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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. -
Carrier Screening for Genetic Diseases Policy Number: PG0442 ADVANTAGE | ELITE | HMO Last Review: 07/25/2019
Carrier Screening for Genetic Diseases Policy Number: PG0442 ADVANTAGE | ELITE | HMO Last Review: 07/25/2019 INDIVIDUAL MARKETPLACE | PROMEDICA MEDICARE PLAN | PPO GUIDELINES This policy does not certify benefits or authorization of benefits, which is designated by each individual policyholder contract. Paramount applies coding edits to all medical claims through coding logic software to evaluate the accuracy and adherence to accepted national standards. This guideline is solely for explaining correct procedure reporting and does not imply coverage and reimbursement. SCOPE X Professional X Facility DESCRIPTION Carrier screening is testing asymptomatic individuals to identify those who are heterozygous for serious or lethal single-gene disorders with the purpose of informing the risk of conceiving an affected child. Risk-based carrier screening is performed in individuals having an increased risk based on population carrier prevalence, and personal or family history. Conditions selected for screening can be based on ethnicities at high risk (e.g., Tay- Sachs disease in individuals of Ashkenazi Jewish descent) or may be pan-ethnic (e.g., screening for cystic fibrosis carriers). Ethnicity-based screening for some conditions has been offered for decades and, in some cases, has reduced the prevalence of diseases. While methods for carrier screening of conditions individually may have been onerous in the past, contemporary molecular techniques including next-generation sequencing allow simultaneously identifying carriers of a wide range of disorders efficiently and inexpensively. Expanded carrier screening (ECS) involves screening individuals or couples for disorders in many genes (up to 100s). The disorders included may also span a range of disease severity or phenotype. Arguments for ECS include potential issues in assessing ethnicity, ability to identify more potential conditions, efficiency, and cost. -
Binding of Undamaged Double Stranded DNA to Vaccinia Virus
Schormann et al. BMC Structural Biology (2015) 15:10 DOI 10.1186/s12900-015-0037-1 RESEARCH ARTICLE Open Access Binding of undamaged double stranded DNA to vaccinia virus uracil-DNA Glycosylase Norbert Schormann1, Surajit Banerjee2, Robert Ricciardi3 and Debasish Chattopadhyay1* Abstract Background: Uracil-DNA glycosylases are evolutionarily conserved DNA repair enzymes. However, vaccinia virus uracil-DNA glycosylase (known as D4), also serves as an intrinsic and essential component of the processive DNA polymerase complex during DNA replication. In this complex D4 binds to a unique poxvirus specific protein A20 which tethers it to the DNA polymerase. At the replication fork the DNA scanning and repair function of D4 is coupled with DNA replication. So far, DNA-binding to D4 has not been structurally characterized. Results: This manuscript describes the first structure of a DNA-complex of a uracil-DNA glycosylase from the poxvirus family. This also represents the first structure of a uracil DNA glycosylase in complex with an undamaged DNA. In the asymmetric unit two D4 subunits bind simultaneously to complementary strands of the DNA double helix. Each D4 subunit interacts mainly with the central region of one strand. DNA binds to the opposite side of the A20-binding surface on D4. Comparison of the present structure with the structure of uracil-containing DNA-bound human uracil-DNA glycosylase suggests that for DNA binding and uracil removal D4 employs a unique set of residues and motifs that are highly conserved within the poxvirus family but different in other organisms. Conclusion: The first structure of D4 bound to a truly non-specific undamaged double-stranded DNA suggests that initial binding of DNA may involve multiple non-specific interactions between the protein and the phosphate backbone. -
Novel Gene Fusions in Glioblastoma Tumor Tissue and Matched Patient Plasma
