GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies
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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. -
Sphingolipid Metabolism Diseases ⁎ Thomas Kolter, Konrad Sandhoff
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1758 (2006) 2057–2079 www.elsevier.com/locate/bbamem Review Sphingolipid metabolism diseases ⁎ Thomas Kolter, Konrad Sandhoff Kekulé-Institut für Organische Chemie und Biochemie der Universität, Gerhard-Domagk-Str. 1, D-53121 Bonn, Germany Received 23 December 2005; received in revised form 26 April 2006; accepted 23 May 2006 Available online 14 June 2006 Abstract Human diseases caused by alterations in the metabolism of sphingolipids or glycosphingolipids are mainly disorders of the degradation of these compounds. The sphingolipidoses are a group of monogenic inherited diseases caused by defects in the system of lysosomal sphingolipid degradation, with subsequent accumulation of non-degradable storage material in one or more organs. Most sphingolipidoses are associated with high mortality. Both, the ratio of substrate influx into the lysosomes and the reduced degradative capacity can be addressed by therapeutic approaches. In addition to symptomatic treatments, the current strategies for restoration of the reduced substrate degradation within the lysosome are enzyme replacement therapy (ERT), cell-mediated therapy (CMT) including bone marrow transplantation (BMT) and cell-mediated “cross correction”, gene therapy, and enzyme-enhancement therapy with chemical chaperones. The reduction of substrate influx into the lysosomes can be achieved by substrate reduction therapy. Patients suffering from the attenuated form (type 1) of Gaucher disease and from Fabry disease have been successfully treated with ERT. © 2006 Elsevier B.V. All rights reserved. Keywords: Ceramide; Lysosomal storage disease; Saposin; Sphingolipidose Contents 1. Sphingolipid structure, function and biosynthesis ..........................................2058 1.1. -
A Mouse B16 Melanoma Mutant Deficient in Glycolipids
Proc. Natl. Acad. Sci. USA Vol. 91, pp. 2703-2707, March 1994 Biochemistry A mouse B16 melanoma mutant deficient in glycolipids (glucosyltransferase/glucosylceramide/glucocerebroside) SHINICHI ICHIKAWA*t, NOBUSHIGE NAKAJO*, HISAKO SAKIYAMAt, AND YOSHIo HIRABAYASHI* *Laboratory for Glyco Cell Biology, Frontier Research Program, The Institute of Chemical and Physical Research (RIKEN), 2-1 Hirosawa, Wako-shi, Saitama 351-01, Japan; and *Division of Physiology and Pathology, National Institute of Radiological Sciences, 4-9-1 Anagawa, Chiba-shi, Chiba 260, Japan Communicated by Saul Roseman, December 21, 1993 ABSTRACT Mouse B16 melanoma cell line, GM-95 (for- cosyltransferase would provide an ideal tool. Although sev- merly designated as MEC-4), deficient in sialyllactosylceram- eral glycosylation mutant cells have been isolated by treat- ide was examined for its primary defect. Glycolipids from the ment with a mutagen followed by selection with lectins, mutant cells were analyzed by high-performance TLC. No defects in these mutants were involved in either glycoprotein glycolipid was detected in GM-95 cells, even when total lipid syntheses (for review, see ref. 3), nucleotide sugar syntheses, from 107 cells was analyzed. In contrast, the content of or nucleotide sugar transporters (4). Mutants defective in ceramide, a precursor lipid molecule of glycolipids, was nor- glycolipid-specific transferases have rarely been found. Re- mal. Thus, the deficiency of glycolipids was attributed to the cently, Tsuruoka et al. (5) isolated a mouse mammary car- first glucosylation step of ceramide. The ceramide glucosyl- cinoma mutant that gained GM3 expression by selection with transferase (EC 2.4.1.80) activity was not detected in GM-95 antilactosylceramide (anti-LacCer) monoclonal antibody cells. -
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]. -
The Counsyl Foresight™ Carrier Screen
