Mucopolysaccharidosis Type IIIA, and a Child with One SGSH Mutation and One GNS Mutation Is a Carrier
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Epidemiology of Mucopolysaccharidoses Update
diagnostics Review Epidemiology of Mucopolysaccharidoses Update Betul Celik 1,2 , Saori C. Tomatsu 2 , Shunji Tomatsu 1 and Shaukat A. Khan 1,* 1 Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA; [email protected] (B.C.); [email protected] (S.T.) 2 Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA; [email protected] * Correspondence: [email protected]; Tel.: +302-298-7335; Fax: +302-651-6888 Abstract: Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by a lysosomal enzyme deficiency or malfunction, which leads to the accumulation of glycosaminoglycans in tissues and organs. If not treated at an early stage, patients have various health problems, affecting their quality of life and life-span. Two therapeutic options for MPS are widely used in practice: enzyme replacement therapy and hematopoietic stem cell transplantation. However, early diagnosis of MPS is crucial, as treatment may be too late to reverse or ameliorate the disease progress. It has been noted that the prevalence of MPS and each subtype varies based on geographic regions and/or ethnic background. Each type of MPS is caused by a wide range of the mutational spectrum, mainly missense mutations. Some mutations were derived from the common founder effect. In the previous study, Khan et al. 2018 have reported the epidemiology of MPS from 22 countries and 16 regions. In this study, we aimed to update the prevalence of MPS across the world. We have collected and investigated 189 publications related to the prevalence of MPS via PubMed as of December 2020. In total, data from 33 countries and 23 regions were compiled and analyzed. -
Mini-Review on “Molecular Diagnosis of 65 Families With
Mashima R, Okuyama T. J Rare Dis Res Treat. (2016) 2(1): 43-46 Journal of www.rarediseasesjournal.com Rare Diseases Research & Treatment Mini-Review Open Access Mini-review on “Molecular diagnosis of 65 families with mucopoly- saccharidosis type II (Hunter syndrome) characterized by 16 novel mutations in the IDS gene: Genetic, pathological, and structural stud- ies on iduronate-2-sulfatase.” Ryuichi Mashima1* and Torayuki Okuyama1,2 1Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan 2Center for Lysosomal Storage Disorders, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan ABSTRACT Article Info Article Notes Mucopolysaccharidosis type II (MPS II; Hunter syndrome; OMIM #309900) Received: November 29, 2016 is an X-linked congenital disorder characterized by an accumulation of Accepted: December 28, 2016 glycosaminoglycans in the body. Accumulating evidence has suggested that the prevalence of the severe type of MPS II is almost 70%. In addition, novel *Correspondence: mutations that are relevant to MPS II pathogenesis are being increasingly Ryuichi Mashima, Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10- discovered, so the databases of genetic data regarding pathogenic mutations 1 Okura, Setagaya-ku, Tokyo 157-8535, Japan, E-mail: have been growing. We have recently reported a collection of 16 novel [email protected] pathogenic mutations of the iduronate-2-sulfatase (IDS) gene in 65 families with MPS II in a Japanese population1. We also proposed that a homology- © 2016 Ryuichi Mashima. -
Supplementary Materials
1 Supplementary Materials: Supplemental Figure 1. Gene expression profiles of kidneys in the Fcgr2b-/- and Fcgr2b-/-. Stinggt/gt mice. (A) A heat map of microarray data show the genes that significantly changed up to 2 fold compared between Fcgr2b-/- and Fcgr2b-/-. Stinggt/gt mice (N=4 mice per group; p<0.05). Data show in log2 (sample/wild-type). 2 Supplemental Figure 2. Sting signaling is essential for immuno-phenotypes of the Fcgr2b-/-lupus mice. (A-C) Flow cytometry analysis of splenocytes isolated from wild-type, Fcgr2b-/- and Fcgr2b-/-. Stinggt/gt mice at the age of 6-7 months (N= 13-14 per group). Data shown in the percentage of (A) CD4+ ICOS+ cells, (B) B220+ I-Ab+ cells and (C) CD138+ cells. Data show as mean ± SEM (*p < 0.05, **p<0.01 and ***p<0.001). 