with heparan sulfate. Exploration of the responsiveness of not only CSF GAGs but also pathway and disease-relevant biomarkers during drug development will be crucial for monitoring disease progression, and the development of effective therapies for nMPS II. Full article

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

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12 pages, 1164 KiB

Open AccessArticle

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

by Tsubasa Oguni, Shunji Tomatsu, Misa Tanaka, Kenji Orii, Toshiyuki Fukao, Jun Watanabe, Seiji Fukuda, Yoshitomo Notsu, Dung Chi Vu, Thi Bich Ngoc Can, Atsushi Nagai, Seiji Yamaguchi, Takeshi Taketani, Michael H. Gelb and Hironori Kobayashi

Int. J. Mol. Sci. 2020, 21(6), 2025; https://doi.org/10.3390/ijms21062025 - 16 Mar 2020

Cited by 2 | Viewed by 2703

Abstract

Mucopolysaccharidoses (MPSs) are rare lysosomal storage diseases caused by the accumulation of undegraded glycosaminoglycans in cells and tissues. The effectiveness of early intervention for MPS has been reported. Multiple-assay formats using tandem mass spectrometry have been developed. Here, we developed a method for [...] Read more.

Mucopolysaccharidoses (MPSs) are rare lysosomal storage diseases caused by the accumulation of undegraded glycosaminoglycans in cells and tissues. The effectiveness of early intervention for MPS has been reported. Multiple-assay formats using tandem mass spectrometry have been developed. Here, we developed a method for simultaneous preparation and better measurement of the activities of five enzymes involved in MPSs, i.e., MPS I, MPS II, MPS IIIB, MPS IVA, and MPS VI, which were validated using 672 dried blood spot samples obtained from healthy newborns and 23 patients with MPS. The mean values of the enzyme activities and standard deviations in controls were as follows: α-iduronidase (IDUA), 4.19 ± 1.53 µM/h; iduronate-2-sulfatase (I2S), 8.39 ± 2.82 µM/h; N-acetyl-α-glucosaminidase (NAGLU), 1.96 ± 0.57 µM/h; N-acetylgalactosamine-6-sulfatase (GALNS), 0.50 ± 0.20 µM/h; and N-acetylgalactosamine-4-sulfatase (ARSB), 2.64 ± 1.01 µM/h. All patients displayed absent or low enzyme activity. In MPS I, IIIB, and VI, each patient group was clearly separated from controls, whereas there was some overlap between the control and patient groups in MPS II and IVA, suggesting the occurrence of pseudo-deficiencies. Thus, we established a multiplex assay for newborn screening using liquid chromatography tandem mass spectrometry, allowing simultaneous pretreatment and measurement of five enzymes relevant to MPSs. Full article

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

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13 pages, 2793 KiB

Open AccessArticle

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

by Gustavo Monteiro Viana, Esteban Alberto Gonzalez, Marcela Maciel Palacio Alvarez, Renan Pelluzzi Cavalheiro, Cinthia Castro do Nascimento, Guilherme Baldo, Vânia D’Almeida, Marcelo Andrade de Lima, Alexey V. Pshezhetsky and Helena Bonciani Nader

Int. J. Mol. Sci. 2020, 21(4), 1459; https://doi.org/10.3390/ijms21041459 - 20 Feb 2020

Cited by 10 | Viewed by 3953

Abstract

Mucopolysaccharidosis type I (MPS I) is caused by genetic deficiency of α-l-iduronidase and impairment of lysosomal catabolism of heparan sulfate and dermatan sulfate. In the brain, these substrates accumulate in the lysosomes of neurons and glial cells, leading to neuroinflammation and [...] Read more.

Mucopolysaccharidosis type I (MPS I) is caused by genetic deficiency of α-l-iduronidase and impairment of lysosomal catabolism of heparan sulfate and dermatan sulfate. In the brain, these substrates accumulate in the lysosomes of neurons and glial cells, leading to neuroinflammation and neurodegeneration. Their storage also affects lysosomal homeostasis-inducing activity of several lysosomal proteases including cathepsin B (CATB). In the central nervous system, increased CATB activity has been associated with the deposition of amyloid plaques due to an alternative pro-amyloidogenic processing of the amyloid precursor protein (APP), suggesting a potential role of this enzyme in the neuropathology of MPS I. In this study, we report elevated levels of protein expression and activity of CATB in cortex tissues of 6-month-old MPS I (Idua -/- mice. Besides, increased CATB leakage from lysosomes to the cytoplasm of Idua -/- cortical pyramidal neurons was indicative of damaged lysosomal membranes. The increased CATB activity coincided with an elevated level of the 16-kDa C-terminal APP fragment, which together with unchanged levels of β-secretase 1 was suggestive for the role of this enzyme in the amyloidogenic APP processing. Neuronal accumulation of Thioflavin-S-positive misfolded protein aggregates and drastically increased levels of neuroinflammatory glial fibrillary acidic protein (GFAP)-positive astrocytes and CD11b-positive activated microglia were observed in Idua -/- cortex by confocal fluorescent microscopy. Together, our results point to the existence of a novel CATB-associated alternative amyloidogenic pathway in MPS I brain induced by lysosomal storage and potentially leading to neurodegeneration. Full article

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

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19 pages, 2047 KiB

Open AccessArticle

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

by Lidia Gaffke, Karolina Pierzynowska, Magdalena Podlacha, Dżesika Hoinkis, Estera Rintz, Joanna Brokowska, Zuzanna Cyske and Grzegorz Wegrzyn

Int. J. Mol. Sci. 2020, 21(4), 1204; https://doi.org/10.3390/ijms21041204 - 11 Feb 2020

Cited by 39 | Viewed by 2771

Abstract

Mucopolysaccharidoses (MPS), a group of inherited metabolic disorders caused by deficiency in enzymes involved in degradation of glycosaminoglycans (GAGs), are examples (and models) of monogenic diseases. Accumulation of undegraded GAGs in lysosomes was supposed to be the major cause of MPS symptoms; however, [...] Read more.

