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Vasilev, Filipp, Aitalina Sukhomyasova, and Takanobu Otomo. "Mucopolysaccharidosis-Plus Syndrome." International Journal of Molecular Sciences 21, no. 2 (January 9, 2020): 421. http://dx.doi.org/10.3390/ijms21020421.
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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.
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Scarpa, Maurizio, Charles Marques Lourenço, and Hernán Amartino. "Epilepsy in mucopolysaccharidosis disorders." Molecular Genetics and Metabolism 122 (December 2017): 55–61. http://dx.doi.org/10.1016/j.ymgme.2017.10.006.
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Kaczor-Kamińska, Marta, Kamil Kamiński, and Maria Wróbel. "Heparan Sulfate, Mucopolysaccharidosis IIIB and Sulfur Metabolism Disorders." Antioxidants 11, no. 4 (March 30, 2022): 678. http://dx.doi.org/10.3390/antiox11040678.
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Mucopolysaccharidosis, type IIIB (MPS IIIB) is a rare disease caused by mutations in the N-alpha-acetylglucosaminidase (NAGLU) gene resulting in decreased or absent enzyme activity. On the cellular level, the disorder is characterized by the massive lysosomal storage of heparan sulfate (HS)—one species of glycosaminoglycans. HS is a sulfur-rich macromolecule, and its accumulation should affect the turnover of total sulfur in cells; according to the studies presented here, it, indeed, does. The lysosomal degradation of HS in cells produces monosaccharides and inorganic sulfate (SO42−). Sulfate is a product of L-cysteine metabolism, and any disruption of its levels affects the entire L-cysteine catabolism pathway, which was first reported in 2019. It is known that L-cysteine level is elevated in cells with the Naglu−/− gene mutation and in selected tissues of individuals with MPS IIIB. The level of glutathione and the Naglu−/− cells’ antioxidant potential are significantly reduced, as well as the activity of 3-mercaptopyruvate sulfurtransferase (MPST, EC 2.8.1.2) and the level of sulfane sulfur-containing compounds. The direct reason is not yet known. This paper attempts to identify some of cause-and-effect correlations that may lead to this condition and identifies research directions that should be explored.
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Baxi, Kalgi, Ashish Jagati, and Pooja Agarwal. "Mucopolysachharidosis-II: A Rare Case Report." Nepal Journal of Dermatology, Venereology & Leprology 18, no. 1 (October 8, 2020): 80–82. http://dx.doi.org/10.3126/njdvl.v18i1.25996.
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Mucopolysaccharidosis belongs to a group of metabolic disorders caused by absence or defective activity of lysosomal enzymes. Mucopolysaccharides are major components of intercellular connective tissue and defect in their metabolism leads to an accumulation of incompletely degraded mucopolysaccharides in the lysosomes which affect various body systems through enzymatic activity. We present a case of mucopolysaccharidosis type II with hallmark cutaneous features, mild mental retardation associated with radiological changes.
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Alden, Tord D., Hernán Amartino, Amauri Dalla Corte, Christina Lampe, Paul R. Harmatz, and Leonardo Vedolin. "Surgical management of neurological manifestations of mucopolysaccharidosis disorders." Molecular Genetics and Metabolism 122 (December 2017): 41–48. http://dx.doi.org/10.1016/j.ymgme.2017.09.011.
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Zapolnik, Paweł, and Antoni Pyrkosz. "Nanoemulsions as Gene Delivery in Mucopolysaccharidosis Type I—A Mini-Review." International Journal of Molecular Sciences 23, no. 9 (April 26, 2022): 4785. http://dx.doi.org/10.3390/ijms23094785.
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Mucopolysaccharidosis type I (MPS I) is a rare monogenic disease in which glycosaminoglycans’ abnormal metabolism leads to the storage of heparan sulfate and dermatan sulfate in various tissues. It causes its damage and impairment. Patients with the severe form of MPS I usually do not live up to the age of ten. Currently, the therapy is based on multidisciplinary care and enzyme replacement therapy or hematopoietic stem cell transplantation. Applying gene therapy might benefit the MPS I patients because it overcomes the typical limitations of standard treatments. Nanoparticles, including nanoemulsions, are used more and more in medicine to deliver a particular drug to the target cells. It allows for creating a specific, efficient therapy method in MPS I and other lysosomal storage disorders. This article briefly presents the basics of nanoemulsions and discusses the current state of knowledge about their usage in mucopolysaccharidosis type I.
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Zapolnik, Paweł, and Antoni Pyrkosz. "Nanoemulsions as Gene Delivery in Mucopolysaccharidosis Type I—A Mini-Review." International Journal of Molecular Sciences 23, no. 9 (April 26, 2022): 4785. http://dx.doi.org/10.3390/ijms23094785.
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Mucopolysaccharidosis type I (MPS I) is a rare monogenic disease in which glycosaminoglycans’ abnormal metabolism leads to the storage of heparan sulfate and dermatan sulfate in various tissues. It causes its damage and impairment. Patients with the severe form of MPS I usually do not live up to the age of ten. Currently, the therapy is based on multidisciplinary care and enzyme replacement therapy or hematopoietic stem cell transplantation. Applying gene therapy might benefit the MPS I patients because it overcomes the typical limitations of standard treatments. Nanoparticles, including nanoemulsions, are used more and more in medicine to deliver a particular drug to the target cells. It allows for creating a specific, efficient therapy method in MPS I and other lysosomal storage disorders. This article briefly presents the basics of nanoemulsions and discusses the current state of knowledge about their usage in mucopolysaccharidosis type I.
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Zahoor, Muhammad Yasir, Huma Arshad Cheema, Sadaqat Ijaz, Muhammad Nadeem Anjum, Khushnooda Ramzan, and Munir Ahmad Bhinder. "Mapping of IDUA gene variants in Pakistani patients with mucopolysaccharidosis type 1." Journal of Pediatric Endocrinology and Metabolism 32, no. 11 (November 26, 2019): 1221–27. http://dx.doi.org/10.1515/jpem-2019-0188.
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Abstract Background Mucopolysaccharidosis type 1 (MPS1) is a rare debilitating multisystem lysosomal disorder resulting due to the deficiency of α-L-iduronidase enzyme (IDUA), caused by recessive mutations in the IDUA gene. Lack or improper amount of the IDUA enzyme results in the improper metabolism of mucopolysaccharides or glycosaminoglycans (GAGs). These large sugar molecules accumulate in lysosomes within cells leading to different systemic complications. The estimated global incidence of MPS1 is 1:100,000 live births for the Hurler and 1:800,000 for the Scheie phenotypes. Methods Thirteen MPS1-affected children from 12 unrelated cohorts were enrolled. All coding and flanking regions of the IDUA gene were sequenced. Bioinformatics tools were used for data analysis and protein prediction for clinical correlations. Results Six IDUA gene mutations were mapped co-segregating with the recessive pattern of inheritance including a novel variant. A novel missense variant c.908T > C (p.L303P) was mapped in two affected siblings in a cohort in the homozygous form. The variant c.1469T > C (p.L490P) was mapped in five unrelated patients and c.784delC (p.H262Tfs*55) was mapped in three unrelated patients, while mutations c.1598C > G (p.P533R), c.314G > A (p.R105Q) and c.1277ins9 (p.[A394-L395-L396]) were mapped in a single patient each. Conclusions Multisystem disorders and a wide range of clinical presentation impede the evaluation of patients as well as make it difficult to differentiate between different phenotypes of MPS. Early and accurate diagnosis is crucial for the disease management and implementation of an expanded new-born genetic screening program for inborn errors of metabolism including MPS1. We recommend c.784delC (p.H262Tfs*55) and c.1469T > C (p.L490P) as first-line genetic markers for the molecular diagnosis of MPS1 in Pakistan.