3 Supplemental Figure 3. Phenotypes of Sting activated dendritic cells. (A) Representative of western blot analysis from immunoprecipitation with Sting of Fcgr2b-/- mice (N= 4). The band was shown in STING protein of activated BMDC with DMXAA at 0, 3 and 6 hr. and phosphorylation of STING at Ser357. (B) Mass spectra of phosphorylation of STING at Ser357 of activated BMDC from Fcgr2b-/- mice after stimulated with DMXAA for 3 hour and followed by immunoprecipitation with STING. (C) Sting-activated BMDC were co-cultured with LYN inhibitor PP2 and analyzed by flow cytometry, which showed the mean fluorescence intensity (MFI) of IAb expressing DC (N = 3 mice per group). 4 Supplemental Table 1. Lists of up and down of regulated proteins Accession No. -
Beta-Galactosidase Deficiency: Beta-Galactosidase Activity, Leukocytes Test Code: LO Turnaround Time: 7 Days - 10 Days CPT Codes: 82657 X1
2460 Mountain Industrial Boulevard | Tucker, Georgia 30084 Phone: 470-378-2200 or 855-831-7447 | Fax: 470-378-2250 eglgenetics.com Beta-Galactosidase Deficiency: Beta-Galactosidase Activity, Leukocytes Test Code: LO Turnaround time: 7 days - 10 days CPT Codes: 82657 x1 Condition Description Beta-galactosidase deficiency is associated with three distinct autosomal recessive lysosomal storage disorders: GM1 gangliosidosis (GM1), mucopolysaccharidosis type IVB (MPS IVB), and galactosialidosis. GM1 and MPS IVB are referred to as GLB1-related disorders as they are the result of biallelic mutations in GLB1. Galactosialidosis is caused by mutations in CTSA (cathepsin A) and results in decreased activity of beta-galactosidase and neuraminidase. Deficiency of beta-galactosidase leads to the accumulation of sphingolipid intermediates in lysosomes of neuronal tissue, resulting in the CNS deterioration typical of GM1. Deficiency of this enzyme also leads to accumulation of the glycosaminoglycan (GAG) keratan sulfate in cartilage which is suspected to cause the skeletal findings associated with MPS IVB. Patients with GM1 have a characteristic abnormal pattern of oligosaccharide elevations in urine detectable by TLC and MALDI-TOF mass spectrometry. Patients with MPS IVB have detectable bands of keratan sulfate by GAG analysis with TLC. Keratan sulfate is also present in MPS IVA and the clinical presentation of MPS IVB is not distinguishable from that of MPS IVA. Patients with galactosialidosis also have characteristic oligosaccharide elevations and decreased neuraminidase 1 enzyme levels. Neuraminidase testing and molecular analysis of CTSA is recommended to confirm a diagnosis of galactosialidosis. Determination of beta-galactosidase levels is not recommended for carrier detection. GM1 gangliosidosis has been classified into three major clinical forms according to the age of onset and severity of symptoms: type I (infantile), type II (late infantile/juvenile) and type III (adult). -
Mucopolysaccharidosis Type II: One Hundred Years of Research, Diagnosis, and Treatment
International Journal of Molecular Sciences Review Mucopolysaccharidosis Type II: One Hundred Years of Research, Diagnosis, and Treatment Francesca D’Avanzo 1,2 , Laura Rigon 2,3 , Alessandra Zanetti 1,2 and Rosella Tomanin 1,2,* 1 Laboratory of Diagnosis and Therapy of Lysosomal Disorders, Department of Women’s and Children ‘s Health, University of Padova, Via Giustiniani 3, 35128 Padova, Italy; [email protected] (F.D.); [email protected] (A.Z.) 2 Fondazione Istituto di Ricerca Pediatrica “Città della Speranza”, Corso Stati Uniti 4, 35127 Padova, Italy; [email protected] 3 Molecular Developmental Biology, Life & Medical Science Institute (LIMES), University of Bonn, 53115 Bonn, Germany * Correspondence: [email protected] Received: 17 January 2020; Accepted: 11 February 2020; Published: 13 February 2020 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 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. -
Towards the Elucidation of Orphan Lysosomal Transporters Quentin Verdon