cancers Article Novel Gene Fusions in Glioblastoma Tumor Tissue and Matched Patient Plasma 1, 1, 1 1 1 Lan Wang y, Anudeep Yekula y, Koushik Muralidharan , Julia L. Small , Zachary S. Rosh , Keiko M. Kang 1,2, Bob S. Carter 1,* and Leonora Balaj 1,* 1 Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA; [email protected] (L.W.); [email protected] (A.Y.); [email protected] (K.M.); [email protected] (J.L.S.); [email protected] (Z.S.R.); [email protected] (K.M.K.) 2 School of Medicine, University of California San Diego, San Diego, CA 92092, USA * Correspondence: [email protected] (B.S.C.); [email protected] (L.B.) These authors contributed equally. y Received: 11 March 2020; Accepted: 7 May 2020; Published: 13 May 2020 Abstract: Sequencing studies have provided novel insights into the heterogeneous molecular landscape of glioblastoma (GBM), unveiling a subset of patients with gene fusions. Tissue biopsy is highly invasive, limited by sampling frequency and incompletely representative of intra-tumor heterogeneity. Extracellular vesicle-based liquid biopsy provides a minimally invasive alternative to diagnose and monitor tumor-specific molecular aberrations in patient biofluids. Here, we used targeted RNA sequencing to screen GBM tissue and the matched plasma of patients (n = 9) for RNA fusion transcripts. We identified two novel fusion transcripts in GBM tissue and five novel fusions in the matched plasma of GBM patients. The fusion transcripts FGFR3-TACC3 and VTI1A-TCF7L2 were detected in both tissue and matched plasma. -
Low Levels of 18 Hexosaminidase a in Healthy Individuals with Apparent Deficiency of This Enzyme
Am J Hum Genet 28:339-349, 1976 Low Levels of 18 Hexosaminidase A in Healthy Individuals with Apparent Deficiency of This Enzyme R. NAVON,1 B. GEIGER,2 Y. BEN YOSEPH,2 AND M. C. RATTAZZI3 INTRODUCTION The association between Tay-Sachs disease (TSD; GM,2 gangliosidosis type I) and generalized deficiency of /8 hexosaminidase A (hex A) activity with artificial sub- strates, first reported by Okada and O'Brien [1], is now well established. Using natural substrates, it has also been shown that tissues from patients with TSD cannot degrade GM2 ganglioside in vitro [2, 3] and that purified hex A, but ap- parently not purified /f hexosaminidase B (hex B), can hydrolyze GM2 ganglioside to a measurable extent [3, 4]. Thus, hex A deficiency is commonly believed to be the cause of the accumulation of GM2 ganglioside in patients with TSD. However, it has recently been reported that purified hex B can cleave GM2 ganglioside in vitro [5], raising the question of its participation in the catabolism of this glyco- lipid in vivo. In a recent publication [6], Navon et al. described a Jewish family in which four healthy adult individuals showed a severe deficiency of hex A activity. Using a heat inactivation method based on the differential thermal lability of hex A and hex B [7, 8], it was shown that, in these subjects, hex A activity with artificial substrates was comparable to that of patients with TSD [6]. Further studies em- ploying radioactive natural substrates, however, showed that leukocytes from these "variant" individuals were capable of hydrolysis of GA12 ganglioside in vitro [9]. -
GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies
International Journal of Molecular Sciences Review GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies Andrés Felipe Leal 1 , Eliana Benincore-Flórez 1, Daniela Solano-Galarza 1, Rafael Guillermo Garzón Jaramillo 1 , Olga Yaneth Echeverri-Peña 1, Diego A. Suarez 1,2, Carlos Javier Alméciga-Díaz 1,* and Angela Johana Espejo-Mojica 1,* 1 Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Bogotá 110231, Colombia; [email protected] (A.F.L.); [email protected] (E.B.-F.); [email protected] (D.S.-G.); [email protected] (R.G.G.J.); [email protected] (O.Y.E.-P.); [email protected] (D.A.S.) 2 Faculty of Medicine, Universidad Nacional de Colombia, Bogotá 110231, Colombia * Correspondence: [email protected] (C.J.A.-D.); [email protected] (A.J.E.-M.); Tel.: +57-1-3208320 (ext. 4140) (C.J.A.-D.); +57-1-3208320 (ext. 4099) (A.J.E.-M.) Received: 6 July 2020; Accepted: 7 August 2020; Published: 27 August 2020 Abstract: GM2 gangliosidoses are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the β-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidoses have been described: Tay–Sachs disease, Sandhoff disease, and the AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidoses patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidoses, but different therapeutic strategies have been studied including hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, and gene therapy. -
Hexosaminidase a in Tay–Sachs Disease