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De Filippis, Concetta, Barbara Napoli, Laura Rigon, Giulia Guarato, Reinhard Bauer, Rosella Tomanin, and Genny Orso. "Drosophila D-idua Reduction Mimics Mucopolysaccharidosis Type I Disease-Related Phenotypes." Cells 11, no. 1 (December 31, 2021): 129. http://dx.doi.org/10.3390/cells11010129.
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Deficit of the IDUA (α-L-iduronidase) enzyme causes the lysosomal storage disorder mucopolysaccharidosis type I (MPS I), a rare pediatric neurometabolic disease, due to pathological variants in the IDUA gene and is characterized by the accumulation of the undegraded mucopolysaccharides heparan sulfate and dermatan sulfate into lysosomes, with secondary cellular consequences that are still mostly unclarified. Here, we report a new fruit fly RNAi-mediated knockdown model of a IDUA homolog (D-idua) displaying a phenotype mimicking some typical molecular features of Lysosomal Storage Disorders (LSD). In this study, we showed that D-idua is a vital gene in Drosophila and that ubiquitous reduction of its expression leads to lethality during the pupal stage, when the precise degradation/synthesis of macromolecules, together with a functional autophagic pathway, are indispensable for the correct development to the adult stage. Tissue-specific analysis of the D-idua model showed an increase in the number and size of lysosomes in the brain and muscle. Moreover, the incorrect acidification of lysosomes led to dysfunctional lysosome-autophagosome fusion and the consequent block of autophagy flux. A concomitant metabolic drift of glycolysis and lipogenesis pathways was observed. After starvation, D-idua larvae showed a quite complete rescue of both autophagy/lysosome phenotypes and metabolic alterations. Metabolism and autophagy are strictly interconnected vital processes that contribute to maintain homeostatic control of energy balance, and little is known about this regulation in LSDs. Our results provide new starting points for future investigations on the disease’s pathogenic mechanisms and possible pharmacological manipulations.
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Marsden, Deborah, and Harvey Levy. "Newborn Screening of Lysosomal Storage Disorders." Clinical Chemistry 56, no. 7 (July 1, 2010): 1071–79. http://dx.doi.org/10.1373/clinchem.2009.141622.
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Abstract Background: Newborn screening is a state-based public health program established as a means for the early detection and treatment of certain medical conditions to minimize developmental disability and mortality. The program was initiated more than 40 years ago to detect and prevent phenylketonuria. Recent technological advances have expanded the scope of newborn screening to include more than 30 inborn errors of metabolism. Consideration is now being given to inclusion of screening for lysosomal storage disorders (LSDs). Content: Some lysosomal storage disorders (LSDs) express early in infancy or childhood and are treatable. Initiation of treatment in presymptomatic patients or in syptomatic patients before important symptoms are present may improve the long-term outcome. Therefore, early diagnosis is critical. Based on the availability of therapy and development of a screening method, 6 of the more than 40 known LSDs are candidates for newborn screening in the US: Gaucher disease, Pompe disease, Fabry disease, Niemann-Pick disease, mucopolysaccharidosis I, and Krabbe disease. This report reviews the history of newborn screening, the technology that has allowed for expanded screening during the last decade, LSDs and their treatment, and the evolving methods that might allow additional expansion of newborn screening to include certain LSDs. Summary: Recent and evolving technological advances may be implemented for newborn screening for LSDs. This screening will identify presymptomatic newborns, allowing for early treatment and prevention or limitation of morbidity otherwise associated with these inherited rare diseases.
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Singh, Ankur, Rajniti Prasad, and Om Prakash Mishra. "Spectrum of Lysosomal Storage Disorders at Tertiary Centre: Retrospective Case-Record Analysis." Journal of Pediatric Genetics 09, no. 02 (January 2, 2020): 087–92. http://dx.doi.org/10.1055/s-0039-3402070.
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AbstractLysosomal storage disorders (LSDs) are relatively common slow progressive inborn error of metabolism encountered by clinicians. This work intends to highlight the more common LSDs, their clinical presentation, outcome, and mutation (wherever feasible) collected from the genetic clinic at tertiary care center in Eastern Uttar Pradesh. The data for analysis were collected retrospectively from genetic records from a follow-up clinic. All cases < 18 years of age were analyzed. Cases with LSDs with confirmed enzyme results were enrolled in this study. Clinical profile, screening test results, and outcome were collected. There were 32 cases including 27 males and 5 females in this cohort: 8 Gaucher disease (GD) patient and 24 non-GD patients. GD (type 1) is the commonest LSD in GD group. Anemia, thrombocytopenia, splenomegaly, and hepatomegaly were the consistent finding in patients with GD (type 1). L483P mutation was reported in two GD patients. One GD patient is on enzyme replacement therapy for 2 years and is currently doing well. The commonest disorders in non-GD were mucopolysaccharidosis (MPS) (n = 11), metachromatic leukodystrophy (n = 4), I-cell disease (n = 3), Niemann-Pick A/B (n = 3). MPS-II is the commonest MPS among non-GD group.
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Mashima, Ryuichi, Torayuki Okuyama, and Mari Ohira. "Biomarkers for Lysosomal Storage Disorders with an Emphasis on Mass Spectrometry." International Journal of Molecular Sciences 21, no. 8 (April 14, 2020): 2704. http://dx.doi.org/10.3390/ijms21082704.
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Lysosomal storage disorders (LSDs) are characterized by an accumulation of various substances, such as sphingolipids, mucopolysaccharides, and oligosaccharides. The LSD enzymes responsible for the catabolism are active at acidic pH in the lysosomal compartment. In addition to the classically established lysosomal degradation biochemistry, recent data have suggested that lysosome plays a key role in the autophagy where the fusion of autophagosome and lysosome facilitates the degradation of amino acids. A failure in the lysosomal function leads to a variety of manifestations, including neurovisceral disorders. While affected individuals appear to be normal at birth, they gradually become symptomatic in childhood. Biomarkers for each condition have been well-documented and their proper selection helps to perform accurate clinical diagnoses. Based on the natural history of disorders, it is now evident that the existing treatment becomes most effective when initiated during presymptomatic period. Neonatal screening provides such a platform for inborn error of metabolism in general and is now expanding to LSDs as well. These are implemented in some areas and countries, including Taiwan and the U.S. In this short review, we will discuss several issues on some selected biomarkers for LSDs involving Fabry, Niemann–Pick disease type C, mucopolysaccharidosis, and oligosaccharidosis, with a focus on mass spectrometry application to biomarker discovery and detection.
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De Pasquale, Valeria, Marianna Caterino, Michele Costanzo, Roberta Fedele, Margherita Ruoppolo, and Luigi Michele Pavone. "Targeted Metabolomic Analysis of a Mucopolysaccharidosis IIIB Mouse Model Reveals an Imbalance of Branched-Chain Amino Acid and Fatty Acid Metabolism." International Journal of Molecular Sciences 21, no. 12 (June 12, 2020): 4211. http://dx.doi.org/10.3390/ijms21124211.
