DOCSLIB.ORG

Hyperglycopeptiduria in Genetic Mucolipidoses

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Hyperglycopeptiduria in Genetic Mucolipidoses Tohoku J. exp. Med., 1974, 112, 373-380 Hyperglycopeptiduria in Genetic Mucolipidoses TADAO ORII, TAKAMICHI CHIBA, RYOJI MINAMI, KAZUKO S UKEGAWA and TooRu NAKAO Department of Pediatrics, Sapporo Medical College, Sapporo ORII, T., CHmA, T., MINAMI, R., SUKEUAWA,K. and NAKAO, T. Hyper glycopeptiduria in Genetic Mucolipidoses. Tohoku J. exp. Med., 1974, 112 (4), 373-380 -Urinary cetylpyridinium chloride (CPC)-precipitates and non-CPC- precipitates in normal male children and seven patients with a new type of mucolipidosis, GM1-gangliosidosis type 1, I-cell disease, Hurler syndrome, Morquio syndrome, Gaucher's disease adult type and Tay-Sachs disease were studied using several methods including Sephadex G-25 gel filtration, ECTEOLA-cellulose column chromatography and enzymatic digestion with chondroitinase ABC. 1) Considerable amounts of glycopeptide fractions were detected in the urine of the patients with a new type of mucolipidosis, Gm1-gangliosidosis type 1, I-cell disease and also Gaucher's disease adult type compared with that of normal male children and other patients. 2) The total acid mucopolysaccharides excreted into the urine from two patients with Hurler syndrome and Morquio syndrome were much higher than those excreted in normal male children and other patients. 3) Large amounts of the chondroitinase ABC-resistant acid mucopolysaccharides were found in the urine of patients with Hurler syndrome, Morquio syndrome and Gm,-gangliosidosis type 1. mucolipidoses; glycopeptiduria; Gaucher's disease A group of storage disease which exhibits signs and symptoms of both mucopolysaccharidoses and sphingolipidoses has tentatively been classified as the mucolipidoses by Spranger and Wiedemann (1970). With the exception of the Austin type of sulfatidosis, it has been reported by several workers that the patients with mucolipidosis generally show normal urinary excretion of uronic acid-containing mucopolysaccharides. However, in one patient with GMrganglio sidosis type 2, Wolfe et al. (1970) have found greatly elevated amount of urinary undersulfated keratan sulfate-like glycosaminoglycans. For these reasons, the present study was undertaken in order to determine whether large amounts of glycopeptides are excreted in some patients with mucolipidosis compared with those of mucopolysaccharidosis and sphingolipidosis. MATERIALS AND METHODS Analytical procedures were the same as previously described by Orii et al. (1972). Urine was collected from 75 healthy children (3?5 years) and from seven patients: each one case of a new type mucolipidosis (Orii et al. 1972), Gm,-gangliosidosis type 1, I-cell disease, Hurler syndrome, Morquio syndrome, Gaucher's disease adult type and Tay-Sachs Received for publication, February 19, 1974. A part of this study was presented at the symposium of carbohydrate complex in the 44th Annual Meeting of the Japanese Biochemical Society, Oct., 1971, Sendai. 373 374 T. Orii et al. disease. Urine specimens were kept frozen until assay. Isolation of CPC-precipitates - Urine specimens were centrifuged at 1,200•~g for 10 min and the supernatants were diluted with distilled water and then specific gravity was adjusted to about 1,010. Further, urine samples were adjusted to pH 5.0 with 1.0 M HC1, and a warm solution of 5% CPC was added (1.7 ml/100 ml of urine). After standing overnight at 4•Ž and centrifuging, precipitates were washed several times with 95% ethanol saturated with sodium acetate. The residues, containing the sodium salt of the crude mucopolysaccharides, were then dissolved in 10% sodium acetate and insoluble materials were removed by centrifugation. To the supernatant solution was added 4 volumes of ethanol, and the precipitates formed were washed several times with 80% ethanol. Furthermore, in order to determine relative proportions of chondroitinase ABC- digested and -undigested mucopolysaccharides, the method 1 of