Towards the Elucidation of Orphan Lysosomal Transporters Quentin Verdon To cite this version: Quentin Verdon. Towards the Elucidation of Orphan Lysosomal Transporters. Cancer. Université Paris Saclay (COmUE), 2016. English. NNT : 2016SACLS144. tel-01827233 HAL Id: tel-01827233 https://tel.archives-ouvertes.fr/tel-01827233 Submitted on 2 Jul 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. NNT : 2016SACLS144 THESE DE DOCTORAT DE L’UNIVERSITE PARIS-SACLAY PREPAREE A L’UNIVERSITE PARIS-SUD ECOLE DOCTORALE N°568 BIOSIGNE | Signalisations et réseaux intégratifs en biologie Spécialité de doctorat : aspects moléculaires et cellulaires de la biologie Par Mr Quentin Verdon Towards the elucidation of orphan lysosomal transporters: several shots on target and one goal Thèse présentée et soutenue à Paris le 29/06/2016 » : Composition du Jury : Mr Le Maire Marc Professeur, Université Paris-Sud Président Mr Birman Serge Directeur de recherche, CNRS Rapporteur Mr Murray James Assistant professor, Trinity college Dublin Rapporteur Mr Goud Bruno Directeur de recherche, CNRS Examinateur Mr Gasnier Bruno Directeur de recherche, CNRS Directeur de thèse Mme Sagné Corinne Chargée de recherche, INSERM Co-directeur de thèse Table of contents Remerciements (acknowledgements) 6 Abbreviations 7 Abstracts 10 Introduction 12 1 Physiology of lysosomes 12 1.1 Discovery and generalities 12 1.2 Degradative function 13 1.3. -
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(19) TZZ¥Z___T (11) EP 3 505 181 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 03.07.2019 Bulletin 2019/27 A61K 38/46 (2006.01) C12N 9/16 (2006.01) (21) Application number: 18248241.4 (22) Date of filing: 28.12.2018 (84) Designated Contracting States: (72) Inventors: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB • DICKSON, Patricia GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Torrance, CA California 90502 (US) PL PT RO RS SE SI SK SM TR • CHOU, Tsui-Fen Designated Extension States: Torrance, CA California 90502 (US) BA ME • EKINS, Sean Designated Validation States: Brooklyn, NY New York 11215 (US) KH MA MD TN • KAN, Shih-Hsin Torrance, CA California 90502 (US) (30) Priority: 28.12.2017 US 201762611472 P • LE, Steven 05.04.2018 US 201815946505 Torrance, CA California 90502 (US) • MOEN, Derek R. (71) Applicants: Torrance, CA California 90502 (US) • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (74) Representative: J A Kemp Torrance, CA 90502 (US) 14 South Square • Phoenix Nest Inc. Gray’s Inn Brooklyn NY 11215 (US) London WC1R 5JJ (GB) (54) PREPARATION OF ENZYME REPLACEMENT THERAPY FOR MUCOPOLYSACCHARIDOSIS IIID (57) The present disclosure relates to compositions for use in a method of treating Sanfilippo syndrome (also known as Sanfilippo disease type D, Sanfilippo D, mu- copolysaccharidosis type IIID, MPS IIID). The method can entail injecting to the spinal fluid of a MPS IIID patient an effective amount of a composition comprising a re- combinant human acetylglucosamine-6-sulfatase (GNS) protein comprising the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 1 and having the en- zymatic activity of the human GNS protein. -
SUMF1 Enhances Sulfatase Activities in Vivo in Five Sulfatase Deficiencies
SUMF1 enhances sulfatase activities in vivo in five sulfatase deficiencies Alessandro Fraldi, Alessandra Biffi, Alessia Lombardi, Ilaria Visigalli, Stefano Pepe, Carmine Settembre, Edoardo Nusco, Alberto Auricchio, Luigi Naldini, Andrea Ballabio, et al. To cite this version: Alessandro Fraldi, Alessandra Biffi, Alessia Lombardi, Ilaria Visigalli, Stefano Pepe, et al.. SUMF1 enhances sulfatase activities in vivo in five sulfatase deficiencies. Biochemical Journal, Portland Press, 2007, 403 (2), pp.305-312. 10.1042/BJ20061783. hal-00478708 HAL Id: hal-00478708 https://hal.archives-ouvertes.fr/hal-00478708 Submitted on 30 Apr 2010 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Biochemical Journal Immediate Publication. Published on 8 Jan 2007 as manuscript BJ20061783 SUMF1 enhances sulfatase activities in vivo in five sulfatase deficiencies Alessandro Fraldi*1, Alessandra Biffi*2,3¥, Alessia Lombardi1, Ilaria Visigalli2, Stefano Pepe1, Carmine Settembre1, Edoardo Nusco1, Alberto Auricchio1, Luigi Naldini2,3, Andrea Ballabio1,4 and Maria Pia Cosma1¥ * These authors contribute equally to this work 1TIGEM, via P Castellino, 111, 80131 Naples, Italy 2San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), H. San Raffaele Scientific Institute, Milan 20132, Italy 3Vita Salute San Raffaele University Medical School, H. -