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Mucopolysaccharidoses (MPSs) are inherited disorders of the glycosaminoglycan (GAG) metabolism. The defective digestion of GAGs within the intralysosomal compartment of affected patients leads to a broad spectrum of clinical manifestations ranging from cardiovascular disease to neurological impairment. The molecular mechanisms underlying the progression of the disease downstream of the genetic mutation of genes encoding for lysosomal enzymes still remain unclear. Here, we applied a targeted metabolomic approach to a mouse model of PS IIIB, using a platform dedicated to the diagnosis of inherited metabolic disorders, in order to identify amino acid and fatty acid metabolic pathway alterations or the manifestations of other metabolic phenotypes. Our analysis highlighted an increase in the levels of branched-chain amino acids (BCAAs: Val, Ile, and Leu), aromatic amino acids (Tyr and Phe), free carnitine, and acylcarnitines in the liver and heart tissues of MPS IIIB mice as compared to the wild type (WT). Moreover, Ala, Met, Glu, Gly, Arg, Orn, and Cit amino acids were also found upregulated in the liver of MPS IIIB mice. These findings show a specific impairment of the BCAA and fatty acid catabolism in the heart of MPS IIIB mice. In the liver of affected mice, the glucose-alanine cycle and urea cycle resulted in being altered alongside a deregulation of the BCAA metabolism. Thus, our data demonstrate that an accumulation of BCAAs occurs secondary to lysosomal GAG storage, in both the liver and the heart of MPS IIIB mice. Since BCAAs regulate the biogenesis of lysosomes and autophagy mechanisms through mTOR signaling, impacting on lipid metabolism, this condition might contribute to the progression of the MPS IIIB disease.
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Eremushkin, M. A., D. I. Otvetchikova, I. N. Otvetchikov, and V. A. Kolyshenkov. "Analysis of the Existing Treatment Methods of Musculoskeletal Disorders in Adult Patients with Mucopolysaccharidosis (Literature Review)." Bulletin of Restorative Medicine 99, no. 5 (October 29, 2020): 101–6. http://dx.doi.org/10.38025/2078-1962-2020-99-5-101-106.
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Need for optimal treatment approaches for adult patients with mucopolysaccharidosis is an urgent problem today. This happened dueto the fact that previously patients with MS rarely lived to adulthood and were observed mainly by pediatricians. But with the evolution of medical technologies and the emergence of modern methods of treatment and rehabilitation of such patients, the number of adult patients with MS is increasing. Clinicians have more and more questions in choosing a strategy for managing each specific clinical case. Currently, a comprehensive approach to treatment allows for the use of a multidisciplinary team to pay due attention to concomitant diseases that occur in patients with impaired GAG metabolism. Due to the rarity of this disease in the modern literature, there are as mall number of publications that cover only certain aspects of the disease, but there are no works devoted to a comprehensive approach to the treatment and rehabilitation of such patients. The analysis of literature data on diagnostics, methods of examination,options for conservative and surgical treatment depending on the type of detected pathology and functional needs of a patient with different types of MS is carried out. Recommendations for testing and evaluating functional status are described, and the most common options for conservative and surgical treatment that take into account specific problems that reduce the patient’s quality of life are presented. It is necessary to study the problem of MPs in adult patients in more detail, as well as to coordinate specialists who have experience in managing patients with metabolic disorders, in order to improve the results of treatment and rehabilitation of patients with this pathology.
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Gaffke, Lidia, Zuzanna Szczudło, Magdalena Podlacha, Zuzanna Cyske, Estera Rintz, Jagoda Mantej, Karolina Krzelowska, Grzegorz Węgrzyn, and Karolina Pierzynowska. "Impaired ion homeostasis as a possible associate factor in mucopolysaccharidosis pathogenesis: transcriptomic, cellular and animal studies." Metabolic Brain Disease 37, no. 2 (December 20, 2021): 299–310. http://dx.doi.org/10.1007/s11011-021-00892-4.
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AbstractMucopolysaccharidoses (MPS) are a group of diseases caused by mutations resulting in deficiencies of lysosomal enzymes which lead to the accumulation of partially undegraded glycosaminoglycans (GAG). This phenomenon causes severe and chronic disturbances in the functioning of the organism, and leads to premature death. The metabolic defects affect also functions of the brain in most MPS types (except types IV, VI, and IX). The variety of symptoms, as well as the ineffectiveness of GAG-lowering therapies, question the early theory that GAG storage is the only cause of these diseases. As disorders of ion homeostasis increasingly turn out to be co-causes of the pathogenesis of various human diseases, the aim of this work was to determine the perturbations related to the maintenance of the ion balance at both the transcriptome and cellular levels in MPS. Transcriptomic studies, performed with fibroblasts derived from patients with all types/subtypes of MPS, showed extensive changes in the expression of genes involved in processes related to ion binding, transport and homeostasis. Detailed analysis of these data indicated specific changes in the expression of genes coding for proteins participating in the metabolism of Ca2+, Fe2+ and Zn2+. The results of tests carried out with the mouse MPS I model (Idua−/−) showed reductions in concentrations of these 3 ions in the liver and spleen. The results of these studies indicate for the first time ionic concentration disorders as possible factors influencing the course of MPS and show them as hypothetical, additional therapeutic targets for this rare disease.
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Moskot, Marta, Joanna Jakóbkiewicz-Banecka, Anna Kloska, Ewa Piotrowska, Magdalena Narajczyk, and Magdalena Gabig-Cimińska. "The Role of Dimethyl Sulfoxide (DMSO) in Gene Expression Modulation and Glycosaminoglycan Metabolism in Lysosomal Storage Disorders on an Example of Mucopolysaccharidosis." International Journal of Molecular Sciences 20, no. 2 (January 14, 2019): 304. http://dx.doi.org/10.3390/ijms20020304.
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Obstacles to effective therapies for mucopolysaccharidoses (MPSs) determine the need for continuous studies in order to enhance therapeutic strategies. Dimethyl sulfoxide (DMSO) is frequently utilised as a solvent in biological studies, and as a vehicle for drug therapy and the in vivo administration of water-insoluble substances. In the light of the uncertainty on the mechanisms of DMSO impact on metabolism of glycosaminoglycans (GAGs) pathologically accumulated in MPSs, in this work, we made an attempt to investigate and resolve the question of the nature of GAG level modulation by DMSO, the isoflavone genistein solvent employed previously by our group in MPS treatment. In this work, we first found the cytotoxic effect of DMSO on human fibroblasts at concentrations above 3%. Also, our results displayed the potential role of DMSO in the regulation of biological processes at the transcriptional level, then demonstrated a moderate impact of the solvent on GAG synthesis. Interestingly, alterations of lysosomal ultrastructure upon DMSO treatment were visible. As there is growing evidence in the literature that DMSO can affect cellular pathways leading to numerous changes, it is important to expand our knowledge concerning this issue.
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Oliveira, Allan Chiaratti de, Amélia Miyashiro Nunes dos Santos, Ana Maria Martins, and Vânia D'Almeida. "Screening for inborn errors of metabolism among newborns with metabolic disturbance and/or neurological manifestations without determined cause." Sao Paulo Medical Journal 119, no. 5 (September 6, 2001): 160–64. http://dx.doi.org/10.1590/s1516-31802001000500002.