Mucopolysaccharidoses (MPS), a group of inherited metabolic disorders caused by deficiency in enzymes involved in degradation of glycosaminoglycans (GAGs), are examples (and models) of monogenic diseases. Accumulation of undegraded GAGs in lysosomes was supposed to be the major cause of MPS symptoms; however, their complexity and variability between particular types of the disease can be hardly explained by such a simple storage mechanism. Here we show that transcriptomic (RNA-seq) analysis of the material derived from fibroblasts of patients suffering from all types and subtypes of MPS, supported by RT-qPCR results, revealed surprisingly large changes in expression of genes involved in various cellular processes, indicating complex mechanisms of MPS. Although each MPS type and subtype was characterized by specific changes in gene expression profile, there were genes with significantly changed expression relative to wild-type cells that could be classified as common for various MPS types, suggesting similar disturbances in cellular processes. Therefore, both common features of all MPS types, and differences between them, might be potentially explained on the basis of changes in certain cellular processes arising from disturbed regulations of genes’ expression. These results may shed a new light on the mechanisms of genetic diseases, indicating how a single mutation can result in complex pathomechanism, due to perturbations in the network of cellular reactions. Moreover, they should be considered in studies on development of novel therapies, suggesting also why currently available treatment methods fail to correct all/most symptoms of MPS. We propose a hypothesis that disturbances in some cellular processes cannot be corrected by simple reduction of GAG levels; thus, combined therapies are necessary which may require improvement of these processes. Full article

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

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26 pages, 4455 KiB

Open AccessArticle

Genetic Base of Behavioral Disorders in Mucopolysaccharidoses: Transcriptomic Studies

by Karolina Pierzynowska, Lidia Gaffke, Magdalena Podlacha and Grzegorz Węgrzyn

Int. J. Mol. Sci. 2020, 21(3), 1156; https://doi.org/10.3390/ijms21031156 - 10 Feb 2020

Cited by 19 | Viewed by 3254

Abstract

Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases caused by mutations leading to defective degradation of glycosaminoglycans (GAGs) and their accumulation in cells. Among 11 known types and subtypes of MPS, neuronopathy occurs in seven (MPS I, II, IIIA, IIIB, IIIC, IIID, [...] Read more.

Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases caused by mutations leading to defective degradation of glycosaminoglycans (GAGs) and their accumulation in cells. Among 11 known types and subtypes of MPS, neuronopathy occurs in seven (MPS I, II, IIIA, IIIB, IIIC, IIID, VII). Brain dysfunctions, occurring in these seven types/subtypes include various behavioral disorders. Intriguingly, behavioral symptoms are significantly different between patients suffering from various MPS types. Molecular base of such differences remains unknown. Here, we asked if expression of genes considered as connected to behavior (based on Gene Ontology, GO terms) is changed in MPS. Using cell lines of all MPS types, we have performed transcriptomic (RNA-seq) studies and assessed expression of genes involved in behavior. We found significant differences between MPS types in this regard, with the most severe changes in MPS IIIA (the type considered as the behaviorally most severely affected), while the lowest changes in MPS IVA and MPS VI (types in which little or no behavioral disorders are known). Intriguingly, relatively severe changes were found also in MPS IVB (in which, despite no behavioral disorder noted, the same gene is mutated as in GM1 gangliosidosis, a severe neurodegenerative disease) and MPS IX (in which only a few patients were described to date, thus, behavioral problems are not well recognized). More detailed analyses of expression of certain genes allowed us to propose an association of specific changes in the levels of transcripts in specific MPS types to certain behavioral disorders observed in patients. Therefore, this work provides a principle for further studies on the molecular mechanism of behavioral changes occurring in MPS patients. Full article

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

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18 pages, 2300 KiB

Open AccessArticle

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

by Hsiang-Yu Lin, Ru-Yi Tu, Schu-Rern Chern, Yun-Ting Lo, Sisca Fran, Fang-Jie Wei, Sung-Fa Huang, Shin-Yu Tsai, Ya-Hui Chang, Chung-Lin Lee, Shuan-Pei Lin and Chih-Kuang Chuang

Int. J. Mol. Sci. 2020, 21(1), 114; https://doi.org/10.3390/ijms21010114 - 23 Dec 2019

Cited by 14 | Viewed by 5511

Abstract

Hunter syndrome (mucopolysaccharidosis II; MPS II) is caused by a defect of the iduronate-2-sulfatase (IDS) gene. Few studies have reported integrated mutation data of Taiwanese MPS II phenotypes. In this study, we summarized genotype and phenotype correlations of confirmed MPS II [...] Read more.

Hunter syndrome (mucopolysaccharidosis II; MPS II) is caused by a defect of the iduronate-2-sulfatase (IDS) gene. Few studies have reported integrated mutation data of Taiwanese MPS II phenotypes. In this study, we summarized genotype and phenotype correlations of confirmed MPS II patients and asymptomatic MPS II infants in Taiwan. Regular polymerase chain reaction and DNA sequencing were used to identify genetic abnormalities of 191 cases, including 51 unrelated patients with confirmed MPS II and 140 asymptomatic infants. IDS activity was analyzed in individual novel IDS variants using in vitro expression studies. Nineteen novel mutations were identified, in which the percentages of IDS activity of the novel missense mutations c.137A>C, c.311A>T, c.454A>C, c.797C>G, c.817C>T, c.998C>T, c.1106C>G, c.1400C>T, c.1402C>T, and c.1403G>A were significantly decreased (p < 0.001), c.254C>T and c.1025A>G were moderately decreased (p < 0.01), and c.851C>T was slightly decreased (p < 0.05) comparing with normal enzyme activity. The activities of the other six missense mutations were reduced but were insignificant. The results of genomic studies and their phenotypes were highly correlated. A greater understanding of the positive correlations may help to prevent the irreversible manifestations of Hunter syndrome, particularly in infants suspected of having asymptomatic MPS II. In addition, urinary glycosaminoglycan assay is important to diagnose Hunter syndrome since gene mutations are not definitive (could be non-pathogenic). Full article