Saito et al. (1968) was employed. The reaction mixtures contained, in 50 ƒÊl, 20 ,al of CPC-precipitate (contain- ing 80ƒÊg as uronic acid), 10 ƒÊl of Tris buffer, and chondroitinase ABC 10 ƒÊl (0.3 unit). These mixtures were incubated at 37•Ž for 3 hours and then the mixture, before and after the incubation, was spotted on a paper (Toyo Roshi No. 51A). After desalting by chromatography in n-butanol-ethanol-water (52:32:16 by vol.) for 48 hours, descending paper chromatography was performed in n-butyric acid-0.5M ammonia (5:3, by vol.) for 36 hours. Each region of origin was cut out and mucopolysaccharides were eluted with 0.01 M HCl solution. Isolation of non-CPC-precipitates -After removal of CPC-precipitates, the supernat ants were concentrated and dialyzed with Diaflo membrane UM-2 (Amicon, model 202), precipitated by addition of 99% ethanol saturated with sodium acetate; the precipitates were washed with 95% ethanol saturated with sodium acetate dissolved in 10% sodium acetate and precipitated with 80% ethanol. Subsequently, crude non-CPC-precipitates were filtered through a column (1.8•~72.5 cm) of Sephadex G-25 (fine) with 180 ml of 0.05 M NaCI. 6-ml fractions were collected. Fractions filtered up to the void volume of the column from normal children and patients were collected, concentrated separately and applied to a column (1.8•~80 cm) of ECTEOLA-cellulose which was eluted with 600 ml each of water, 0.02 M HC1, 1.3 M NaCl and finally 4.0 M NaCl (Anseth et al. 1970). Each fraction was desalted on Sephadex G-25 column and lyophylized. A number of analytical determinations were carried out: uronic acid (Dische 1947), hexosamine (Svennerholm 1956), hexose (Roe 1955), sialic acid (Warren 1959), total sulfate (Dodgson and Price 1962), protein (Lowry et al. 1951), creatinine (Bonsnes and Taussky 1945), and paper chromatographic identification of hexose and hexosamine (Strecker and Montreuil 1971; Trevelyan et al. 1950). RESULTS Tables 1 and 2 indicate that two cases of Hurler and Morquio syndromes excrete large amounts of the urinary acid mucopolysaccharides compared with those of normal male children and other patients, and Table 1 also shows that with the exception of two cases of Hurler syndrome and Tay-Sachs disease, values of the dry weight of non-CPC-precipitates from all of the patients are much higher than that from normal male children. Further, the composition of non- CPC-precipitates derived from the urine of seven patients is shown in Table 3. Considerable amounts of non-CPC-precipitates were obtained in the urine of four patients, Cases 1, 2, 6 and 7. These non-CPC-precipitates contained large amounts of hexose or hexosamine and little uronic acid. Table 4 indicates that three cases of Hurler, Morquio syndromes and also GM1-gangliosidosis have very Genetic Mucolipidoses 375 TABLE1. Excretion of urinary crude acid mucopolysaccharideand glycopeptide fractions in seven patients with genetic storage disease * Percent of total dry weight is given in parentheses . TABLE 2. Composition of crude acid mucopolysaccharide fraction from the urine TABLE 3. Composition of crude non-cetylpyridinium chloride precipitable glycopeptidefractions from the urine high proportions of the chondroitinase ABC-resistant mucopolysaccharidesthan those from other patients and normal male children. Gel filtration of the non- CPC-precipitateson Sephadex G-25 column showed that each fraction filtered up to the void volume contained 80.2%, 48.0%, 40.2%, 90.4%, 66.8%, 58.6%, 69.7% and 74.4% of uronic acid in Cases 1?7 and normal male children, respectively. 