Synergistic Enteral Regimen for Treatment of the Gangliosidoses Eligibility Criteria Conditions & Interventions More Informa

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Synergistic Enteral Regimen for Treatment of the Gangliosidoses Eligibility Criteria Conditions & Interventions More Informa

Synergistic Enteral Regimen for Treatment of the Gangliosidoses Status: Recruiting Eligibility Criteria Sex: All Age: up to 204 Months old This study is NOT accepting healthy volunteers Inclusion Criteria: 1. Subjects must have a documented infantile or juvenile gangliosidosis disease. 2. Age: 17 years or less at time of enrollment 3. Subjects and their caregivers must be willing to work with a ketogenic diet team for management of the subject's ketogenic diet. Exclusion Criteria: 1. A desire to not participate 2. Patients who are older than 17 years will not be enrolled in this study. 3. Children with severe renal impairment will not be enrolled in this study. 4. Post- pubertal females who are pregnant, or who are unwilling to use highly-effective methods to prevent pregnancy, will be excluded from this study. 5. Breast-feeding females will be excluded from this study. 6. Subjects who have an allergy to miglustat or any of the components within the drug product will be excluded from this study. Conditions & Interventions Interventions: Drug: miglustat, Other: Ketogenic Diet Conditions: GM1 Gangliosidoses, GM2 Gangliosidoses, Tay-Sachs Disease, Sandhoff Disease Keywords: infantile Tay-Sachs disease, juvenile Tay-Sachs disease, infantile GM1 gangliosidosis, juvenile GM1 gangliosidosis, infantile GM2 gangliosidosis, juvenile GM2 gangliosidosis, Sandhoff disease, gangliosidoses, miglustat, ketogenic diet, SYNER-G regimen, Syner-G, Zavesca, Tay-Sachs disease, Tay Sachs disease More Information Contact(s): Jeanine Jarnes - [email protected] Principal Investigator: Jeanine Jarnes Phase: Phase 4 IRB Number: 1311M46101 System ID: NCT02030015 Thank you for choosing StudyFinder. Please visit http://studyfinder.umn.edu to find a Study which is right for you and contact [email protected] if you have questions or need assistance..

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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.
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NTSAD Web Page on Miglustat Fran Platt Substrate Reduction Therapy
NTSAD Web Page on Miglustat Fran Platt Substrate Reduction Therapy for LSDs Background Several lysosomal storage diseases (LSDs) involve the storage of fatty molecules within cells of the body that are called sphingolipids (1). This is because an enzyme that normally works to break these molecules down in the lysosome, the waste disposal/recycling center of our cells, does not work properly (2, 3). Some sphingolipids are modified by the cells of our bodies by adding sugars, creating a family of specialized sphingolipids called glycosphingolipids (GSLs) (1). For example, in Gaucher disease a glycosphingolipid called glucosylceramide is not broken down and is stored, whereas in Tay-Sachs and Sandhoff disease it is a glycosphingolipid called GM2 ganglioside that is stored (1). Glycosphingolipids are made in the cells of our bodies by a single metabolic pathway that begins with the addition of a sugar molecule called glucose to a sphingolipid molecule called ceramide (1). The fact that there is only a single major pathway to make most glycosphingolipids offers a potential way of treating these diseases using a small molecule drug (4). How would a drug work? The principle behind this treatment is called substrate reduction therapy (SRT)(4). The idea is to partially block the cells in our body from making glycosphingolipids, specifically stopping them from adding glucose to ceramide, which is the first step in this pathway. This would mean fewer glycosphingolipids are made, so fewer would require breaking down in the lysosome. The aim is to balance the rates of glycosphingolipid manufacture with their impaired rate of breakdown.