Bioinformatics Classification of Mutations in Patients with Mucopolysaccharidosis IIIA
Metabolic Brain Disease (2019) 34:1577–1594 https://doi.org/10.1007/s11011-019-00465-6 ORIGINAL ARTICLE Bioinformatics classification of mutations in patients with Mucopolysaccharidosis IIIA Himani Tanwar1 & D. Thirumal Kumar1 & C. George Priya Doss1 & Hatem Zayed2 Received: 30 April 2019 /Accepted: 8 July 2019 /Published online: 5 August 2019 # The Author(s) 2019 Abstract Mucopolysaccharidosis (MPS) IIIA, also known as Sanfilippo syndrome type A, is a severe, progressive disease that affects the central nervous system (CNS). MPS IIIA is inherited in an autosomal recessive manner and is caused by a deficiency in the lysosomal enzyme sulfamidase, which is required for the degradation of heparan sulfate. The sulfamidase is produced by the N- sulphoglucosamine sulphohydrolase (SGSH) gene. In MPS IIIA patients, the excess of lysosomal storage of heparan sulfate often leads to mental retardation, hyperactive behavior, and connective tissue impairments, which occur due to various known missense mutations in the SGSH, leading to protein dysfunction. In this study, we focused on three mutations (R74C, S66W, and R245H) based on in silico pathogenic, conservation, and stability prediction tool studies. The three mutations were further subjected to molecular dynamic simulation (MDS) analysis using GROMACS simulation software to observe the structural changes they induced, and all the mutants exhibited maximum deviation patterns compared with the native protein. Conformational changes were observed in the mutants based on various geometrical parameters, such as conformational stability, fluctuation, and compactness, followed by hydrogen bonding, physicochemical properties, principal component analysis (PCA), and salt bridge analyses, which further validated the underlying cause of the protein instability. Additionally, secondary structure and surrounding amino acid analyses further confirmed the above results indicating the loss of protein function in the mutants compared with the native protein. -
EGL Test Description
2460 Mountain Industrial Boulevard | Tucker, Georgia 30084 Phone: 470-378-2200 or 855-831-7447 | Fax: 470-378-2250 eglgenetics.com Mucopolysaccharidosis Type III: SGSH, GNS, HGSNAT, and NAGLU Gene Deletion/Duplication Panel Test Code: HV Turnaround time: 2 weeks CPT Codes: 81228 x1 Condition Description Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome), is a member of a group of inherited metabolic disorders collectively termed mucopolysaccharidoses (MPS's). The MPS's are caused by a deficiency of lysosomal enzymes required for the degradation of mucopolysaccharides or glycosaminoglycans (GAGs) within the lysosome [1]. When functioning normally, the lysosomal enzymes break down these GAGs, however when the enzyme is deficient, the GAGs build up in the lysosomes causing damage to the body's tissues. The MPS's share a chronic progressive course with multisystem involvement and characteristic physical features such as coarse facies, hypertelorism, and coarse hair. The MPS patients are also characterized by developmental regression, hepatosplenomegaly and characteristic laboratory and radiographic abnormalities. Clinical features of MPS III are similar to other MPS's and include hyperactivity, aggressiveness, and developmental delays in childhood. Mental abilities decline as the disease progresses. Involvement of other organ systems tends to be mild and dysmorphic features are more subtle than those observed in other type of mucopolysaccharidosis [1]. MPS III is caused by a deficiency of any of four lysosomal membrane enzymes, which leads to impaired degradation of heparan sulfate. The forms of MPS III are clinically indistinguishable each other and are caused by mutations in distinct genes. All four forms of MPS III result in buildup of the same GAG, heparin sulfate. -