376 T. Orii et al. TABLE4. Analysis of urinary acid mucopolysaccharidesafter chondroitinase ABC digestion * Mole ratios based on hexosamine=1 .0. TABLE 5. ECTEOLA -cellulose column fractionation of non-cetylpyridinium precipitable glycopeptide fractions filtered up to the void volume through a column of Sephadex G-25 ,fine Percent of total dry weight is given in parentheses. Each fraction filtered up to the void volume on Sephadex G-25 gel filtration, was applied to a column of ECTEOLA-cellulose. Table 5 indicates that 86.3% of the total dry weight in mg per g of creatinine from normal male children and 77.6% -89.3% of those from seven patients were eluted up to a HCl concentration of 0.02 M. Table 6 also shows that 97.1% of the total hexosamine from normal male children and 74.0% -92.8% of those from seven patients were eluted up to a HCl concentration of 0.02 M. These main fractions were poor in uronic acid and sulfate and rich in hexose and hexosamine. Significantamounts of these glycopep tide fractions were obtained from four patients with a new type of mucolipidosis, Genetic Mucolipidoses 377 TABLE6. Compositions of non-cetylpyridinium chloride precipitable glycopeptide fractions after ECTEOLA-cellulose column fractionation GM1-gangliosidosis, I-cell disease and Gaucher's disease. Table 7 indicates that H2O fractions from the normal male children and seven patients after the ECTEOLA- cellulose column chromatography showed on analysis high molar ratios of hexose to hexosamine and low molar ratios of sulfate or uronic acid to hexosamine, respectively, and composition of the fractions eluted up to the concentration of 0.02 M HCl did not differ significantly between them. It appears in Fig. 1 that the predominant carbohydrate constituents in the combined H2O and 0.02 M HC1 fractions derived from Cases 1, 2, 3 and normal male children are galactose and glucosamine. 378 T. Orii et al. TABLE7. Mole ratios of non-cetylpyridinium chloride precipitable glycopeptidefractions * Mole ratios based on hexosamine=1 .00. DISCUSSION With the exception of one patient with GM,-gangliosidosis type 2, pattern of CPC-precipitates and non-CPC-precipitates in mucolipidoses has been scarcely reported. In one patient with fucosidosis, Durand et al. (1966) reported that excess amount of an acid mucoid, unidentified, abnormal material which was not acid mucopolysaccharides was present in urinary sediment. Further, in two patients with mucolipidosis type 1, Spranger et al. (1968) detected increased amounts of hexosamine-containing uromucoid. However, these abnormal materi als excreted have not been studied in detail.
Load more

Recommended publications
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • The Metabolism of Tay-Sachs Ganglioside: Catabolic Studies with Lysosomal Enzymes from Normal and Tay-Sachs Brain Tissue
    The Metabolism of Tay-Sachs Ganglioside: Catabolic Studies with Lysosomal Enzymes from Normal and Tay-Sachs Brain Tissue JOHN F. TALLMAN, WILLIAM G. JOHNSON, and ROSCOE 0. BRADY From the Developmental and Metabolic Neurology Branch, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland 20014, and the Department of Biochemistry, Georgetown University School of Medicine, Washington, D. C. 20007 A B S T R A C T The catabolism of Tay-Sachs ganglioside, date fronm the 19th century and over 599 cases have been N-acetylgalactosaminyl- (N-acetylneuraminosyl) -galac- reported (1). Onset of the disease is in the first 6 months tosylglucosylceramide, has been studied in lysosomal of life and is characterized by apathy, hyperacusis, motor preparations from normal human brain and brain ob- weakness, and appearance of a macular cherry-red spot tained at biopsy from Tay-Sachs patients. Utilizing Tay- in the retina. Seizures and progressive mental deteriora- Sachs ganglioside labeled with '4C in the N-acetylgalac- tion follow with blindness, deafness, and spasticity, lead- tosaminyl portion or 3H in the N-acetylneuraminosyl ing to a state of decerebrate rigidity. These infants usu- portion, the catabolism of Tay-Sachs ganglioside may be ally die by 3 yr of age (2). initiated by either the removal of the molecule of A change in the chemical composition of the brain of N-acetylgalactosamine or N-acetylneuraminic acid. The such patients was first detected by Klenk who showed activity of the N-acetylgalactosamine-cleaving enzyme that there was an increase in the ganglioside content (hexosaminidase) is drastically diminished in such compared with normal human brain tissue (3).