The Counsyl Foresight™ Carrier Screen 180 Kimball Way | South San Francisco, CA 94080 www.counsyl.com | [email protected] | (888) COUNSYL The Counsyl Foresight Carrier Screen - Disease Reference Book 11-beta-hydroxylase-deficient Congenital Adrenal Hyperplasia .................................................................................................................................................................................... 8 21-hydroxylase-deficient Congenital Adrenal Hyperplasia ...........................................................................................................................................................................................10 6-pyruvoyl-tetrahydropterin Synthase Deficiency ..........................................................................................................................................................................................................12 ABCC8-related Hyperinsulinism........................................................................................................................................................................................................................................ 14 Adenosine Deaminase Deficiency .................................................................................................................................................................................................................................... 16 Alpha Thalassemia............................................................................................................................................................................................................................................................. -
Oral Ambroxol Increases Brain Glucocerebrosidase Activity in a Nonhuman Primate
Received: 17 November 2016 | Revised: 24 January 2017 | Accepted: 12 February 2017 DOI 10.1002/syn.21967 SHORT COMMUNICATION Oral ambroxol increases brain glucocerebrosidase activity in a nonhuman primate Anna Migdalska-Richards1 | Wai Kin D. Ko2 | Qin Li2,3 | Erwan Bezard2,3,4,5 | Anthony H. V. Schapira1 1Department of Clinical Neurosciences, Institute of Neurology, University College Abstract London, NW3 2PF, United Kingdom Mutations in the glucocerebrosidase 1 (GBA1) gene are related to both Parkinson disease (PD) and 2Motac Neuroscience, Manchester, United Gaucher disease (GD). In both cases, the condition is associated with deficiency of glucocerebrosi- Kingdom dase (GCase), the enzyme encoded by GBA1. Ambroxol is a small molecule chaperone that has 3 Institute of Laboratory Animal Sciences, been shown in mice to cross the blood-brain barrier, increase GCase activity and reduce alpha- China Academy of Medical Sciences, Beijing synuclein protein levels. In this study, we analyze the effect of ambroxol treatment on GCase City, People’s Republic of China activity in healthy nonhuman primates. We show that daily administration of ambroxol results in 4University de Bordeaux, Institut des Maladies Neurodeg en eratives, UMR 5293, increased brain GCase activity. Our work further indicates that ambroxol should be investigated as Bordeaux F-33000, France a novel therapy for both PD and neuronopathic GD in humans. 5CNRS, Institut des Maladies Neurodeg en eratives, UMR 5293, Bordeaux F-33000, France KEYWORDS Correspondence ambroxol, glucocerebrosidase, -
Assessment of a Targeted Gene Panel for Identification of Genes Associated with Movement Disorders
Supplementary Online Content Montaut S, Tranchant C, Drouot N, et al; French Parkinson’s and Movement Disorders Consortium. Assessment of a targeted gene panel for identification of genes associated with movement disorders. JAMA Neurol. Published online June 18, 2018. doi:10.1001/jamaneurol.2018.1478 eMethods. Supplemental methods. eTable 1. Name, phenotype and inheritance of the genes included in the panel. eTable 2. Probable pathogenic variants identified in a cohort of 23 patients with cerebellar ataxia using WES analysis. eTable 3. Negative cases in a cohort of 23 patients with cerebellar ataxia studied using WES analysis. eTable 4. Variants of unknown significance (VUSs) identified in the cohort. eFigure 1. Examples of pedigrees of cases with identified causative variants. eFigure 2. Pedigrees suggesting mendelian inheritance in negative cases. eFigure 3. Examples of pedigrees of cases with identified