Journal of Genetics (2020)99:42 Ó Indian Academy of Sciences https://doi.org/10.1007/s12041-020-01208-8 (0123456789().,-volV)(0123456789().,-volV) RESEARCH ARTICLE In silico analysis of the effects of disease-associated mutations of b-hexosaminidase A in Tay–Sachs disease MOHAMMAD IHSAN FAZAL1, RAFAL KACPRZYK2 and DAVID J. TIMSON3* 1Brighton and Sussex Medical School, University of Sussex, Falmer, Brighton BN1 9PX, UK 2School of Biological Sciences, Queen’s University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK 3School of Pharmacy and Biomolecular Sciences, University of Brighton, Huxley Building, Lewes Road, Brighton BN2 4GJ, UK *For correspondence. E-mail: [email protected]. Received 6 September 2019; revised 25 February 2020; accepted 24 April 2020 Abstract. Tay–Sachs disease (TSD), a deficiency of b-hexosaminidase A (Hex A), is a rare but debilitating hereditary metabolic disorder. Symptoms include extensive neurodegeneration and often result in death in infancy. We report an in silico study of 42 Hex A variants associated with the disease. Variants were separated into three groups according to the age of onset: infantile (n=28), juvenile (n=9) and adult (n=5). Protein stability, aggregation potential and the degree of conservation of residues were predicted using a range of in silico tools. We explored the relationship between these properties and the age of onset of TSD. There was no significant relationship between protein stability and disease severity or between protein aggregation and disease severity. Infantile TSD had a significantly higher mean con- servation score than nondisease associated variants. This was not seen in either juvenile or adult TSD. -
Vacuolated Lymphocytes, a Clinical Finding in GM1 Gangliosidosis
Vacuolated lymphocytes, a clinical finding in GM1 gangliosidosis Linfocitos vacuolados, un hallazgo clínico en la gangliosidosis GM1 10.20960/revmedlab.00018 00018 Caso clínico Vacuolated lymphocytes, a clinical finding in GM1 gangliosidosis Linfocitos vacuolados, un hallazgo clínico en la gangliosidosis GM1 Silvia Montolio Breva1, Rafael Sánchez Parrilla1, Cristina Gutiérrez Fornes1, and María Teresa Sans Mateu2 1Laboratori Clínic ICS Camp de Tarragona. Terres de l’Ebre. Hospital Universitari Joan XXIII. Tarragona, Spain. 2Direcció Clínica Laboratoris ICS Camp de Tarragona. Terres de l'Ebre, Tarragona. Spain Received: 06/04/2020 Accepted: 08/05/2020 Correspondence: Silvia Montolio Breva. Laboratori Clínic ICS Camp de Tarragona. Terres de l’Ebre. Hospital Universitari Joan XXIII. C/ Dr. Mallafrè Guasch, 4, 43005 Tarragona e-mail: [email protected] Conflicts of interest: The authors declare no conflicts of interests. CASE REPORT A 7-month-old infant was brought to the emergency department of our hospital with fever and respiratory distress accompanied by cough and nasal mucus. After clinical assessment, the diagnostic orientation was compatible with pneumonia. Apart from these common symptoms, there were several clinical signs worth mentioning. On physical examination, cherry-red spots were observed all over the thorax, as well as, hypospadias. The results of complementary tests (cranial radiography, abdominal sonography…) also confirmed macrocephaly, hypotonia, ecchymosis and hepatosplenomegaly. Biochemical analysis showed a remarkable increase in the following parameters: Aspartate amino transferase (AST) 114 UI/L (VR: 5-34 UI/L), lactate dehydrogenase (LDH) 1941 UI/L (VR: 120-246 UI/L) and alkaline phosphatase (ALP) 1632 UI/L (VR: 46-116 UI/L). -
O-Glcnacase Fragment Discovery with Fluorescence Polarimetry
Articles Cite This: ACS Chem. Biol. 2018, 13, 1353−1360 O‑GlcNAcase Fragment Discovery with Fluorescence Polarimetry Vladimir S. Borodkin,*,†,∥ Karim Rafie,†,∥ Nithya Selvan,†,§,∥ Tonia Aristotelous,‡ Iva Navratilova,‡ Andrew T. Ferenbach,† and Daan M. F. van Aalten*,† † ‡ Centre for Gene Regulation and Expression and Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, United Kingdom *S Supporting Information ABSTRACT: The attachment of the sugar N-acetyl-D-glucosamine (GlcNAc) to specific serine and threonine residues on proteins is referred to as protein O-GlcNAcylation. O-GlcNAc transferase (OGT) is the enzyme responsible for carrying out the modification, while O-GlcNAcase (OGA) reverses it. Protein O-GlcNAcylation has been implicated in a wide range of cellular processes including transcription, proteostasis, and stress response. Dysregulation of O-GlcNAc has been linked to diabetes, cancer, and neurodegenerative and cardiovascular disease. OGA has been proposed to be a drug target for the treatment of Alzheimer’s and cardiovascular disease given that increased O-GlcNAc levels appear to exert a protective effect. The search for specific, potent, and drug-like OGA inhibitors with bioavailability in the brain is therefore a field of active research, requiring orthogonal high-throughput assay platforms. Here, we describe the synthesis of a novel probe for use in a fluorescence polarization based assay for the discovery of inhibitors of OGA. We show that the probe is suitable for use with both human OGA, as well as the orthologous bacterial counterpart from Clostridium perfringens, CpOGA, and the lysosomal hexosaminidases HexA/B. We structurally characterize CpOGA in complex with a ligand identified from a fragment library screen using this assay. -
GM1 Gangliosidosis and Morquio B Disease