    [Show full text]
  • 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.
    [Show full text]
  • The Nature of Mutation in Krabbe Disease
    Am J Hum Genet 30:644-652, 1978 The Nature of Mutation in Krabbe Disease YOAV BEN-YOSEPH,1 MELINDA HUNGERFORD, AND HENRY L. NADLER Krabbe disease (globoid cell leukodystrophy) is a disorder of galactolipid metabolism, inherited in an autosomal recessive manner [1]. Onset in early infancy is followed by rapidly progressive degeneration of the central nervous system, ending in death before the age of 2 years. The primary defect has been ascribed to a deficiency of galactosylceramide /3-galactosidase activity [2]. In addition, a deficiency of /3- galactosidase activities towards psychosine (galactosylsphingosine) [3], monogalac- tosyl diglyceride [4], and lactosylceramide [5] have been reported. The inability to degrade these substrates, found in tissues of children who died of Krabbe disease, indicates that the same enzyme may be acting on the four galactolipids. These activities are, however, normal in patients with GM, gangliosidosis. Hydrolysis of lactosyl- ceramide under different assay conditions [6] and /3-galactosidase activities towards GM, ganglioside, asialo-GMl ganglioside, and asialofetuin (ASF) are deficient in GM, gangliosidosis, but normal in Krabbe disease [7]. Thus, the mutation in Krabbe disease is not allelic with the GM, gangliosidosis mutation, and the observation that antibodies to GM, /3-galactosidase do not precipitate the activities of galactosylceramide 38- galactosidase [8, 9] supports the conclusion that these two /3-galactosidase enzymes are different proteins coded by separate loci. The present study defines the nature of the mutation in Krabbe disease. Using antibodies evoked against the normal galactosylceramide ,3-galactosidase enzyme purified from placenta, we found normal quantities of antigenically cross reacting material of the inactive mutant enzyme in brain, liver, and skin fibroblasts of patients with Krabbe disease.
    [Show full text]
  • Correction of the Enzymic Defect in Cultured Fibroblasts from Patients with Fabry's Disease: Treatment with Purified A-Galactosidase from Ficin
    Pediat. Res. 7: 684-690 (1973) Fabry's disease genetic disease ficin trihexosylceramide a-galactosidase Correction of the Enzymic Defect in Cultured Fibroblasts from Patients with Fabry's Disease: Treatment with Purified a-Galactosidase from Ficin GLYN DAWSON1341, REUBEN MATALON, AND YU-TEH LI Departments of Pediatrics and Biochemistry, Joseph P. Kennedy, Jr., Mental Retardation Research Center, University of Chicago, Chicago, Illinois, USA Extract Cultured skin fibroblasts from patients with Fabry's disease showed the characteristic a-galactosidase deficiency and accumulated a four- to sixfold excess of trihexosylceram- ide (GL-3). To demonstrate the correction, cells previously labeled with U-14G-glucose were grown in medium containing a purified a-galactosidase preparation obtained from ficin. The results demonstrated that a-galactosidase was taken up rapidly from the medium and that, despite its apparent instability in the fibroblasts, it was able to become incorporated into lysosomes and catabolize the stored trihexosylceramide. These findings support the reports of therapeutic endeavors by renal transplantation and plasma infusion in Fabry's disease and suggest the extension of such studies to other related disorders in which the cultured skin fibroblasts are chemically abnormal, namely, Gaucher's disease, lactosylceramidosis, and GM2-gangliosidosis type II. Speculation It may be possible to replace the specific missing lysosomal hydrolase in various sphingolipidoses and other storage diseases. Although we do not propose to effect enzyme replacement therapy in vivo with a plant enzyme, such studies in tissue culture are valid, and eventually human a-galactosidase, of comparable activity and purity, will become available. Introduction tially unaffected, periodic crises of pain occur and this may be explained by the accumulation of GL-3 in the Fabry's disease (angiokeratoma corporis diffusum uni- dorsal root ganglia [21, 23].