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References and Further Reading
110_Valk_References 13.04.2005 12:37 Uhr Seite 905 References and Further Reading 1 Myelin and White Matter Dambska M,Laure-Kaminowska M.Myelination as a parameter of normal and retarded brain maturation. Brain Dev 1990; Asotra K, Macklin WB. Protein kinase C activity modulates 12: 214–220 myelin gene expression in enriched oligodendrocytes. Davison AN, Dobbing J. Myelination as a vulnerable period in J Neurosci Res 1993; 34: 571–588 brain development. Br Med Bull 1966; 20: 40–44 Baumann N, Pham-Dinh D. Biology of oligodendrocyte and Deshmukh DS,Vorbrodt AW,Lee PK,Bear WD,Kuizon S.Studies myelin in the mammalian central nervous system. Physiol on the submicrosomal fractions of bovine oligodendroglia: Rev 2001; 81: 871–927 lipid composition and glycolipid biosynthesis. Neurochem Benjamins JA, Iwata R, Hazlett J. Kinetics of entry of proteins Res 1988; 13: 571–582 into the myelin membrane. J Neurochem 1978; 31: 1077– De Vries GH, Norton WT. The fatty acid composition of sphin- 1085 golipids from bovine CNS axons and myelin. J Neurochem Benveniste EN, Merrill JE. Stimulation of oligodendroglial pro- 1974; 22: 251–257 liferation and maturation by interleukin-2. Nature 1986; Dietrich RB, Bradley WG, Zaragoza IV, Otto RJ, Taira RK, Wilson 321: 610–613 GH, Kangerloo H. MR evaluation of early myelination pat- Berlet HH,Volk B.Studies of human myelin proteins during old terns in normal and developmentally delayed infants.AJNR age. Mech Ageing Dev 1980; 14: 211–222 Am J Neuroradiol 1988; 9: 69–76 Berndt JA, Kim JG, Hudson LD. Identification of cis-regulatory Dobbing J.Vulnerable periods in developing brain.In: Davison elements in the myelin proteolipid protein (PLP) gene.
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INAUGURAL-DISSERTATION Zur Erlangung Des Doktorgrades Der Medizin
Aus der Universitätsklinik für Kinderheilkunde und Jugendmedizin Abteilung Kinderheilkunde III mit Poliklinik Ärztliche Direktorin: Frau Professor Dr. I. Krägeloh-Mann Bestimmung von sphingolipidabbauenden Enzymen in Granulozyten, Monozyten und Lymphozyten zur Optimierung der Labordiagnostik bei Sphingolipid-Speichererkrankungen INAUGURAL-DISSERTATION zur Erlangung des Doktorgrades der Medizin der MEDIZINISCHEN FAKULTÄT der Eberhard-Karls-Universität zu Tübingen vorgelegt von SEBASTIAN GEORG CHRISTOPHER STROBEL aus Burlington/USA 2005 Dekan: Professor Dr. med. C. D. Claussen 1. Berichterstatter: Professor Dr. rer. nat. G. Bruchelt 2. Berichterstatter: Privatdozentin Dr. rer. nat. H. Schmid Für meine Eltern und Geschwister 4 INHALTSVERZEICHNIS Inhalt Seite 1. Einleitung 8 1.1. Einführung 8 1.2. Lysosomale Speicherkrankheiten 10 1.2.1. Stoffwechsel der Sphingolipide 10 1.2.1.1. Funktion der Sphingolipide 10 1.2.1.2. Biosynthese der Sphingolipide 11 1.2.1.3. Abbau der Sphingolipide 14 1.2.1.4. Störungen im lysosomalen Sphingolipidabbau: Lipidspeicherkrankheiten 15 1.2.1.5. Synthese und Reifung lysosomaler Enzyme 17 1.2.1.6. Speicherung und Freisetzung der lysosomalen Enzyme 19 1.2.2. Erkrankungen durch Störungen des Sphingolipidabbaus 20 1.2.2.1. Metachromatische Leukodystrophie (MLD) 23 1.2.2.2. ß-Galaktosidase-Mangel (GM1 Gangliosidose, Morquio B) 27 1.2.2.3. GM2 Gangliosidosen 35 1.2.3. Diagnostik der Sphingolipidosen 40 1.2.3.1. Biochemische Diagnostik 40 1.2.3.1.1. Analyse der gespeicherten Materialien aus Biopsien 40 1.2.3.1.2. Enzymatische Nachweisverfahren 41 1.2.3.1.3. Metabolische Untersuchungen 43 1.2.3.2. Molekulare Nachweisverfahren und genetische Diagnostik 44 1.2.3.3.