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

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Graphical abstract

14 pages, 4397 KiB

Open AccessArticle

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

by Mitsuyo Maeda, Toshiyuki Seto, Chiho Kadono, Hideto Morimoto, Sachiho Kida, Mitsuo Suga, Motohiro Nakamura, Yosky Kataoka, Takashi Hamazaki and Haruo Shintaku

Int. J. Mol. Sci. 2019, 20(23), 5829; https://doi.org/10.3390/ijms20235829 - 20 Nov 2019

Cited by 9 | Viewed by 3956

Abstract

Mucopolysaccharidosis type II (MPS II) is a rare lysosomal storage disease (LSD) involving a genetic error in iduronic acid-2-sulfatase (IDS) metabolism that leads to accumulation of glycosaminoglycans within intracellular lysosomes. The primary treatment for MPS II, enzyme replacement therapy, is not effective for [...] Read more.

Mucopolysaccharidosis type II (MPS II) is a rare lysosomal storage disease (LSD) involving a genetic error in iduronic acid-2-sulfatase (IDS) metabolism that leads to accumulation of glycosaminoglycans within intracellular lysosomes. The primary treatment for MPS II, enzyme replacement therapy, is not effective for central nervous system (CNS) symptoms, such as intellectual disability, because the drugs do not cross the blood–brain barrier. Recently, autophagy has been associated with LSDs. In this study, we examined the morphologic relationship between neuronal damage and autophagy in IDS knockout mice using antibodies against subunit c of mitochondrial adenosine triphosphate (ATP) synthetase and p62. Immunohistological changes suggesting autophagy, such as vacuolation, were observed in neurons, microglia, and pericytes throughout the CNS, and the numbers increased over postnatal development. Oral administration of chloroquine, which inhibits autophagy, did not suppress damage to microglia and pericytes, but greatly reduced neuronal vacuolation and eliminated neuronal cells with abnormal inclusions. Thus, decreasing autophagy appears to prevent neuronal degeneration. These results suggest that an autophagy modulator could be used in addition to conventional enzyme replacement therapy to preserve the CNS in patients with MPS II. Full article

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

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22 pages, 5805 KiB

Open AccessArticle

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

by J. Víctor Álvarez, Susana B. Bravo, María García-Vence, María J. De Castro, Asteria Luzardo, Cristóbal Colón, Shunji Tomatsu, Francisco J. Otero-Espinar and María L. Couce

Int. J. Mol. Sci. 2019, 20(18), 4610; https://doi.org/10.3390/ijms20184610 - 18 Sep 2019

Cited by 13 | Viewed by 4511

Abstract

Morquio A syndrome, or mucopolysaccharidosis type IVA (MPS IVA), is a lysosomal storage disease due to mutations in the N-acetylgalactosamine-6-sulfatase (GALNS) gene. Systemic skeletal dysplasia and the related clinical features of MPS IVA are due to disruption of cartilage and its [...] Read more.

Morquio A syndrome, or mucopolysaccharidosis type IVA (MPS IVA), is a lysosomal storage disease due to mutations in the N-acetylgalactosamine-6-sulfatase (GALNS) gene. Systemic skeletal dysplasia and the related clinical features of MPS IVA are due to disruption of cartilage and its extracellular matrix, leading to an imbalance of growth. Enzyme replacement therapy (ERT) with recombinant human GALNS, alpha elosulfase, provides a systemic treatment. However, this therapy has a limited impact on skeletal dysplasia because the infused enzyme cannot penetrate cartilage and bone. Therefore, an alternative therapeutic approach to reach the cartilage is an unmet challenge. We have developed a new drug delivery system based on a nanostructure lipid carrier with the capacity to immobilize enzymes used for ERT and to target the lysosomes. This study aimed to assess the effect of the encapsulated enzyme in this new delivery system, using in vitro proteomic technology. We found a greater internalization of the enzyme carried by nanoparticles inside the cells and an improvement of cellular protein routes previously impaired by the disease, compared with conventional ERT. This is the first qualitative and quantitative proteomic assay that demonstrates the advantages of a new delivery system to improve the MPS IVA ERT. Full article

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

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13 pages, 1972 KiB

Open AccessArticle

Development of Substrate Degradation Enzyme Therapy for Mucopolysaccharidosis IVA Murine Model

by Kazuki Sawamoto and Shunji Tomatsu

Int. J. Mol. Sci. 2019, 20(17), 4139; https://doi.org/10.3390/ijms20174139 - 24 Aug 2019

Cited by 7 | Viewed by 2615

Abstract

Mucopolysaccharidosis IVA (MPS IVA) is caused by a deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Conventional enzyme replacement therapy (ERT) is approved for MPS IVA. However, the fact that the infused enzyme cannot penetrate avascular lesions in cartilage leads to minimal impact [...] Read more.