    [Show full text]
  • HHS Public Access Author Manuscript
    HHS Public Access Author manuscript Author Manuscript Author ManuscriptJ Registry Author Manuscript Manag. Author Author Manuscript manuscript; available in PMC 2015 May 11. Published in final edited form as: J Registry Manag. 2014 ; 41(4): 182–189. Exclusion of Progressive Brain Disorders of Childhood for a Cerebral Palsy Monitoring System: A Public Health Perspective Richard S. Olney, MD, MPHa, Nancy S. Doernberga, and Marshalyn Yeargin-Allsopp, MDa aNational Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention (CDC) Abstract Background—Cerebral palsy (CP) is defined by its nonprogressive features. Therefore, a standard definition and list of progressive disorders to exclude would be useful for CP monitoring and epidemiologic studies. Methods—We reviewed the literature on this topic to 1) develop selection criteria for progressive brain disorders of childhood for public health surveillance purposes, 2) identify categories of disorders likely to include individual conditions that are progressive, and 3) ascertain information about the relative frequency and natural history of candidate disorders. Results—Based on 19 criteria that we developed, we ascertained a total of 104 progressive brain disorders of childhood, almost all of which were Mendelian disorders. Discussion—Our list is meant for CP surveillance programs and does not represent a complete catalog of progressive genetic conditions, nor is the list meant to comprehensively characterize disorders that might be mistaken for cerebral
    [Show full text]
  • Mouse Model of GM2 Activator Deficiency Manifests Cerebellar Pathology and Motor Impairment
    Proc. Natl. Acad. Sci. USA Vol. 94, pp. 8138–8143, July 1997 Medical Sciences Mouse model of GM2 activator deficiency manifests cerebellar pathology and motor impairment (animal modelyGM2 gangliosidosisygene targetingylysosomal storage disease) YUJING LIU*, ALEXANDER HOFFMANN†,ALEXANDER GRINBERG‡,HEINER WESTPHAL‡,MICHAEL P. MCDONALD§, KATHERINE M. MILLER§,JACQUELINE N. CRAWLEY§,KONRAD SANDHOFF†,KINUKO SUZUKI¶, AND RICHARD L. PROIA* *Section on Biochemical Genetics, Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, ‡Laboratory of Mammalian Genes and Development, National Institute of Child Health and Development, and §Section on Behavioral Neuropharmacology, Experimental Therapeutics Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892; †Institut fu¨r Oganische Chemie und Biochemie der Universita¨tBonn, Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany; and ¶Department of Pathology and Laboratory Medicine, and Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599 Communicated by Stuart A. Kornfeld, Washington University School of Medicine, St. Louis, MO, May 12, 1997 (received for review March 21, 1997) ABSTRACT The GM2 activator deficiency (also known as disorder, the respective genetic lesion results in impairment of the AB variant), Tay–Sachs disease, and Sandhoff disease are the the degradation of GM2 ganglioside and related substrates. major forms of the GM2 gangliosidoses, disorders caused by In humans, in vivo GM2 ganglioside degradation requires the defective degradation of GM2 ganglioside. Tay–Sachs and Sand- GM2 activator protein to form a complex with GM2 ganglioside. hoff diseases are caused by mutations in the genes (HEXA and b-Hexosaminidase A then is able to interact with the activator- HEXB) encoding the subunits of b-hexosaminidase A.