VUSs. eResults. Supplemental results. This supplementary material has been provided by the authors to give readers additional information about their work. © 2018 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 eMethods. Supplemental methods Patients selection In the multicentric, prospective study, patients were selected from 25 French, 1 Luxembourg and 1 Algerian tertiary MDs centers between September 2014 and July 2016. Inclusion criteria were patients (1) who had developed one or several chronic MDs (2) with an age of onset below 40 years and/or presence of a family history of MDs. Patients suffering from essential tremor, tic or Gilles de la Tourette syndrome, pure cerebellar ataxia or with clinical/paraclinical findings suggestive of an acquired cause were excluded. -
Attenuation of Ganglioside GM1 Accumulation in the Brain of GM1 Gangliosidosis Mice by Neonatal Intravenous Gene Transfer
Gene Therapy (2003) 10, 1487–1493 & 2003 Nature Publishing Group All rights reserved 0969-7128/03 $25.00 www.nature.com/gt RESEARCH ARTICLE Attenuation of ganglioside GM1 accumulation in the brain of GM1 gangliosidosis mice by neonatal intravenous gene transfer N Takaura1, T Yagi2, M Maeda2, E Nanba3, A Oshima4, Y Suzuki5, T Yamano1 and A Tanaka1 1Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan; 2Department of Neurobiology and Anatomy, Osaka City University Graduate School of Medicine, Osaka, Japan; 3Gene Research Center, Tottori University, Yonago, Japan; 4Department of Pediatrics, Takagi Hospital, Saitama, Japan; and 5Pediatrics, Clinical Research Center, Nasu Institute for Developmental Disabilities, International University of Health and Welfare, Ohtawara, Japan A single intravenous injection with 4 Â 107 PFU of recombi- ganglioside GM1 was above the normal range in all treated nant adenovirus encoding mouse b-galactosidase cDNA to mice, which was speculated to be the result of reaccumula- newborn mice provided widespread increases of b-galacto- tion. However, the values were still definitely lower in most of sidase activity, and attenuated the development of the the treated mice than those in untreated mice. In the disease including the brain at least for 60 days. The b- histopathological study, X-gal-positive cells, which showed galactosidase activity showed 2–4 times as high a normal the expression of exogenous b-galactosidase gene, were activity in the liver and lung, and 50 times in the heart. In the observed in the brain. It is noteworthy that neonatal brain, while the activity was only 10–20% of normal, the administration via blood vessels provided access to the efficacy of the treatment was distinct. -
N-Acetyl-L-Leucine Improves Functional Recovery and Attenuates Cortical Cell
www.nature.com/scientificreports OPEN N‑Acetyl‑l‑leucine improves functional recovery and attenuates cortical cell death and neuroinfammation after traumatic brain injury in mice Nivedita Hegdekar1, Marta M. Lipinski1,2* & Chinmoy Sarkar1* Traumatic brain injury (TBI) is a major cause of mortality and long‑term disability around the world. Even mild to moderate TBI can lead to lifelong neurological impairment due to acute and progressive neurodegeneration and neuroinfammation induced by the injury. Thus, the discovery of novel treatments which can be used as early therapeutic interventions following TBI is essential to restrict neuronal cell death and neuroinfammation. We demonstrate that orally administered N‑acetyl‑l‑ leucine (NALL) signifcantly improved motor and cognitive outcomes in the injured mice, led to the attenuation of cell death, and reduced the expression of neuroinfammatory markers after controlled cortical impact (CCI) induced experimental TBI in mice. Our data indicate that partial restoration of autophagy fux mediated by NALL may account for the positive efect of treatment in the injured mouse brain. Taken together, our study indicates that treatment with NALL would be expected to improve neurological function after injury by restricting cortical cell death and neuroinfammation. Therefore, NALL is a promising novel, neuroprotective drug candidate for the treatment of TBI. Traumatic brain injury (TBI) is a major health concern all over the world. Between 1990 and 2016, the prevalence of TBI increased by around 8.4%1. Almost 27 million new cases of TBI were reported worldwide in 2016, with an incidence rate of 369 per 100,000 people 1. In the US around 1.7 million cases of TBI are reported each year 2,3. -