Review Article Journal of Genetic Medicine J Genet Med 2021;18(1):16-23 JGM https://doi.org/10.5734/JGM.2021.18.1.16 ISSN 1226-1769 (Print) 2383-8442 (Online) GLB1-related disorders: GM1 gangliosidosis and Morquio B disease Sung Yoon Cho and Dong-Kyu Jin* Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea GLB1-related disorders comprise two phenotypically unique disorders: GM1 gangliosidosis and Morquio B disease. These autosomal recessive disorders are caused by b-galactosidase deficiency. A hallmark of GM1 gangliosidosis is central nervous system degeneration where ganglioside synthesis is highest. The accumulation of keratan sulfate is the suspected cause of the bone findings in Morquio B disease. GM1 gangliosidosis is clinically characterized by a neurodegenerative disorder associat- ed with dysostosis multiplex, while Morquio B disease is characterized by severe skeletal manifestations and the preservation of intelligence. Morquio B disease and GM1 gangliosidosis may be on a continuum of skeletal involvement. There is currently no effective treatment for GLB1-related disorders. Recently, multiple interventions have been developed and there are several ongoing clinical trials. Key words: GM1 gangliosidosis, Mucopolysaccharidoses IVB, Morquio B disease, Beta-galactosidase, GLB1. Introduction ganglioside synthesis is highest. Keratan sulfate accumulation is the suspected causative agent for the bone findings associ- GLB1-related disorders comprise two phenotypically unique ated with Morquio B disease. This review focused on the clinical, disorders, GM1 gangliosidosis (MIM 230500) and Morquio radiographic, and genetic characteristics of these two disorders B disease (mucopolysaccharidosis type IVB, MPS IVB, MIM and introduced recent clinical trials on GLB1-related disorders. -
In-Silico Chaperone Model for ATSD and Case Study
CASE REPORT OF CHAPERONE THERAPY FOR ADULT TAY-SACHS DISEASE AND COMPARISON TO AN IN-SILICO PHARMACOKINETIC AND CELLULAR SIMULATION John G. (Jack) Keimel and Lawrence Charnas MD PhD, University of Minnesota, Minneapolis, Minnesota ABSTRACT CELLULAR MODELS CELLULAR SIMULATION RESULTS CASE STUDY OF PYRIMETHAMINE IN AN ATSD PATIENT Background: Individuals with Adult Tay-Sachs Disease (ATSD) Model 2: Model 3: Model Calibration: Patient History: Drug Regimen: develop ataxia and dysarthria by early teenage years and later lose Endoplasmic Reticulum Lysosome A single constant calibration factor, “cal”, sets the translation rate of α, A male confirmed with ATSD (alpha mutations: +1IVS12 (G>C) and At the request of the patient and parents, pyrimethamine ability to walk. No therapy has yet been shown clinically effective. α , and β HexA monomers. The factor was chosen such that, for Dimer Formation GM2 GM2 Degradation m G269S ) had been taking a substrate reduction therapy, miglustat, (PYR) 25mg QD was begun for two weeks followed by 75mg ATSD is caused by inadequate β-hexosaminidase-A (HexA) activity normal individuals with no PYR present, the steady state lysosomal for greater than four years, but at age 25 showed accelerated QD for eight weeks. Folic acid (5mg QD) was initiated with the and GM2 ganglioside accumulation in neuronal lysosomes. The concentration of HexA is equal to the above calculated value of 25μM. decline in coordination and leg muscle strength, verified by EMG first dose of PYR to offset partial dihydrofolate reductase most prevalent ATSD mutation, αG269S, is not believed to impact [PYR] [PYR] αβ evaluations. The patient lost the ability to climb stairs and required inhibition caused by PYR. -
Oxidative Demethylation of DNA Damage by Escherichia Coli Alkb
Oxidative déméthylation of DNA damage by Escherichia coli AlkB and its human homologs ABH2 and ABH3 A thesis submitted for the degree of Ph D. by Sarah Catherine Trewick Clare Hall Laboratories Cancer Research UK London Research Institute South Mimms, Potters Bar Hertfordshire, EN6 3LD and Department of Biochemistry University College London Gower Street, London, WCIE 6BT ProQuest Number: U642489 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest U642489 Published by ProQuest LLC(2015). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 ABSTRACT The E. coli AlkB protein was implicated in the repair or tolerance of DNA méthylation damage. However, despite the early isolation of an E. coli alkB mutant, the function of the AlkB protein had not been resolved (Kataoka et al, 1983). The E. coli alkB mutant is defective in processing methylated single stranded DNA, therefore, it was suggested that the AlkB protein either repairs or tolerates lesions generated in single stranded DNA, such as 1-methyladenine (1-meA) or 3-methylcytosine (3-meC), or that AlkB only acts on single stranded DNA (Dinglay et al, 2000).