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(12) United States Patent (10) Patent No.: US 8,604,011 B2 Melon (45) Date of Patent: Dec
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by UCL Discovery Mitochondrial Dysfunction and Neurodegeneration in Lysosomal Storage Disorders Nicoletta Plotegher and Michael R. Duchen Correspondence: [email protected] Keywords: calcium, mitochondria, neurodegeneration, autophagy, alpha-synuclein, lysosomes, oxidative stress, mitophagy, metabolism, Parkinson’s disease, Gaucher’s Disease Abstract Lysosomal storage disorders (LSDs) are rare inherited debilitating and often fatal disorders. Caused by mutations of lysosomal proteins, they are characterized by the accumulation of undegraded material in lysosomes and by lysosomal dysfunction. While the LSDs are multisystemic diseases, the majority present neurologic symptoms and neurodegeneration. Only very recently has a role emerged for mitochondrial dysfunction in the pathophysiology of some LSDs, suggesting a direct or indirect impact of lysosomal dysfunction on mitochondria. Moreover, mitochondrial damage may also cause lysosomal dysfunction, further supporting the activity of common signaling pathways and cross-talk between the two organelles. Thus, the interface between lysosomal and mitochondrial (dys)function is emerging as an important contributor to the pathogenesis of the LSDs and other neurodegenerative disorders. In this review, we explore the mechanisms linking lysosomal and mitochondrial dysfunction, in order to assess whether specific mitochondrial pathways represent a new therapeutic frontier in the management of the LSDs. 1 Etiopathogenesis of Lysosomal Storage Disorders Lysosomal storage disorders (LSD) are a class of more than 50 rare inherited metabolic diseases caused by genetic mutations in either lysosomal enzymes, non-enzymatic lysosomal proteins or non-lysosomal proteins, affecting lysosomal function. The loss of function of these proteins leads to accumulation of storage material in the endosomal, autophagic and/or lysosomal systems, influencing a number of cell signaling pathways and reducing cell survival [1].
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A Rare Case of Sandhoff Disease: Two in the Same Family
International Journal of Contemporary Pediatrics Lakshmi S et al. Int J Contemp Pediatr. 2015 Feb;2(1):42-45 http://www.ijpediatrics.com pISSN 2349-3283 | eISSN 2349-3291 DOI: 10.5455/2349-3291.ijcp20150210 Case Report A rare case of Sandhoff disease: two in the same family S. Lakshmi*, G. Fatima Shirly Anitha, S. Vinoth Department of Paediatrics, Chengalpattu Medical College, Chengalpattu, Tamil Nadu, India Received: 13 January 2015 Accepted: 23 January 2015 *Correspondence: Dr. S. Lakshmi, E-mail: [email protected] Copyright: © the author(s), publisher and licensee Medip Academy. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. ABSTRACT Sandhoff disease is a rare lysosomal storage disorder which is inherited in an autosomal recessive pattern. Prevalence of Sandhoff disease is 1 in 384000 live births. Here we report a 14 month old male child who presented with macrocephaly, regression of developmental milestones and seizures. Fundus examination showed macular cherry red spot. Enzyme studies revealed reduced levels of beta hexosaminidase A and B, following which a diagnosis of Sandhoff disease was made. Mother was offered prenatal diagnosis of the fetus in the subsequent pregnancy, which was also found to have the same enzyme deficiency and the pregnancy was medically terminated. Early identification of this neurodegenerative disorder, helped in preventing the birth of subsequent affected children in the same family, thereby reducing the burden on the family as well as the society.
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Revision Notes in Psychiatry 2Nd Edition
Revision Notes in Psychiatry This page intentionally left blank Revision Notes in Psychiatry 2nd edition BASANT K. PURI MA, PhD, MB, BChir, BSc (Hons) MathSci, MRCPsych, DipStat, MMath Senior Lecturer/Consultant in Psychiatry and Imaging, MRC CSC, Imperial College London; Honorary Consultant in Imaging, Department of Imaging, Hammersmith Hospital, London ANNE D. HALL BA, MB, BCh, MRCPsych Consultant Psychiatrist, South Kensington and Chelsea Mental Health Centre, Chelsea and Westminster Hospital, London A member of the Hodder Headline Group LONDON First published in Great Britain in 1998 Second edition published in 2004 by Arnold, a member of the Hodder Headline Group, 338 Euston Road, London NW1 3BH http://www.arnoldpublishers.com Distributed in the United States of America by Oxford University Press Inc., 198 Madison Avenue, New York, NY10016 Oxford is a registered trademark of Oxford University Press © 2004 BK Puri and AD Hall All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronically or mechanically, including photocopying, recording or any information storage or retrieval system, without either prior permission in writing from the publisher, or a licence permitting restricted copying. In the United Kingdom such licences are issued by the Copyright Licensing Agency: 90 Tottenham Court Road, London W1T 4LP. Whilst the advice and information in this book are believed to be true and accurate at the date of going to press, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. In particular, (but without limiting the generality of the preceding disclaimer) every effort has been made to check drug dosages; however it is still possible that errors have been missed.