Mucopolysaccharidosis IVA (MPS IVA) is caused by a deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Conventional enzyme replacement therapy (ERT) is approved for MPS IVA. However, the fact that the infused enzyme cannot penetrate avascular lesions in cartilage leads to minimal impact on the bone lesion. Moreover, short half-life, high cost, instability, and narrow optimal pH range remain unmet challenges in ERT. Thermostable keratanase, endo-β-N-acetylglucosaminidase, has a unique character of a wide optimal pH range of pH 5.0–7.0. We hypothesized that this endoglycosidase degrades keratan sulfate (KS) polymer in circulating blood and, therefore, ameliorates the accumulation of KS in multiple tissues. We propose a novel approach, Substrate Degradation Enzyme Therapy (SDET), to treat bone lesion of MPS IVA. We assessed the effect of thermostable keratanase on blood KS level and bone pathology using Galns knock-out MPS IVA mice. After a single administration of 2 U/kg (= 0.2 mg/kg) of the enzyme at 8 weeks of age via intravenous injection, the level of serum KS was significantly decreased to normal range level, and this suppression was maintained for at least 4 weeks. We administered 2 U/kg of the enzyme to MPS IVA mice every fourth week for 12 weeks (total of 3 times) at newborns or 8 weeks of age. After a third injection, serum mono-sulfated KS levels were kept low for 4 weeks, similar to that in control mice, and at 12 weeks, bone pathology was markedly improved when SDET started at newborns, compared with untreated MPS IVA mice. Overall, thermostable keratanase reduces the level of KS in blood and provides a positive impact on cartilage lesions, demonstrating that SDET is a novel therapeutic approach to MPS IVA. Full article

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

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Review

Jump to: Research, Other

15 pages, 1157 KiB

Open AccessReview

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

by Lars Schlotawa, Laura A. Adang, Karthikeyan Radhakrishnan and Rebecca C. Ahrens-Nicklas

Int. J. Mol. Sci. 2020, 21(10), 3448; https://doi.org/10.3390/ijms21103448 - 13 May 2020

Cited by 30 | Viewed by 5169

Abstract

Multiple sulfatase deficiency (MSD, MIM #272200) is an ultra-rare disease comprising pathophysiology and clinical features of mucopolysaccharidosis, sphingolipidosis and other sulfatase deficiencies. MSD is caused by impaired posttranslational activation of sulfatases through the formylglycine generating enzyme (FGE) encoded by the sulfatase modifying factor [...] Read more.

Multiple sulfatase deficiency (MSD, MIM #272200) is an ultra-rare disease comprising pathophysiology and clinical features of mucopolysaccharidosis, sphingolipidosis and other sulfatase deficiencies. MSD is caused by impaired posttranslational activation of sulfatases through the formylglycine generating enzyme (FGE) encoded by the sulfatase modifying factor 1 (SUMF1) gene, which is mutated in MSD. FGE is a highly conserved, non-redundant ER protein that activates all cellular sulfatases by oxidizing a conserved cysteine in the active site of sulfatases that is necessary for full catalytic activity. SUMF1 mutations result in unstable, degradation-prone FGE that demonstrates reduced or absent catalytic activity, leading to decreased activity of all sulfatases. As the majority of sulfatases are localized to the lysosome, loss of sulfatase activity induces lysosomal storage of glycosaminoglycans and sulfatides and subsequent cellular pathology. MSD patients combine clinical features of all single sulfatase deficiencies in a systemic disease. Disease severity classifications distinguish cases based on age of onset and disease progression. A genotype- phenotype correlation has been proposed, biomarkers like excreted storage material and residual sulfatase activities do not correlate well with disease severity. The diagnosis of MSD is based on reduced sulfatase activities and detection of mutations in SUMF1. No therapy exists for MSD yet. This review summarizes the unique FGE/ sulfatase physiology, pathophysiology and clinical aspects in patients and their care and outlines future perspectives in MSD. Full article

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

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14 pages, 709 KiB

Open AccessReview

Evading the AAV Immune Response in Mucopolysaccharidoses

by Matthew Piechnik, Kazuki Sawamoto, Hidenori Ohnishi, Norio Kawamoto, Yasuhiko Ago and Shunji Tomatsu

Int. J. Mol. Sci. 2020, 21(10), 3433; https://doi.org/10.3390/ijms21103433 - 13 May 2020

Cited by 5 | Viewed by 3948

Abstract

The humoral immune response elicited by adeno-associated virus (AAV)-mediated gene therapy for the treatment of mucopolysaccharidoses (MPS) poses a significant challenge to achieving therapeutic levels of transgene expression. Antibodies targeting the AAV capsid as well as the transgene product diminish the production of [...] Read more.

The humoral immune response elicited by adeno-associated virus (AAV)-mediated gene therapy for the treatment of mucopolysaccharidoses (MPS) poses a significant challenge to achieving therapeutic levels of transgene expression. Antibodies targeting the AAV capsid as well as the transgene product diminish the production of glycosaminoglycan (GAG)-degrading enzymes essential for the treatment of MPS. Patients who have antibodies against AAV capsid increase in number with age, serotype, and racial background and are excluded from the clinical trials at present. In addition, patients who have undergone AAV gene therapy are often excluded from the additional AAV gene therapy with the same serotype, since their acquired immune response (antibody) against AAV will limit further efficacy of treatment. Several methods are being developed to overcome this immune response, such as novel serotype design, antibody reduction by plasmapheresis and immunosuppression, and antibody evasion using empty capsids and enveloped AAV vectors. In this review, we examine the mechanisms of the anti-AAV humoral immune response and evaluate the strengths and weaknesses of current evasion strategies in order to provide an evidence-based recommendation on evading the immune response for future AAV-mediated gene therapies for MPS. Full article

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

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30 pages, 525 KiB

Open AccessReview

Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations

by Rossella Parini and Federica Deodato

Int. J. Mol. Sci. 2020, 21(8), 2975; https://doi.org/10.3390/ijms21082975 - 23 Apr 2020

Cited by 72 | Viewed by 5868

Abstract

The aim of this review is to summarize the evidence on efficacy, effectiveness and safety of intravenous enzyme replacement therapy (ERT) available for mucopolysaccharidoses (MPSs) I, II, IVA, VI and VII, gained in phase III clinical trials and in observational post-approval studies. Post-marketing [...] Read more.