    [Show full text]
  • Mucopolysaccharidoses and Mucolipidoses
    J Clin Pathol: first published as 10.1136/jcp.s3-8.1.64 on 1 January 1974. Downloaded from J. clin. Path., 27, Suppl. (Roy. Coll. Path.), 8, 64-93 Mucopolysaccharidoses and mucolipidoses F. VAN HOOF From the Laboratoire de Chimie Physiologique, Universite Catholique de Louvain, and International Institute of Cellular and Molecular Pathology, Brussels, Belgium Many different syndromes are classified as muco- THE CHEMICAL ERA polysaccharidoses, and, despite remarkable progress Chemical studies, performed mainly by groups in the biochemical understanding of these diseases, working with A. Dorfman, in Chicago and K. much remains to be learned and many cases still Meyer, in New York, have provided most of the escape classification. new knowledge in the field by analysis of tissue and Mucopolysaccharidoses are inborn storage dis- urinary mucopolysaccharides in patients (Dorfman eases, characterized by a complex accumulation of and Lorincz, 1957; Meyer, Grumbach, Linker, and mucopolysaccharides and of glycolipids within the Hoffman, 1958; Meyer, Hoffman, Linker, lysosomes. Sixteen human diseases correspond to Grumbach, and Sampson, 1959). These provided the this definition, of which nine have been presently basis for the subdivision of the 'Hurler syndrome' explained by the deficiency of an acid hydrolase. into six subgroups (McKusick, Kaplan, Wise, They are somewhat arbitrarily divided into muco- Hanley, Suddarth, Sevick, and Maumanee, 1965). polysaccharidoses and mucolipidoses. In muco- The possibility that mucopolysaccharidoses could polysaccharidoses, mucopolysaccharides are the result from an excessive biosynthesis of muco- main storage substances, although an abnormal polysaccharides was suggested by Matalon and accumulation of complex lipids is practically always Dorfman (1966). copyright. disclosed at least by the ultiastructural examination.
    [Show full text]
  • Prevalence of Lysosomal Storage Diseases in Portugal
    European Journal of Human Genetics (2004) 12, 87–92 & 2004 Nature Publishing Group All rights reserved 1018-4813/04 $25.00 www.nature.com/ejhg ARTICLE Prevalence of lysosomal storage diseases in Portugal Rui Pinto1,2, Carla Caseiro1, Manuela Lemos1, Lurdes Lopes1, Augusta Fontes1, Helena Ribeiro1, Euge´nia Pinto1, Elisabete Silva1,So´nia Rocha1, Ana Marca˜o2, Isaura Ribeiro1,2,Lu´cia Lacerda1,2, Gil Ribeiro1,2, Olga Amaral1,2,MCSa´ Miranda*,1,2 1Instituto de Gene´tica Me´dica Jacinto de Magalha˜es, Porto, Portugal; 2Instituto de Biologia Molecular & Celular (IBMC), Portugal Lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders individually considered as rare, and few data on its prevalence has been reported in the literature. The overall birth prevalence of the 29 different LSDs studied in the Portuguese population was calculated to be 25/100 000 live births, twice the prevalence previously described in Australia and in The Netherlands. The comparison of the prevalence profile of the LSDs presenting a prevalence higher than 0.5/100 000 in the Portuguese, Dutch and Australian populations showed, in the Portuguese, the existence of a higher prevalence of GM2 gangliosidoses (B variant), mucolipidoses (II and III), Niemman-Pick type C and metachromatic leukodystrophy (MLD), and a lower prevalence of Pompe and Fabry. The highest prevalence value for a single LSD is the one of GM2 gangliosidoses (B variant), corresponding to 3/100 000, a value which is significantly higher than the prevalence of the most frequent LSD in Dutch, Pompe disease (2/100 000) and Australians, Gaucher’s disease (GD) (1.8/100 000).