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CONTEXT: Inborn Errors of Metabolism are hereditary affections resulting from incompetence in enzymatic reactions of intermediary metabolism. At present, several hundred hereditary metabolic disturbances are known, many of which correspond to severe life-threatening disorders. OBJECTIVE: The early detection of carriers has motivated the screening for these disturbances among newborns at the Neonatal Unit of Hospital São Paulo, in an attempt to initiate support treatment, when available, before clinical manifestations become evident. DESIGN: Prospective study of risk patients. SETTING: Laboratory for Inborn Errors of Metabolism at the Center for Medical Genetics of the Departments of Pediatrics and Morphology of Universidade Federal de São Paulo/Escola Paulista de Medicina.Newborn care unit at a tertiary care hospital. PARTICIPANTS: 101 children admitted into the Neonatal Unit were included in this study by presenting hypoglycemia, metabolic acidosis, jaundice, difficulty in gaining weight, diarrhea, vomiting, hepato- and/or splenomegaly, cataracts, apnea, convulsions, hypo- or hypertonia. DIAGNOSTIC TESTS: Tests routinely utilized, performed for qualitative research of abnormal substances excreted in the urine in situations of metabolic disorder. RESULTS: Children were included in the study mainly because of presenting hypoglycemia, jaundice and metabolic acidosis. Sixty-four newborns presented at least one positive test result. Most of the positivity was due to transitory metabolic alterations of the newborn, such as the case of Transitory Neonatal Tyrosinemia, presented by 29 patients. Nine infants were referred to the Center for Medical Genetics of Universidade Federal de São Paulo for continuation of the diagnostic investigation. For three of them, the tests applied permitted us to formulate a diagnostic hypothesis of mucopolysaccharidosis, tyrosinemia type I and non-ketotic hyperglycinemia, respectively. CONCLUSIONS: The high positivity observed in the tests reflects the newborn's own metabolic immaturity. The selection of 9% of the studied cases for outpatient follow-up confirms that Inborn Errors of Metabolism must be suspected whenever a patient presents metabolic disturbances or neurological manifestations without a determined cause. They should be researched in parallel with the other diagnostic possibilities and not just taken to be exceptional diagnoses.
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Gul, Rutaba, Sabika Firasat, Mulazim Hussain, Muhammad Tufail, Waheed Ahmad, and Kiran Afshan. "Neurological manifestations in Pakistani lysosomal storage disorders patients and molecular characterization of Gaucher disease." Genetika 53, no. 3 (2021): 1017–29. http://dx.doi.org/10.2298/gensr2103017g.
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Lysosomal storage disorders (LSDs) are a large group of inborn errors of metabolism each caused by genetic mutations of a particular lysosomal protein encoding gene. These inherited conditions are characterized by lysosomal dysfunction with wide variety of organ impact sometimes organ failure with growing age. Neurological complications in LSD cases range from severe neurodegenerations in 70% cases to mild symptoms or absence of neuropathy in others. Each LSD is monogenic but heterogeneous from a molecular standpoint with a large number of mutations described in the respective gene. Some mutations are particular to specific populations, reflecting consequences of founder effect. Present study aimed to access the demographic and clinical profiles of forty-five LSD affected families enrolled during January 2018 to December 2019 at local hospitals to find out neurological symptoms in Pakistani LSD cases. Furthermore, molecular genetic analysis of Gaucher?s disease affected families was performed to unveil underlying disease causing mutation/s. Neurological manifestations were present in twenty-eight families including eleven Mucopolysaccharidosis-1 (MPS-I), four Gaucher?s disease (GD) and all MPS-II, MPS-III, Niemann-Pick, Griscelli and Chediak-Higashi cases. Neurological involvement was not found in eight MPS-I, one GD, all MPS-IV and Pycnodysostosis affected families. Screening of GBA gene in GD families revealed a reported missense mutation p.L483P in all analyzed families. Clinical heterogeneity of MPS-1 and GD is evident from literature however mutational analysis of all enrolled GD families depicted segregation of a reported missense variant p.L483P of GBA gene with disease phenotype in all families. Our findings highlight importance of homeostatic role of lysosomes in neuronal development as twenty eight out of forty families had neurological manifestations. Furthermore, identification of same mutation in GD patients with or without neuronal involvement may be related to some unknown differences in the expression of genetic modifiers or exposure to environmental triggers.
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Stepien, Karolina M., Abigail Methley, Ramona Naicker, Kinza Noman, and Cliff Chen. "Implications for neuropsychology assessments in adult mucopolysaccharidosis: A systematic review to inform service development in a large tertiary lysosomal disorders centre." Molecular Genetics and Metabolism 135, no. 2 (February 2022): S116. http://dx.doi.org/10.1016/j.ymgme.2021.11.308.
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Shukla, Praveen, Christopher C. Dvorak, Janel Long-Boyle, and Sandhya Kharbanda. "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." International Journal of Molecular Sciences 21, no. 16 (August 6, 2020): 5634. http://dx.doi.org/10.3390/ijms21165634.
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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.
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Nakamura-Utsunomiya, Akari. "Bone Biomarkers in Mucopolysaccharidoses." International Journal of Molecular Sciences 22, no. 23 (November 23, 2021): 12651. http://dx.doi.org/10.3390/ijms222312651.
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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.
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Rai, Shalu, Deepankar Misra, Akansha Misra, Ankit Jain, Ashish Verma, Dimple Grover, and Ayesha Haris. "A novel approach in diagnosing multiple dentigerous cysts using CBCT illustration indicative of Mucopolysaccharidosis VI – a case report." Journal of Medicine and Life 15, no. 4 (April 2022): 579–86. http://dx.doi.org/10.25122/jml-2021-0288.
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Mucopolysaccharidosis VI is a genetic disorder affecting multiple organs with sundry clinical presentations. The main etiological factor reflects the disturbances in mucopolysaccharide metabolism leading to deposition of acid mucopolysaccharide in various tissues. The pathognomonic features of the disease include a large head, short neck, corneal opacity, open mouth associated with an enlarged tongue, enlargement of the skull, and long anteroposterior dimension with unerupted dentition, dentigerous cyst-like follicles, condylar defects, and gingival hyperplasia. An 18-year-old boy with Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI) is described in this article, emphasizing the oral manifestations and radiographic illustration of lesions in the jaws. It also emphasizes the essential role of cone-beam computed tomography to identify and analyze multicentric pathologies in the jaws.
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Amendum, Paige, Shaukat Khan, Seiji Yamaguchi, Hironori Kobayashi, Yasuhiko Ago, Yasuyuki Suzuki, Betul Celik, et al. "Glycosaminoglycans as Biomarkers for Mucopolysaccharidoses and Other Disorders." Diagnostics 11, no. 9 (August 28, 2021): 1563. http://dx.doi.org/10.3390/diagnostics11091563.
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Glycosaminoglycans (GAGs) are present in proteoglycans, which play critical physiological roles in various tissues. They are known to be elevated in mucopolysaccharidoses (MPS), a group of rare inherited metabolic diseases in which the lysosomal enzyme required to break down one or more GAG is deficient. In a previous study, we found elevation of GAGs in a subset of patients without MPS. In the current study, we aim to investigate serum GAG levels in patients with conditions beyond MPS. In our investigated samples, the largest group of patients had a clinical diagnosis of viral or non-viral encephalopathy. Clinical diagnoses and conditions also included epilepsy, fatty acid metabolism disorders, respiratory and renal disorders, liver disorders, hypoglycemia, developmental disorders, hyperCKemia, myopathy, acidosis, and vomiting disorders. While there was no conclusive evidence across all ages for any disease, serum GAG levels were elevated in patients with encephalopathy and some patients with other conditions. These preliminary findings suggest that serum GAGs are potential biomarkers in MPS and other disorders. In conclusion, we propose that GAGs elevated in blood can be used as biomarkers in the diagnosis and prognosis of various diseases in childhood; however, further designed experiments with larger sample sizes are required.