The aim of this review is to summarize the evidence on efficacy, effectiveness and safety of intravenous enzyme replacement therapy (ERT) available for mucopolysaccharidoses (MPSs) I, II, IVA, VI and VII, gained in phase III clinical trials and in observational post-approval studies. Post-marketing data are sometimes conflicting or controversial, possibly depending on disease severity, differently involved organs, age at starting treatment, and development of anti-drug antibodies (ADAs). There is general agreement that ERT is effective in reducing urinary glycosaminoglycans and liver and spleen volume, while heart and joints outcomes are variable in different studies. Effectiveness on cardiac valves, trachea and bronchi, hearing and eyes is definitely poor, probably due to limited penetration in the specific tissues. ERT does not cross the blood–brain barrier, with the consequence that the central nervous system is not cured by intravenously injected ERT. All patients develop ADAs but their role in ERT tolerance and effectiveness has not been well defined yet. Lack of reliable biomarkers contributes to the uncertainties about effectiveness. The data obtained from affected siblings strongly indicates the need of neonatal screening for treatable MPSs. Currently, other treatments are under evaluation and will surely help improve the prognosis of MPS patients. Full article

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

14 pages, 988 KiB

Open AccessReview

Pathogenesis of Mucopolysaccharidoses, an Update

by Simona Fecarotta, Antonietta Tarallo, Carla Damiano, Nadia Minopoli and Giancarlo Parenti

Int. J. Mol. Sci. 2020, 21(7), 2515; https://doi.org/10.3390/ijms21072515 - 04 Apr 2020

Cited by 61 | Viewed by 8679

Abstract

The recent advancements in the knowledge of lysosomal biology and function have translated into an improved understanding of the pathophysiology of mucopolysaccharidoses (MPSs). The concept that MPS manifestations are direct consequences of lysosomal engorgement with undegraded glycosaminoglycans (GAGs) has been challenged by new [...] Read more.

The recent advancements in the knowledge of lysosomal biology and function have translated into an improved understanding of the pathophysiology of mucopolysaccharidoses (MPSs). The concept that MPS manifestations are direct consequences of lysosomal engorgement with undegraded glycosaminoglycans (GAGs) has been challenged by new information on the multiple biological roles of GAGs and by a new vision of the lysosome as a signaling hub involved in many critical cellular functions. MPS pathophysiology is now seen as the result of a complex cascade of secondary events that lead to dysfunction of several cellular processes and pathways, such as abnormal composition of membranes and its impact on vesicle fusion and trafficking; secondary storage of substrates; impairment of autophagy; impaired mitochondrial function and oxidative stress; dysregulation of signaling pathways. The characterization of this cascade of secondary cellular events is critical to better understand the pathophysiology of MPS clinical manifestations. In addition, some of these pathways may represent novel therapeutic targets and allow for the development of new therapies for these disorders. Full article

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

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26 pages, 2047 KiB

Open AccessReview

Mucopolysaccharidosis IVA: Diagnosis, Treatment, and Management

by Kazuki Sawamoto, José Víctor Álvarez González, Matthew Piechnik, Francisco J. Otero, Maria L. Couce, Yasuyuki Suzuki and Shunji Tomatsu

Int. J. Mol. Sci. 2020, 21(4), 1517; https://doi.org/10.3390/ijms21041517 - 23 Feb 2020

Cited by 56 | Viewed by 13006

Abstract

Mucopolysaccharidosis type IVA (MPS IVA, or Morquio syndrome type A) is an inherited metabolic lysosomal disease caused by the deficiency of the N-acetylglucosamine-6-sulfate sulfatase enzyme. The deficiency of this enzyme accumulates the specific glycosaminoglycans (GAG), keratan sulfate, and chondroitin-6-sulfate mainly in bone, cartilage, [...] Read more.

Mucopolysaccharidosis type IVA (MPS IVA, or Morquio syndrome type A) is an inherited metabolic lysosomal disease caused by the deficiency of the N-acetylglucosamine-6-sulfate sulfatase enzyme. The deficiency of this enzyme accumulates the specific glycosaminoglycans (GAG), keratan sulfate, and chondroitin-6-sulfate mainly in bone, cartilage, and its extracellular matrix. GAG accumulation in these lesions leads to unique skeletal dysplasia in MPS IVA patients. Clinical, radiographic, and biochemical tests are needed to complete the diagnosis of MPS IVA since some clinical characteristics in MPS IVA are overlapped with other disorders. Early and accurate diagnosis is vital to optimizing patient management, which provides a better quality of life and prolonged life-time in MPS IVA patients. Currently, enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) are available for patients with MPS IVA. However, ERT and HSCT do not have enough impact on bone and cartilage lesions in patients with MPS IVA. Penetrating the deficient enzyme into an avascular lesion remains an unmet challenge, and several innovative therapies are under development in a preclinical study. In this review article, we comprehensively describe the current diagnosis, treatment, and management for MPS IVA. We also illustrate developing future therapies focused on the improvement of skeletal dysplasia in MPS IVA. Full article

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

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38 pages, 1218 KiB

Open AccessReview

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

by Francesca D’Avanzo, Laura Rigon, Alessandra Zanetti and Rosella Tomanin

Int. J. Mol. Sci. 2020, 21(4), 1258; https://doi.org/10.3390/ijms21041258 - 13 Feb 2020

Cited by 82 | Viewed by 11452

Abstract

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) was first described by Dr. Charles Hunter in 1917. Since then, about one hundred years have passed and Hunter syndrome, although at first neglected for a few decades and afterwards mistaken for a long time for [...] Read more.