    [Show full text]
  • A New Simultaneous Measurement of Lysosphingolipids by LC-MS/MS
    Clin Chem Lab Med 2017; 55(3): 403–414 Open Access Giulia Polo, Alessandro P. Burlina, Thilini B. Kolamunnage, Michele Zampieri, Carlo Dionisi-Vici, Pietro Strisciuglio, Martina Zaninotto, Mario Plebani and Alberto B. Burlina* Diagnosis of sphingolipidoses: a new simultaneous measurement of lysosphingolipids by LC-MS/MS DOI 10.1515/cclm-2016-0340 population. The results demonstrate that the LC-MS/ Received April 21, 2016; accepted July 15, 2016; previously published MS method can quantify different LysoSLs and can be online August 17, 2016 used to identify patients with Fabry (LysoGb3), Gaucher Abstract and Krabbe (HexSph) diseases, prosaposine deficiency (LysoGb3 and HexSph), and Niemann-Pick disease types Background: Lysosphingolipids (LysoSLs) are deriva- A/B and C (LysoSM and LysoSM-509). tives of sphingolipids which have lost the amide-linked Conclusions: This LC-MS/MS method allows a rapid and acyl chain. More recently, LysoSLs have been identi- simultaneous quantification of LysoSLs and is useful as a fied as storage compounds in several sphingolipidoses, biochemical diagnostic tool for sphingolipidoses. including Gaucher, Fabry and Niemann-Pick diseases. To Keywords: Fabry; Gaucher; glucosylsphingosine; Krabbe; date, different methods have been developed to measure LC-MS/MS; LysoGb3; lysosphingolipids; lysosphingomy- each individual lysosphingolipid in plasma. This report elin; Niemann-Pick; psychosine. describes a rapid liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) assay for simulta- neous quantification of several LysoSLs in plasma. Introduction Methods: We analyzed the following compounds: hexo- sylsphingosine (HexSph), globotriaosylsphingosine Sphingolipidoses are a group of inherited lysosomal storage (LysoGb3), lysosphingomyelin (LysoSM) and lysosphin- disorders (LSD) caused by defects in the lysosomal degrada- gomyelin-509 (LysoSM-509).
    [Show full text]
  • Sphingolipidoses
    J Clin Pathol: first published as 10.1136/jcp.s3-8.1.94 on 1 January 1974. Downloaded from J. clini. Path., 27, Suppl. (Roy. Coll. Path.), 8, 94-105 Sphingolipidoses KONRAD SANDHOFF From the Max-Planck Institute for Psychiatry, Neurochemische Abteilung, Muntich, Gernmany Sphingolipidoses are inborn errors of metabolism, 1882; Sachs, 1896; Fabry, 1898; Anderson, 1898; characterized by the accumulation of sphingo- Alzheimer, 1910; Niemann, 1914; Krabbe, 1916; lipids. These lysosomal diseases (Hers, 1965) are due Scholz, 1925). With progress in the analysis of lipids to a deficiency in the degradative pathway (for these diseases have been more accurately defined as references see Hers and Van Hoof, 1973). So far, specific lipid storage diseases, and it has become neither changes in the extent of sphingolipid bio- feasible to classify them more systematically on the synthesis, ie, an overproduction, nor a deficiency basis of the main accumulating lipid (Aghion, 1934; of a transferase activity have been observed. The Klenk, 1934, 1942; Jatzkewitz, 1958; Svennerholm, latter could result in the absence of the enzyme 1962). However, these nomenclatures, the first product and/or accumulation of its substrates. based on clinical and pathomorphological descrip- Recessive inherited deficiencies of sphingolipid tions and the second based on the main accumulating degrading enzyme activities have been found in all lipid, are not always congruent. For example, tissues that have been tested. The sphingolipid diseases such as infantile GM2-gangliosidosis (Tay- hydrolases studied thus far have been shown to be of Sachs disease) are ganglioside storage diseases, lysosomal origin (for references, see Vaes, 1973). while no ganglioside accumulation has been found Most of these enzymes display an optimal activity in neuronal ceroid-lipofuscinoses (Batten-Vogt dis- in an acidic pH range.
    [Show full text]