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Myelin Abnormalities in the Optic and Sciatic Nerves of Mice with GM1- Gangliosidosis
Myelin abnormalities in the optic and sciatic nerves of mice with GM1- gangliosidosis Author: Karie A. Heinecke Persistent link: http://hdl.handle.net/2345/bc-ir:103611 This work is posted on eScholarship@BC, Boston College University Libraries. Boston College Electronic Thesis or Dissertation, 2014 Copyright is held by the author, with all rights reserved, unless otherwise noted. Boston College The Graduate School of Arts and Sciences Department of Biology MYELIN ABNORMALITIES IN THE OPTIC AND SCIATIC NERVES OF MICE WITH GM1-GANGLIOSIDOSIS a Thesis by KARIE A. HEINECKE submitted in partial fulfillment of the requirements for the degree of Master of Science May 2014 © copyright by KARIE A. HEINECKE 2014 MYELIN ABNORMALITIES IN THE OPTIC AND SCIATIC NERVES OF MICE WITH GM1-GANGLIOSIDOSIS Karie A. Heinecke Advisor: Thomas N. Seyfried, Ph.D. ABSTRACT GM1 gangliosidosis is a glycosphingolipid lysosomal storage disease caused by a genetic deficiency of acid β-galactosidase (β-gal), the enzyme that catabolyzes GM1 within lysosomes. Accumulation of GM1 and its asialo form (GA1) occurs primarily in the brain, leading to progressive neurodegeneration and brain dysfunction. Less information is available on the neurochemical pathology in optic nerve and sciatic nerve of GM1- gangliosidosis. Here we analyzed the lipid content and myelin structure in optic and sciatic nerve in 7 and 10 month old normal β-gal (+/?) and GM1-gangliosidosis β-gal (–/–) mice. Optic nerve weight was lower in the β-gal –/– mice than in unaffected β-gal +/? mice, but no difference was seen between the normal and the β-gal –/– mice for sciatic nerve weight. The concentrations of GM1 and GA1 were significantly higher in optic nerve and sciatic nerve in the β-gal –/– mice than in β-gal +/? mice.
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By the Time She Diagnosed with GM1 Gangliosidoses She Is No More: Case Presentation
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WSC 2001-02 Conference 19
The Armed Forces Institute of Pathology Department of Veterinary Pathology WEDNESDAY SLIDE CONFERENCE 2001-2002 CONFERENCE 19 6 March 2002 Conference Moderator: Dr. Keith Harris Pharmacia Corporation Department of Pathology Skokie, IL 60077 CASE I – 3006 (AFIP 2787431) Signalment: 10-months-old, male, Fischer 344 rat History: This rat was in a study utilizing a surgically induced model of chronic renal failure. Gross Pathology: At necropsy, multiple, tan, raised nodules (<0.5 cm) were noted along the serosal surface of the epididymides, intra-abdominal adipose tissue, and the body wall. Other gross findings were directly related to the surgical model and/or were secondary to renal failure. Laboratory Results: Clinical pathology findings (markedly elevated BUN and creatinine, decreased total protein and albumin, and alterations in electrolytes) were consistent with renal failure, as expected. Contributor’s Morphologic Diagnosis: Skeletal muscle, adipose and serosa (Body wall); mesothelioma Contributor’s Comment: Mesotheliomas are one of the most common neoplasms in the F344 rat. In the F344 rat, spontaneous mesotheliomas are believed to arise from the tunica vaginalis. Most early neoplasms are therefore found adherent to the epididymis or tunica albuginea. The location of the nodules along the epididymides and adjacent adipose and body wall in this rat is consistent with this observation. The papillary appearance and prominent stroma of the submitted neoplasm are typical of this neoplasm in the F344 rat. Many sections also had infiltration of the neoplasm by variable numbers of mast cells, eosinophils, lymphocytes, and macrophages containing intracellular, coarse, brown pigment (hemosiderin). These cellular infiltrates are also common features of this neoplasm.
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