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) was first described by Dr. Charles Hunter in 1917. Since then, about one hundred years have passed and Hunter syndrome, although at first neglected for a few decades and afterwards mistaken for a long time for the similar disorder Hurler syndrome, has been clearly distinguished as a specific disease since 1978, when the distinct genetic causes of the two disorders were finally identified. MPS II is a rare genetic disorder, recently described as presenting an incidence rate ranging from 0.38 to 1.09 per 100,000 live male births, and it is the only X-linked-inherited mucopolysaccharidosis. The complex disease is due to a deficit of the lysosomal hydrolase iduronate 2-sulphatase, which is a crucial enzyme in the stepwise degradation of heparan and dermatan sulphate. This contributes to a heavy clinical phenotype involving most organ-systems, including the brain, in at least two-thirds of cases. In this review, we will summarize the history of the disease during this century through clinical and laboratory evaluations that allowed its definition, its correct diagnosis, a partial comprehension of its pathogenesis, and the proposition of therapeutic protocols. We will also highlight the main open issues related to the possible inclusion of MPS II in newborn screenings, the comprehension of brain pathogenesis, and treatment of the neurological compartment. Full article

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

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14 pages, 4224 KiB

Open AccessReview

Surgical Management of Spinal Disorders in People with Mucopolysaccharidoses

by Hidetomi Terai and Hiroaki Nakamura

Int. J. Mol. Sci. 2020, 21(3), 1171; https://doi.org/10.3390/ijms21031171 - 10 Feb 2020

Cited by 10 | Viewed by 4498

Abstract

Mucopolysaccharidoses (MPS) are a group of inherited, multisystem, lysosomal storage disorders involving specific lysosomal enzyme deficiencies that result in the accumulation of glycosaminoglycans (GAG) secondary to insufficient degradation within cell lysosomes. GAG accumulation affects both primary bone formation and secondary bone growth, resulting [...] Read more.

Mucopolysaccharidoses (MPS) are a group of inherited, multisystem, lysosomal storage disorders involving specific lysosomal enzyme deficiencies that result in the accumulation of glycosaminoglycans (GAG) secondary to insufficient degradation within cell lysosomes. GAG accumulation affects both primary bone formation and secondary bone growth, resulting in growth impairment. Typical spinal manifestations in MPS are atlantoaxial instability, thoracolumbar kyphosis/scoliosis, and cervical/lumbar spinal canal stenosis. Spinal disorders and their severity depend on the MPS type and may be related to disease activity. Enzyme replacement therapy or hematopoietic stem cell transplantation has advantages regarding soft tissues; however, these therapeutic modalities are not effective for bone or cartilage and MPS-related bone deformity including the spine. Because spinal disorders show the most serious deterioration among patients with MPS, spinal surgeries are required although they are challenging and associated with high anesthesia-related risks. The aim of this review article is to provide the current comprehensive knowledge of representative spinal disease in MPS and its surgical management, including the related pathology, symptoms, and examinations. Full article

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

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15 pages, 1063 KiB

Open AccessReview

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

by Walter Acosta and Carole L. Cramer

Int. J. Mol. Sci. 2020, 21(3), 971; https://doi.org/10.3390/ijms21030971 - 01 Feb 2020

Cited by 15 | Viewed by 4314

Abstract

The greatest challenges for therapeutic efficacy of many macromolecular drugs that act on intracellular are delivery to key organs and tissues and delivery into cells and subcellular compartments. Transport of drugs into critical cells associated with disease, including those in organs protected by [...] Read more.

The greatest challenges for therapeutic efficacy of many macromolecular drugs that act on intracellular are delivery to key organs and tissues and delivery into cells and subcellular compartments. Transport of drugs into critical cells associated with disease, including those in organs protected by restrictive biological barriers such as central nervous system (CNS), bone, and eye remains a significant hurdle to drug efficacy and impacts commercial risk and incentives for drug development for many diseases. These limitations expose a significant need for the development of novel strategies for macromolecule delivery. RTB lectin is the non-toxic carbohydrate-binding subunit B of ricin toxin with high affinity for galactose/galactosamine-containing glycolipids and glycoproteins common on human cell surfaces. RTB mediates endocytic uptake into mammalian cells by multiple routes exploiting both adsorptive-mediated and receptor-mediated mechanisms. In vivo biodistribution studies in lysosomal storage disease models provide evidence for the theory that the RTB-lectin transports corrective doses of enzymes across the blood–brain barrier to treat CNS pathologies. These results encompass significant implications for protein-based therapeutic approaches to address lysosomal and other diseases having strong CNS involvement. Full article

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

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20 pages, 2000 KiB

Open AccessReview

Genome Editing for Mucopolysaccharidoses

by Edina Poletto, Guilherme Baldo and Natalia Gomez-Ospina

Int. J. Mol. Sci. 2020, 21(2), 500; https://doi.org/10.3390/ijms21020500 - 13 Jan 2020

Cited by 32 | Viewed by 6166

Abstract

Genome editing holds the promise of one-off and potentially curative therapies for many patients with genetic diseases. This is especially true for patients affected by mucopolysaccharidoses as the disease pathophysiology is amenable to correction using multiple approaches. Ex vivo and in vivo genome [...] Read more.

Genome editing holds the promise of one-off and potentially curative therapies for many patients with genetic diseases. This is especially true for patients affected by mucopolysaccharidoses as the disease pathophysiology is amenable to correction using multiple approaches. Ex vivo and in vivo genome editing platforms have been tested primarily on MSPI and MPSII, with in vivo approaches having reached clinical testing in both diseases. Though we still await proof of efficacy in humans, the therapeutic tools established for these two diseases should pave the way for other mucopolysaccharidoses. Herein, we review the current preclinical and clinical development studies, using genome editing as a therapeutic approach for these diseases. The development of new genome editing platforms and the variety of genetic modifications possible with each tool provide potential applications of genome editing for mucopolysaccharidoses, which vastly exceed the potential of current approaches. We expect that in a not-so-distant future, more genome editing-based strategies will be established, and individual diseases will be treated through multiple approaches. Full article

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

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14 pages, 2252 KiB

Open AccessReview

Mucopolysaccharidosis-Plus Syndrome

by Filipp Vasilev, Aitalina Sukhomyasova and Takanobu Otomo

Int. J. Mol. Sci. 2020, 21(2), 421; https://doi.org/10.3390/ijms21020421 - 09 Jan 2020

Cited by 19 | Viewed by 6089

Abstract

Previously, we reported a novel disease of impaired glycosaminoglycans (GAGs) metabolism without deficiency of known lysosomal enzymes—mucopolysaccharidosis-plus syndrome (MPSPS). MPSPS, whose pathophysiology is not elucidated, is an autosomal recessive multisystem disorder caused by a specific mutation p.R498W in the VPS33A gene. VPS33A functions [...] Read more.