Regulation of Glycolipid Synthesis in HL-60 Cells by Antisense
Proc. Natl. Acad. Sci. USA Vol. 92, pp. 8670-8674, September 1995 Neurobiology Regulation of glycolipid synthesis in HL-60 cells by antisense oligodeoxynucleotides to glycosyltransferase sequences: Effect on cellular differentiation (gangliosides/gene expression/cell maturation) GuicHAo ZENG, TOSHlo ARIGA, XIN-BIN Gu, AND ROBERT K. Yu* Department of Biochemistry and Molecular Biophysics, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0614 Communicated by Saul Roseman, Johns Hopkins University, Baltimore, MD, June 8, 1995 ABSTRACT Treatment of the human promyelocytic leuke- Gal1-Gic-Cer mia cell line HL-60 with antisense oligodeoxynucleotides to UDP-N-acetylgalactosamine: 3-1,4-N-acetylgalactosaminyl- transferase (GM2-synthase; EC 2.4.1.92) and CMP-sialic acid:a- GGM3 synd8s EC 2.4.99.8) sequences ef- 2,8-sialyltransferase (GD3-synthase; Gal-Glc-Cer GD3 synthase Grl-Glc-Cer fectively down-regulated the synthesis of more complex ganglio- SA - SA sides in the ganglioside synthetic pathways after GM3, resulting cm sA aon in a remarkable increase in endogenous GM3 with concomitant decreases in more complex gangliosides. The treated cells un- GM2 synthase derwent monocytic differentiation as judged by morphological clwiges, adherent ability, and nitroblue tetrazolium staining. GaiNAc-Gal-Glc-Cer GaINAc-Gal-Glc-Cer SA These data provide evidence that the increased endogenous sk Q ganglioside GM3 may play an important role in regulating IGM2 SA cellular differentiation and that the antisense DNA technique proves to be a powerful tool in manipulating glycolipid synthesis GalGaNAc-Ca-Glc-Cer Gal-GaINAc-Gal-Glc-Cer in the cell. SA SA SA GDlb The composition of gangliosides-in cells undergoes dramatic changes during cellular growth, differentiation, and oncogenic transformation, suggesting a specific role of gangliosides in the Gal-GaINAc-Gal-Gic-Cer Gal-GaINAc-Gal-Glc-Cer regulation of these cellular events (3-5). -
Sphingolipids and Cell Signaling: Relationship Between Health and Disease in the Central Nervous System
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 6 April 2021 doi:10.20944/preprints202104.0161.v1 Review Sphingolipids and cell signaling: Relationship between health and disease in the central nervous system Andrés Felipe Leal1, Diego A. Suarez1,2, Olga Yaneth Echeverri-Peña1, Sonia Luz Albarracín3, Carlos Javier Alméciga-Díaz1*, Angela Johana Espejo-Mojica1* 1 Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Bogotá D.C., 110231, Colombia; [email protected] (A.F.L.), [email protected] (D.A.S.), [email protected] (O.Y.E.P.) 2 Faculty of Medicine, Universidad Nacional de Colombia, Bogotá D.C., Colombia; [email protected] (D.A.S.) 3 Nutrition and Biochemistry Department, Faculty of Science, Pontificia Universidad Javeriana, Bogotá D.C., Colombia; [email protected] (S.L.A.) * Correspondence: [email protected]; Tel.: +57-1-3208320 (Ext 4140) (C.J.A-D.). [email protected]; Tel.: +57-1-3208320 (Ext 4099) (A.J.E.M.) Abstract Sphingolipids are lipids derived from an 18-carbons unsaturated amino alcohol, the sphingosine. Ceramide, sphingomyelins, sphingosine-1-phosphates, gangliosides and globosides, are part of this group of lipids that participate in important cellular roles such as structural part of plasmatic and organelle membranes maintaining their function and integrity, cell signaling response, cell growth, cell cycle, cell death, inflammation, cell migration and differentiation, autophagy, angiogenesis, immune system. The metabolism of these lipids involves a broad and complex network of reactions that convert one lipid into others through different specialized enzymes. Impairment of sphingolipids metabolism has been associated with several disorders, from several lysosomal storage diseases, known as sphingolipidoses, to polygenic diseases such as diabetes and Parkinson and Alzheimer diseases.