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Moores, C., J. G. Rogers, I. M. Mckenzie, and T. C. K. Brown. "Anaesthesia for Children with Mucopolysaccharidoses." Anaesthesia and Intensive Care 24, no. 4 (August 1996): 459–63. http://dx.doi.org/10.1177/0310057x9602400408.
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The mucopolysaccharidoses are a group of inherited disorders of metabolism, with varying clinical manifestations. A number of them present anaesthetic difficulties. This paper presents a summary table of the syndromes and reviews our experience over ten years with patients with these diagnoses. The clinical presentations, anaesthetic management, and complications are described. The effect of age and diagnosis on airway difficulties was studied. There were 31 patients, 28 of whom required anaesthesia, on a total of 99 occasions, for 115 procedures. The patients with Hunter, Hurler and Maroteaux-Lamy syndromes had significantly more airway difficulties as they grew older, and compared with patients in this group with other syndromes. Patients with Hurler's syndrome may have coronary artery involvement and one patient was given fentanyl and pancuronium for this reason. He proved impossible to intubate and an emergency tracheostomy was performed.
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Çakar, Nafiye Emel, and Pınar Yilmazbaş. "Cases of inborn errors of metabolism diagnosed in children with autism." Ideggyógyászati szemle 74, no. 1-2 (2021): 67–72. http://dx.doi.org/10.18071/isz.74.0067.
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Autism spectrum disorder is a neurodevelopmental disorder with a heterogeneous presentation, the etiology of which is not clearly elucidated. In recent years, comorbidity has become more evident with the increase in the frequency of autism and diagnostic possibilities of inborn errors of metabolism. One hundred and seventy-nine patients with diagnosis of autism spectrum disorder who presented to the Pediatric Metabolism outpatient clinic between 01/September/2018-29/February/2020 constituted the study population. The personal information, routine and specific metabolic tests of the patients were analyzed retrospectively. Out of the 3261 patients who presented to our outpatient clinic, 179 (5.48%) were diagnosed with autism spectrum disorder and were included in the study. As a result of specific metabolic examinations performed, 6 (3.3%) patients were diagnosed with inborn errors of metabolism. Two of our patients were diagnosed with classical phenylketonuria, two with classical homocystinuria, one with mucopolysaccharidosis type 3D (Sanfilippo syndrome) and one with 3-methylchrotonyl Co-A carboxylase deficiency. Inborn errors of metabolism may rarely present with autism spectrum disorder symptoms. Careful evaluation of the history, physical examination and additional findings in patients diagnosed with autism spectrum disorder will guide the clinician in the decision-making process and chose the appropriate specific metabolic investigation. An underlying inborn errors of metabolism may be a treatable cause of autism.
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Leistner, Sandra, and Roberto Giugliani. "A useful routine for biochemical detection and diagnosis of mucopolysaccharidoses." Genetics and Molecular Biology 21, no. 1 (March 1998): 163–67. http://dx.doi.org/10.1590/s1415-47571998000100028.
Full textAbstract:
Mucopolysaccharidoses (MPS) constitute, owing to their biochemical, genetical and clinical characteristics, a large and heterogeneous subgroup among the lysosomal storage diseases (LSD). They are caused by deficiency of specific enzymes, which are responsible for glycosaminoglycan (GAG) breakdown during different steps of its degradation pathway. MPS are responsible for about 32% of inborn errors of metabolism (IEM) and 54% of LSD identified in our laboratory (Regional Laboratory of Inborn Errors of Metabolism (RLIEM), Medical Genetics Unit, Hospital de Clínicas in Porto Alegre), which is a reference center for LSD diagnosis in Brazil. Therefore, we decided to set up a specific laboratory routine for detection and differential diagnosis of MPS in patients with clinical features suggestive of this group of disorders
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Bhuiyan, AKM Motiur Rahman, Maftahul Jannat, Md Zilan Miah Sarker, Mohammad Tanvir Islam, and Amit Roy Chowdhury. "A 16-year-old Girl with Morquio Syndrome: A Case Report." BIRDEM Medical Journal 8, no. 3 (September 10, 2018): 266–69. http://dx.doi.org/10.3329/birdem.v8i3.38137.
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Morquio syndrome is a rare autosomal recessive disorder of mucopolysaccharide metabolism, also called mucopolysaccharidosis type IV. We report a case of Morquio syndrome in a16-year- old girl of normal intelligence, who got herself admitted in Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh. The patient had short stature and skeletal deformity and she belonged to a non-consanguineous marriage of her parents. She was diagnosed on the basis of clinical features, typical radiological changes and positive urinary mucopolysaccharide screening test.Birdem Med J 2018; 8(3): 266-269
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Węsierska, Magdalena, Anna Kloska, Diego L. Medina, Joanna Jakóbkiewicz-Banecka, Magdalena Gabig-Cimińska, Marta Radzińska, Marta Moskot, and Marcelina Malinowska. "Cellular and Gene Expression Response to the Combination of Genistein and Kaempferol in the Treatment of Mucopolysaccharidosis Type I." International Journal of Molecular Sciences 23, no. 3 (January 19, 2022): 1058. http://dx.doi.org/10.3390/ijms23031058.
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Flavonoids are investigated as therapeutics for mucopolysaccharidosis, a metabolic disorder with impaired glycosaminoglycan degradation. Here we determined the effects of genistein and kaempferol, used alone or in combination, on cellular response and gene expression in a mucopolysaccharidosis type I model. We assessed the cell cycle, viability, proliferation, subcellular localization of the translocation factor EB (TFEB), number and distribution of lysosomes, and glycosaminoglycan synthesis after exposure to flavonoids. Global gene expression was analysed using DNA microarray and quantitative PCR. The type and degree of flavonoid interaction were determined based on the combination and dose reduction indexes. The combination of both flavonoids synergistically inhibits glycosaminoglycan synthesis, modulates TFEB localization, lysosomal number, and distribution. Genistein and kaempferol in a 1:1 ratio regulate the expression of 52% of glycosaminoglycan metabolism genes. Flavonoids show synergy, additivity, or slight antagonism in all analysed parameters, and the type of interaction depends on the concentration and component ratios. With the simultaneous use of genistein and kaempferol in a ratio of 4:1, even a 10-fold reduction in the concentration of kaempferol is possible. Flavonoid mixtures, used as the treatment of mucopolysaccharidosis, are effective in reducing glycosaminoglycan production and storage and show a slight cytotoxic effect compared to single-flavonoid usage.
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Albano, Lilian M. J., Sofia S. M. M. Sugayama, Débora R. Bertola, Carlos E. F. Andrade, Cláudia Y. Utagawa, Flávia Puppi, Helena B. Nader, et al. "Clinical and laboratorial study of 19 cases of mucopolysaccharidoses." Revista do Hospital das Clínicas 55, no. 6 (December 2000): 213–18. http://dx.doi.org/10.1590/s0041-87812000000600004.
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The mucopolysaccharidoses (MPS) are a heterogeneous group of inborn errors of lysosomal glycosaminoglycan (GAG) metabolism. The importance of this group of disorders among the inborn errors of metabolism led us to report 19 cases. METHOD: We performed clinical, radiological, and biochemical evaluations of the suspected patients, which allowed us to establish a definite diagnosis in 19 cases. RESULTS: Not all patients showed increased GAG levels in urine; enzyme assays should be performed in all cases with strong clinical suspicion. The diagnosis was made on average at the age of 48 months, and the 19 MPS cases, after a full clinical, radiological, and biochemical study, were classified as follows: Hurler -- MPS I (1 case); Hunter -- MPS II (2 cases); Sanfilippo -- MPS III (2 cases); Morquio -- MPS IV (4 cases); Maroteaux-Lamy -- MPS VI (9 cases); and Sly -- MPS VII (1 case). DISCUSSION: The high relative frequency of Maroteaux-Lamy disease contrasts with most reports in the literature and could express a population variability.