Newborn Screening for Mucopolysaccharidosis Type II in Illinois: an Update
International Journal of Neonatal Screening Article Newborn Screening for Mucopolysaccharidosis Type II in Illinois: An Update Barbara K. Burton 1,2,*, Rachel Hickey 1 and Lauren Hitchins 1 1 Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA; [email protected] (R.H.); [email protected] (L.H.) 2 Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA * Correspondence: [email protected] Received: 12 August 2020; Accepted: 1 September 2020; Published: 3 September 2020 Abstract: Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is a rare, progressive multisystemic lysosomal storage disorder with significant morbidity and premature mortality. Infants with MPS II develop signs and symptoms of the disorder in the early years of life, yet diagnostic delays are very common. Enzyme replacement therapy is an effective treatment option. It has been shown to prolong survival and improve or stabilize many somatic manifestations of the disorder. Our initial experience with newborn screening in 162,000 infants was previously reported. Here, we update that experience with the findings in 339,269 infants. Measurement of iduronate-2-sulfatase (I2S) activity was performed on dried blood spot samples submitted for other newborn screening disorders. A positive screen was defined as I2S activity less than or equal to 10% of the daily median. In this series, 28 infants had a positive screening test result, and four other infants had a borderline result. Three positive diagnoses of MPS II were established, and 25 were diagnosed as having I2S pseudodeficiency. The natural history and the clinical features of MPS II make it an ideal target for newborn screening. -
Diversity of Mutations and Distribution of Single Nucleotide Polymorphic Alleles in the Human -L-Iduronidase (IDUA) Gene
article November/December 2002 ⅐ Vol. 4 ⅐ No. 6 Diversity of mutations and distribution of single nucleotide polymorphic alleles in the human ␣-L-iduronidase (IDUA) gene Peining Li, PhD1,3, Tim Wood, PhD1,4, and Jerry N. Thompson, PhD1,2 Purpose: Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disorder resulting from a deficiency of the lysosomal glycosidase, ␣-L-iduronidase (IDUA). Patients with MPS I present with variable clinical manifestations ranging from severe to mild. To facilitate studies of phenotype-genotype correlation, the authors performed molecular studies to detect mutations in MPS I patients and characterize single nucleotide polymorphism (SNP) in the IDUA gene. Methods: Twenty-two unrelated MPS I patients were subjects for mutation detection using reverse transcriptional polymerase chain reaction (RT-PCR) and genomic PCR sequencing. Polymorphism analyses were performed on controls by restriction enzyme assays of PCR amplicons flanking nine IDUA intragenic single nucleotide polymorphic alleles. Results: Eleven different mutations including two common mutations (Q70X, W402X), five recurrent mutations (D315Y, P533R, R621X, R628X, S633L), and four novel mutations (R162I, G208D, 1352delG, 1952del25bp) were identified from MPS I patients. Multiple SNP alleles coexisting with the disease-causing mutations were detected. Allelic frequencies for nine SNP alleles including A8, A20, Q33H, L118, N181, A314, A361T, T388, and T410 were determined. Conclusions: The results provide further evidence for the mutational heterogeneity among MPS I patients and point out possible common haplotype structures in the IDUA gene. Genet Med 2002:4(6):420–426. Key Words: mucopolysaccharidosis type I, ␣-L-iduronidase (IDUA) gene, mutations, single nucleotide polymor- phism, haplotype Mucopolysaccharidosis type I (MPS I, MIM 252800) is an and results in lysosomal accumulation and excessive urinary autosomal recessive disorder caused by various lesions in the excretion of partially degraded dermatan sulfate and heparan ␣-L-iduronidase (IDUA) gene.