Previously, we reported a novel disease of impaired glycosaminoglycans (GAGs) metabolism without deficiency of known lysosomal enzymes—mucopolysaccharidosis-plus syndrome (MPSPS). MPSPS, whose pathophysiology is not elucidated, is an autosomal recessive multisystem disorder caused by a specific mutation p.R498W in the VPS33A gene. VPS33A functions in endocytic and autophagic pathways, but p.R498W mutation did not affect both of these pathways in the patient’s skin fibroblast. Nineteen patients with MPSPS have been identified: seventeen patients were found among the Yakut population (Russia) and two patients from Turkey. Clinical features of MPSPS patients are similar to conventional mucopolysaccharidoses (MPS). In addition to typical symptoms for conventional MPS, MPSPS patients developed other features such as congenital heart defects, renal and hematopoietic disorders. Diagnosis generally requires evidence of clinical picture similar to MPS and molecular genetic testing. Disease is very severe, prognosis is unfavorable and most of patients died at age of 10–20 months. Currently there is no specific therapy for this disease and clinical management is limited to supportive and symptomatic treatment. Full article

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

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12 pages, 1765 KiB

Open AccessReview

Novel Enzyme Replacement Therapies for Neuropathic Mucopolysaccharidoses

by Yuji Sato and Torayuki Okuyama

Int. J. Mol. Sci. 2020, 21(2), 400; https://doi.org/10.3390/ijms21020400 - 08 Jan 2020

Cited by 32 | Viewed by 4211

Abstract

Although the advent of enzyme replacement therapy (ERT) for mucopolysaccharidoses (MPS) has paved the way for the treatment for these hereditary disorders, the blood brain barrier (BBB) has prevented patients with MPS involving the central nervous system (CNS) from benefitting from ERT. Therefore, [...] Read more.

Although the advent of enzyme replacement therapy (ERT) for mucopolysaccharidoses (MPS) has paved the way for the treatment for these hereditary disorders, the blood brain barrier (BBB) has prevented patients with MPS involving the central nervous system (CNS) from benefitting from ERT. Therefore, finding ways to increase drug delivery into the brain across the BBB remains a crucial challenge for researchers and clinicians in the field. Attempts have been made to boost brain uptake of enzymes by targeting various receptors (e.g., insulin and transferrin), and several other administration routes have also been tested. This review summarizes the available information on clinical trials (completed, ongoing, and planned) of novel therapeutic agents with efficacy against CNS symptoms in neuropathic MPS and also discusses the common associated challenges and pitfalls, some of which may help elucidate the pathogenesis of the neurodegeneration leading to the manifold CNS symptoms. A summary of current knowledge pertaining to the neuropathological progression and resultant neuropsychiatric manifestations is also provided, because it should be useful to ERT researchers looking for better approaches to treating CNS lesions in MPS. Full article

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

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19 pages, 1840 KiB

Open AccessReview

Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

by Juan Camilo Losada Díaz, Jacobo Cepeda del Castillo, Edwin Alexander Rodriguez-López and Carlos J. Alméciga-Díaz

Int. J. Mol. Sci. 2020, 21(1), 232; https://doi.org/10.3390/ijms21010232 - 29 Dec 2019

Cited by 20 | Viewed by 5049

Abstract

The mucopolysaccharidoses (MPS) are a group of 11 lysosomal storage diseases (LSDs) produced by mutations in the enzymes involved in the lysosomal catabolism of glycosaminoglycans. Most of the mutations affecting these enzymes may lead to changes in processing, folding, glycosylation, pH stability, protein [...] Read more.

The mucopolysaccharidoses (MPS) are a group of 11 lysosomal storage diseases (LSDs) produced by mutations in the enzymes involved in the lysosomal catabolism of glycosaminoglycans. Most of the mutations affecting these enzymes may lead to changes in processing, folding, glycosylation, pH stability, protein aggregation, and defective transport to the lysosomes. It this sense, it has been proposed that the use of small molecules, called pharmacological chaperones (PCs), can restore the folding, trafficking, and biological activity of mutated enzymes. PCs have the advantages of wide tissue distribution, potential oral administration, lower production cost, and fewer issues of immunogenicity than enzyme replacement therapy. In this paper, we will review the advances in the identification and characterization of PCs for the MPS. These molecules have been described for MPS II, IVA, and IVB, showing a mutation-dependent enhancement of the mutated enzymes. Although the results show the potential of this strategy, further studies should focus in the development of disease-specific cellular models that allow a proper screening and evaluation of PCs. In addition, in vivo evaluation, both pre-clinical and clinical, should be performed, before they can become a real therapeutic strategy for the treatment of MPS patients. Full article

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

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10 pages, 578 KiB

Open AccessCase Report

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

by Praveen Shukla, Christopher C. Dvorak, Janel Long-Boyle and Sandhya Kharbanda

Int. J. Mol. Sci. 2020, 21(16), 5634; https://doi.org/10.3390/ijms21165634 - 06 Aug 2020

Cited by 4 | Viewed by 3544

Abstract

Busulfan is an alkylating agent routinely used in conditioning regimens prior to allogeneic hematopoietic cell transplantation (HCT) for various nonmalignant disorders, including inborn errors of metabolism. The combination of model-based dosing and therapeutic drug monitoring (TDM) of busulfan pharmacokinetics (PK) to a lower [...] Read more.