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Sheikh, Sadaf Saleem, Dipak Kumar Yadav, and Ayesha Saeed. "Case Report: Hurler syndrome (Mucopolysaccharidosis Type 1) in a young female patient." F1000Research 9 (May 15, 2020): 367. http://dx.doi.org/10.12688/f1000research.23532.1.
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Hurler syndrome is a rare autosomal recessive disorder of mucopolysaccharide metabolism. Here, we present the case of a young female patient who presented with features of respiratory distress. In addition, the patient had gingival hypertrophy, spaced dentition, misaligned eruptive permanent dentition, microdontia, coarse facial features, low set ears, depressed nasal bridge, distended abdomen, pectus carinatum, umbilical hernia and J-shaped Sella Turcica on an X-ray of the skull. A diagnosis of Hurler syndrome (Mucopolysaccharidosis Type I) was made. The patient was kept on ventilator support from the third day; however, she died on the fifth day of admission. Enzyme replacement modality of treatment can increase a patient's survival rate if an early diagnosis can be made. To the best of our knowledge, only a few cases of Hurler syndrome have been reported in Pakistan.
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Mungai, L. N. Wainaina, C. M. Njeru, L. A. Nyamai, and M. Maina. "Mucopolysaccharidosis Type II: A Kenyan Case Series." International Journal of Endocrinology 2021 (December 22, 2021): 1–4. http://dx.doi.org/10.1155/2021/2328402.
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Hunter syndrome, or mucopolysaccharidosis type 2 (MPS2), is a lysosomal storage disorder associated with the involvement of multiple organs such as the central nervous system, hepatomegaly, musculoskeletal, respiratory, cardiac, and hearing. This is due to the accumulation of glycosaminoglycans in body tissues leading to organ failure. Since the laboratories in Kenya do not screen for metabolic diseases, there is the likelihood of assumption that these patients do not exist. These first cases were referred from the eastern part of Kenya where the majority of inhabitants are from the same ethnic community. It was noted that there was increased mortality among boys below the age of 20 years, and hence, the families sought for help in the national referral and teaching hospital. The case series is meant to show that these cases exist and the majority of the patients may be dying before the diagnosis is made. There are no data on MPS2 from Kenya, and the prevalence and incidence are unknown. In this retrospective study, we present a case series of 6 Kenyan boys with MPS2 from a national referral hospital. They were part of 17 patients who had had their blood analyzed for metabolic diseases. All of them were symptomatic with varying degrees of central nervous system involvement. They had undetectable levels of iduronate-2-sulfatase (I2S) enzyme, and three genetic mutations were detected in the IDS gene.
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Draïss, Ghizlane, Adil Fouad, Nourddine Rada, Ouafa Hocar, Naima Fdil, and Mohamed Bouskraoui. "Infantile GM1-Gangliosidosis Revealed by Slate-Grey Mongolian Spots." Open Pediatric Medicine Journal 9, no. 1 (January 31, 2019): 1–4. http://dx.doi.org/10.2174/1874309901909010001.
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Introduction: GM1-gangliosidosis is an inherited metabolic disease caused by mutations in the GLB1 gene resulting in deficiency of β-galactosidase. Three forms have been identified: Infantile, juvenile, and adult. The infantile type progresses rapidly and aggressively and a delayed diagnosis hampers the prevention of many neurological deficits. This delay in diagnosis may be due to the variability of clinical expression of the disorder. Hypothesis: Extensive Mongolian or slate-grey spots deserve special attention as possible indications of associated inborn errors of metabolism, especially GM1-gangliosidosis and mucopolysaccharidosis. Only symptomatic treatments are available for GM1-gangliosidosis; research is underway. Observation: In this article, we report a case of infantile GM1-gangliosidosis revealed by slate-grey Mongolian spots, a rare condition in Morocco, and a review of the literature. Conclusion: The finding of persistent and extensive slate-grey mongolian spots in infant could lead to early detection of GM1-gangliosidosis before irreversible organ damage occurs.
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De Ponti, Giada, Samantha Donsante, Marta Frigeni, Alice Pievani, Alessandro Corsi, Maria Ester Bernardo, Mara Riminucci, and Marta Serafini. "MPSI Manifestations and Treatment Outcome: Skeletal Focus." International Journal of Molecular Sciences 23, no. 19 (September 22, 2022): 11168. http://dx.doi.org/10.3390/ijms231911168.
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Mucopolysaccharidosis type I (MPSI) (OMIM #252800) is an autosomal recessive disorder caused by pathogenic variants in the IDUA gene encoding for the lysosomal alpha-L-iduronidase enzyme. The deficiency of this enzyme causes systemic accumulation of glycosaminoglycans (GAGs). Although disease manifestations are typically not apparent at birth, they can present early in life, are progressive, and include a wide spectrum of phenotypic findings. Among these, the storage of GAGs within the lysosomes disrupts cell function and metabolism in the cartilage, thus impairing normal bone development and ossification. Skeletal manifestations of MPSI are often refractory to treatment and severely affect patients’ quality of life. This review discusses the pathological and molecular processes leading to impaired endochondral ossification in MPSI patients and the limitations of current therapeutic approaches. Understanding the underlying mechanisms responsible for the skeletal phenotype in MPSI patients is crucial, as it could lead to the development of new therapeutic strategies targeting the skeletal abnormalities of MPSI in the early stages of the disease.
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Torres, Danielle de Araujo, Anneliese Lopes Barth, Mariana Pires de Mello Valente, Paulo Pires de Mello, and Dafne Dain Gandelman Horovitz. "Otolaryngologists and the Early Diagnosis of Mucopolysaccharidoses: A Cross-Sectional Study." Diagnostics 9, no. 4 (November 13, 2019): 187. http://dx.doi.org/10.3390/diagnostics9040187.
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Mucopolysaccharidoses (MPS) are a group of inborn errors of metabolism with an aggressive and usually fatal course. Therefore, early treatment is essential because the involvement of head and neck structures is almost always present in MPS. Our study aimed to retrospectively assess—via a chart review and a survey of caregivers—the history of ear, nose and throat (ENT) symptoms, the number of otolaryngology visits prior to diagnosis, and whether otolaryngologists diagnosed the disease in a cohort of MPS patients followed at an academic medical center. Twenty-three patients were evaluated. Age at diagnosis ranged from 0.2 to 33.0 years (median, 3.2 years). Prior to being diagnosed with MPS, 20/23 (87%) patients presented with at least one episode of otalgia, airway disorder, sleep disturbance, speech delay or suspected hearing loss. One patient had an adenotonsillectomy with paracentesis of tympanic membranes. Ten of the 23 patients (43%) were seen by an otolaryngologist before the diagnosis of MPS, none of which had the disease suspected during these visits. Notwithstanding limitations, our results suggest that increased awareness of MPS among otolaryngologists may allow for earlier diagnosis and better management of these patients.
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Melit, Lorena Elena, Oana Marginean, Carmen Duicu, Cristina Campean, and Maria Oana Marginean. "A RARE CASE OF HUNTER SYNDROME – CASE REPORT." Romanian Journal of Pediatrics 64, no. 1 (March 31, 2015): 38–41. http://dx.doi.org/10.37897/rjp.2015.1.8.
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Mucopolysaccharidoses (MPSs) are a group of rare genetic disorders within the larger family of lysosomal diseases. MPSs disorders are caused by a deficiency in the activity of a specific lysosomal enzyme required for the degradation of glycosaminoglycans (GAGs). MPS type II, also called Hunter syndrome consists in a deficiency of an enzyme, iduronate-2-sulphatase. We present a rare case of Hunter syndrome with atypical presentation. It is a case about a boy of 2.7 year old who presented to the Paediatric Clinic with symptoms of a respiratory tract infection and a history of frequent ear infections and respiratory tract infections. His clinical examination showed the following abnormalities: high stature, moderately overweight, facial dysmorphism (coarse facial features, prominent forehead, a depressed nasal bridge), small stubby fingers with flexion of distal interphalangeal joints, joint stiffness, protruding abdomen with umbilical hernia, hepatomegaly and splenomegaly, and also mild mental retardation. The clinical aspect was suggestive for MPS type I, II or VII. Dosage of enzymes with role in mucopolysaccharide lysosomal metabolism revealed low levels of iduronate-2-sulphatase, changes that bent for MPS type II. Enzymatic diagnosis was confirmed by molecular DNA analysis that showed a hemizygote mutation of iduronate2-sulphatase gene in intron 3 (c.419-2A > G). Enzyme replacement therapy with recombinant human iduronate2-sulfatase (Elaprase®) was started. The evolution of the case after almost two years of treatment with Elaprase is favorably, without loss of neurological acquisitions.
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Zubaida, Bibi, Hajira Batool, Huma Arshad Cheema, Nadia Waheed, and Muhammad Naeem. "Novel IDS Variants Identified in Three Unrelated Pakistani Patients Affected with Mucopolysaccharidosis Type II (Hunter Syndrome)." Human Heredity 84, no. 6 (2019): 279–86. http://dx.doi.org/10.1159/000510065.
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<b><i>Introduction:</i></b> Mucopolysaccharidosis type II (MPS-II) or Hunter syndrome is a rare X-linked recessive disorder caused by genetic lesions in the IDS gene, encoding the iduronate-2-sulfatase (IDS) enzyme, disrupting the metabolism of certain sulfate components of the extracellular matrix. Thus, the undegraded components, also known as glycosaminoglycans, accumulate in multiple tissues resulting in multisystemic abnormalities. <b><i>Objective:</i></b> To uncover causative genetic lesions in probands of three unrelated Pakistani families affected with rare X-linked recessive Hunter syndrome. <b><i>Methods:</i></b> Screening of the IDS gene was performed in six individuals (three patients and their mothers) through whole genomic DNA extraction from peripheral blood followed by PCR and Sanger sequencing. MutationTaster, PROVEAN, Human Splicing Finder, Swiss-Model, and SwissPdbViewer were used for in silico analysis of identified variants. <b><i>Results:</i></b> All probands were presented with coarse facies, recurrent respiratory tract infection, and reduced IDS activity. Molecular screening of IDS identified three different pathogenic variants including a novel duplication variant c.114_117dupCGTT, a novel splice site variant c.1006 + 1G>C, and a nonsense variant c.1165C>T. In silico analysis unanimously revealed the pathogenic nature of the variants due to their deleterious effects upon the encoded enzyme. <b><i>Conclusion:</i></b> Identified variants predictably lead to either the expression of a nonfunctional enzyme due to partial loss of SD1 and complete loss of SD2 subdomains or a complete lack of the IDS enzyme as a result of nonsense-mediated mRNA decay. Our study provides the first genetic depiction of MPS-II in Pakistan, expands the global IDS mutation spectrum, may provide insights into the three-dimensional structure of IDS, and should benefit the affected families in genetic counseling and prenatal diagnosis.
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Xia, Haibin, Brian Anderson, Qinwen Mao, and Beverly L. Davidson. "Recombinant Human Adenovirus: Targeting to the Human Transferrin Receptor Improves Gene Transfer to Brain Microcapillary Endothelium." Journal of Virology 74, no. 23 (December 1, 2000): 11359–66. http://dx.doi.org/10.1128/jvi.74.23.11359-11366.2000.
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ABSTRACT Some inborn errors of metabolism due to deficiencies of soluble lysosomal enzymes cause global neurodegenerative disease. Representative examples include the infantile and late infantile forms of the ceroid lipofuscinoses (CLN1 or CLN2 deficiency, respectively) and mucopolysaccharidoses type VII (MPS VII), a deficiency of β-glucuronidase. Treatment of the central nervous system component of these disorders will require widespread protein or enzyme replacement, either through dissemination of the protein or through dissemination of a gene encoding it. We hypothesize that transduction of brain microcapillary endothelium (BME) with recombinant viral vectors, with secretion of enzyme product basolaterally, could allow for widespread enzyme dissemination. To achieve this, viruses should be modified to target the BME. This requires (i) identification of a BME-resident target receptor, (ii) identification of motifs targeted to that molecule, (iii) the construction of modified viruses to allow for binding to the target receptor, and (iv) demonstrated transduction of receptor-expressing cells. In proof of principal experiments, we chose the human transferrin receptor (hTfR), a molecule found at high density on human BME. A nonamer phage display library was panned for motifs which could bind hTfR. Forty-three clones were sequenced, most of which contained an AKxxK/R, KxKxPK/R, or KxK motif. Ten peptides representative of the three motifs were cloned into the HI loop of adenovirus type 5 fiber. All motifs tested retained their ability to trimerize and bind transferrin receptor, and seven allowed for recombinant adenovirus production. Importantly, the fiber-modified viruses facilitated increased gene transfer (2- to 34-fold) to hTfR expressing cell lines and human brain microcapillary endothelia expressing high levels of endogenous receptor. Our data indicate that adenoviruses can be modified in the HI loop for expanded tropism to the hTfR.
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De Risi, Maria, Michele Tufano, Filomena Grazia Alvino, Maria Grazia Ferraro, Giulia Torromino, Ylenia Gigante, Jlenia Monfregola, et al. "Altered heparan sulfate metabolism during development triggers dopamine-dependent autistic-behaviours in models of lysosomal storage disorders." Nature Communications 12, no. 1 (June 9, 2021). http://dx.doi.org/10.1038/s41467-021-23903-5.
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AbstractLysosomal storage disorders characterized by altered metabolism of heparan sulfate, including Mucopolysaccharidosis (MPS) III and MPS-II, exhibit lysosomal dysfunctions leading to neurodegeneration and dementia in children. In lysosomal storage disorders, dementia is preceded by severe and therapy-resistant autistic-like symptoms of unknown cause. Using mouse and cellular models of MPS-IIIA, we discovered that autistic-like behaviours are due to increased proliferation of mesencephalic dopamine neurons originating during embryogenesis, which is not due to lysosomal dysfunction, but to altered HS function. Hyperdopaminergia and autistic-like behaviours are corrected by the dopamine D1-like receptor antagonist SCH-23390, providing a potential alternative strategy to the D2-like antagonist haloperidol that has only minimal therapeutic effects in MPS-IIIA. These findings identify embryonic dopaminergic neurodevelopmental defects due to altered function of HS leading to autistic-like behaviours in MPS-II and MPS-IIIA and support evidence showing that altered HS-related gene function is causative of autism.
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Conijn, Thirsa, Lotte Haverman, Frits A. Wijburg, and Carlijn De Roos. "Reducing posttraumatic stress in parents of patients with a rare inherited metabolic disorder using eye movement desensitization and reprocessing therapy: a case study." Orphanet Journal of Rare Diseases 16, no. 1 (March 10, 2021). http://dx.doi.org/10.1186/s13023-021-01768-7.