Busulfan is an alkylating agent routinely used in conditioning regimens prior to allogeneic hematopoietic cell transplantation (HCT) for various nonmalignant disorders, including inborn errors of metabolism. The combination of model-based dosing and therapeutic drug monitoring (TDM) of busulfan pharmacokinetics (PK) to a lower exposure target has the potential to reduce the regimen-related toxicity while opening marrow niches sufficient for engraftment in diseases such as mucopolysaccharidosis type I (MPS I). We present four cases of the severe form of MPS I or Hurler syndrome, demonstrating successful and stable CD14/15 donor chimerism following the prospective application of model-based dosing and TDM aimed to achieve lower busulfan exposure. All patients received a busulfan-based conditioning regimen with a median cumulative area-under-the-curve (cAUC) target of 63.7 mg h/L (range, 62.4 to 65.0) in protocol-specific combination of chemotherapeutic regimen. The donor source was unrelated umbilical cord blood for three patients and matched sibling donor bone marrow for one patient. The observed median busulfan cAUC was 66.1 mg h/L (range, 65.2 to 70.6) and was within 10% of the intended target. Stable, full donor myeloid chimerism was achieved for three patients, while one patient achieved a stable mixed chimerism (76% donor CD14/15 at 53 months) without a recurring need for enzyme replacement. The normalization of α-L-iduronidase enzyme levels followed the attainment of successful donor myeloid chimerism in all patients. Regimen-related toxicity remained low with no evidence of acute graft-versus-host disease (GVHD) grades II to IV and chronic GVHD. Full article

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

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11 pages, 1918 KiB

Open AccessCase Report

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

by Akari Nakamura-Utsunomiya, Toshio Nakamae, Reiko Kagawa, Shuhei Karakawa, Sonoko Sakata, Fumiaki Sakura, Chihiro Tani, Yoshiko Matsubara, Takashi Ishino, Go Tajima and Satoshi Okada

Int. J. Mol. Sci. 2020, 21(3), 989; https://doi.org/10.3390/ijms21030989 - 02 Feb 2020

Cited by 6 | Viewed by 6906

Abstract

Background: Morquio A syndrome, mucopolysaccharidosis type IVA (MPS IVA), is a lysosomal storage disorder caused by the deficient activity of N-acetylgalactosamine-6-sulfatase (GalNac6S), due to alterations in the GALNS gene. This disorder results in marked abnormalities in bones and connective tissues, and affects multiple [...] Read more.

Background: Morquio A syndrome, mucopolysaccharidosis type IVA (MPS IVA), is a lysosomal storage disorder caused by the deficient activity of N-acetylgalactosamine-6-sulfatase (GalNac6S), due to alterations in the GALNS gene. This disorder results in marked abnormalities in bones and connective tissues, and affects multiple organs. Here, we describe the clinical course of a Japanese boy with MPS IVA who began enzyme replacement therapy (ERT) at the age of 24 months. Patient: the patient presented for kyphosis treatment at 22 months of age. An X-ray examination revealed dysostosis multiplex. Uronic acids were elevated in the urine and the keratan sulfate (KS) fraction was predominant. The leukocyte GalNac6S enzyme activity was extremely low. The patient exhibited the c.463G > A (p.Gly155Arg) mutation in GALNS. Based on these findings, his disease was diagnosed as classical (severe) Morquio A syndrome. An elosulfase alfa infusion was initiated at the age of 24 months. The patient’s body height improved from −2.5 standard deviation (SD) to −2 SD and his physical activity increased during the first 9 months on ERT. However, he gradually developed paralysis in the lower legs with declining growth velocity, which required cervical decompression surgery in the second year of the ERT. The mild mitral regurgitation, serous otitis media, and mild hearing loss did not progress during treatment. Conclusion: early initiation of the elosulfase alfa to our patient showed good effects on the visceral system and muscle strength, while its effect on bones appeared limited. Careful observation is necessary to ensure timely surgical intervention for skeletal disorders associated with neurological symptoms. Centralized and multidisciplinary management is essential to improve the prognosis of pediatric patients with MPS IVA. Full article

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

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13 pages, 2500 KiB

Open AccessCase Report

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

by Patricia Dubot, Frédérique Sabourdy, Geneviève Plat, Charlotte Jubert, Claude Cancès, Pierre Broué, Guy Touati and Thierry Levade

Int. J. Mol. Sci. 2019, 20(21), 5345; https://doi.org/10.3390/ijms20215345 - 28 Oct 2019

Cited by 14 | Viewed by 4476

Abstract

We report the case of a boy who was diagnosed with mucopolysaccharidosis (MPS) VII at two weeks of age. He harbored three missense β-glucuronidase (GUSB) variations in exon 3: two novel, c.422A>C and c.424C>T, inherited from his mother, and the rather common [...] Read more.

We report the case of a boy who was diagnosed with mucopolysaccharidosis (MPS) VII at two weeks of age. He harbored three missense β-glucuronidase (GUSB) variations in exon 3: two novel, c.422A>C and c.424C>T, inherited from his mother, and the rather common c.526C>T, inherited from his father. Expression of these variations in transfected HEK293T cells demonstrated that the double mutation c.422A>C;424C>T reduces β-glucuronidase enzyme activity. Enzyme replacement therapy (ERT), using UX003 (vestronidase alfa), was started at four months of age, followed by a hematopoietic stem cell allograft transplantation (HSCT) at 13 months of age. ERT was well tolerated and attenuated visceromegaly and skin infiltration. After a severe skin and gut graft-versus-host disease, ERT was stopped six months after HSCT. The last follow-up examination (at the age of four years) revealed a normal psychomotor development, stabilized growth curve, no hepatosplenomegaly, and no other organ involvement. Intriguingly, enzyme activity had normalized in leukocytes but remained low in plasma. This case report illustrates: (i) The need for an early diagnosis of MPS, and (ii) the possible benefit of a very early enzymatic and/or cellular therapy in this rare form of lysosomal storage disease. Full article

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

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