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AbstractParents of children with severe inborn errors of metabolism frequently face stressful events related to the disease of their child and are consequently at high risk for developing parental posttraumatic stress disorder (PTSD). Assessment and subsequent treatment of PTSD in these parents is however not common in clinical practice. PTSD can be effectively treated by Eye Movement Desensitization and Reprocessing (EMDR), however no studies have been conducted yet regarding the effect of EMDR for parental PTSD. EMDR is generally offered in multiple weekly sessions which may preclude participation of parents as they are generally overburdened by the ongoing and often intensive care for their child. Therefore, we offered time-limited EMDR with a maximum of four sessions over two subsequent days to two parents of mucopolysaccharidosis type III (MPS III) patients to explore its potential effects. Both qualitative and quantitative outcomes were used to evaluate treatment effects. Both parents felt more resilient and competent to face future difficulties related to the disease of their child, and no adverse effects were reported. Quantitative outcomes showed a clinically significant decrease in post traumatic stress symptoms and comorbid psychological distress from pre- to post treatment, and these beneficial effects were maintained at follow-up. In conclusion, time-limited EMDR may be a highly relevant treatment for traumatized parents of children with MPS III, and probably also for parents of children with other rare progressive disorders. Further research is needed to validate the efficacy of EMDR in this specific population.
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Chen, Cliff, Abigail Methley, Ramona Naicker, Stewart Rust, and Karolina M. Stepien. "Neuropsychology assessment and outcomes in adult mucopolysaccharidosis – A systematic review as the first step to service development in a large tertiary lysosomal storage disorders centre." Molecular Genetics and Metabolism, December 2022, 106980. http://dx.doi.org/10.1016/j.ymgme.2022.106980.
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Kong, Weijing, Shanshan Wu, Jing Zhang, Cheng Lu, Yingxue Ding, and Yan Meng. "Global epidemiology of mucopolysaccharidosis type III (Sanfilippo syndrome): an updated systematic review and meta-analysis." Journal of Pediatric Endocrinology and Metabolism, July 16, 2021. http://dx.doi.org/10.1515/jpem-2020-0742.
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Abstract Objectives Mucopolysaccharidosis III, an autosomal recessive lysosomal storage disorder, is characterized by progressive mental retardation and behavioral problems. Meta-analysis of global mucopolysaccharidosis III epidemiology, which serves as a fundamental reference for public health decision-making, was not available prior to this study. To provide a systematic review and meta-analysis of birth prevalence of mucopolysaccharidosis III in multiple countries. Methods MEDLINE and EMBASE databases were searched for original research articles on the epidemiology of mucopolysaccharidosis III from inception until 1st July, 2020. A checklist adapted from STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) was used to assess the quality of all studies involved. Meta-analysis, adopting a random effects logistic model, was performed to estimate pooled birth prevalence of mucopolysaccharidosis III and its subtypes. Results Twenty-five studies screened out of 1,826 records were included for data extraction. The pooled global mucopolysaccharidosis III birth prevalence was 0.76 cases (95% CI: 0.57–0.96) per 100,000 live births. The pooled global birth prevalence of mucopolysaccharidosis III subtypes (A, B, and C) was 0.52 cases (95% CI: 0.33–0.72), 0.21 cases (95% CI: 0.12–0.30) and 0.01 cases (95% CI: 0.005–0.02) per 100,000 live births, respectively. Conclusions Based on the global population size (7.8 billion) and the life span of patients, there would be 12–19 thousand mucopolysaccharidosis III patients worldwide. To our knowledge, this is the first comprehensive systematic review that presented quantitative data fundamental for evidence-based public health decision-making by evaluating global epidemiology of mucopolysaccharidosis III.
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Broeders, M., Jgj van Rooij, E. Oussoren, Tjm van Gestel, Ca Smith, Sj Kimber, Rm Verdijk, et al. "Modeling cartilage pathology in mucopolysaccharidosis VI using iPSCs reveals early dysregulation of chondrogenic and metabolic gene expression." Frontiers in Bioengineering and Biotechnology 10 (December 6, 2022). http://dx.doi.org/10.3389/fbioe.2022.949063.
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Mucopolysaccharidosis type VI (MPS VI) is a metabolic disorder caused by disease-associated variants in the Arylsulfatase B (ARSB) gene, resulting in ARSB enzyme deficiency, lysosomal glycosaminoglycan accumulation, and cartilage and bone pathology. The molecular response to MPS VI that results in cartilage pathology in human patients is largely unknown. Here, we generated a disease model to study the early stages of cartilage pathology in MPS VI. We generated iPSCs from four patients and isogenic controls by inserting the ARSB cDNA in the AAVS1 safe harbor locus using CRISPR/Cas9. Using an optimized chondrogenic differentiation protocol, we found Periodic acid–Schiff positive inclusions in hiPSC-derived chondrogenic cells with MPS VI. Genome-wide mRNA expression analysis showed that hiPSC-derived chondrogenic cells with MPS VI downregulated expression of genes involved in TGF-β/BMP signalling, and upregulated expression of inhibitors of the Wnt/β-catenin signalling pathway. Expression of genes involved in apoptosis and growth was upregulated, while expression of genes involved in glycosaminoglycan metabolism was dysregulated in hiPSC-derived chondrogenic cells with MPS VI. These results suggest that human ARSB deficiency in MPS VI causes changes in the transcriptional program underlying the early stages of chondrogenic differentiation and metabolism.
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Tummolo, Albina, Giacomina Brunetti, Laura Piacente, Antonio Marzollo, Alessandra Biffi, Alberto Burlina, and Maria Felicia Faienza. "Bone Remodeling in a Mps-1h Girl after Hematopoietic Stem Cell Transplantation along with Enzymatic Replacement Therapy." Endocrine, Metabolic & Immune Disorders - Drug Targets 22 (May 20, 2022). http://dx.doi.org/10.2174/1871530322666220520121839.
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Background: Mucopolysaccharidosis-1H (Hurler syndrome, MPS-1H) is the most severe form of a lysosomal storage disorder (LSD) caused by variants in IDUA, encoding alpha-L-iduronidase (IDUA). MPS-1H is also associated with various degree of skeletal defects due to the accumulation of partially degraded glycosaminoglycans (GAGs) in the lysosomes of connective tissue cells. The efficacy of hematopoietic stem cell transplantation (HSCT) and enzymatic replacement therapy (ERT) on MPS-1H skeletal manifestations are still considered not satisfactory. Case presentation: We report the case of a young girl, who manifested significant changes in bone remodeling markers and osteoclastogenesis potential after HSCT combined with ERT. She received ERT and underwent two HSCT. The skeletal alterations at the time of diagnosis, showed a trend toward improvement of both mobility and radiological features after HSCT. We observed the highest levels of Receptor activator of nuclear factor kappa-Β ligand (RANKL) and RANK/osteoprotegerin (OPG) ratio at diagnosis and during ERT, consistently with a spontaneous osteoclastogenesis. Conversely, after the successful HSCT with ongoing ERT, the highest levels of osteocalcin were observed and all markers of bone formation and resorption improved. Conclusion: The combination therapy of ERT and HSCT was effective in reduction of osteoclast activity and increasing osteoblast activity, and these changes were in keeping with the child's bone phenotype, IDUA activity and glycosaminoglycan (GAG) trends. These results represent one of the few human evidences in this context.