Lysosomal storage disease
Lysosomal storage diseases (LSK) are a group of about 45 hereditary related metabolic disorders caused by malfunctions in the lysosome be triggered. The diseases are monogenic . The term Lysosomal Storage Diseases (LSDs) is mostly used in the Anglo-Saxon specialist literature .
description
The lysosome is in most body cells existing cell organelle . The most important task of the lysosome is the breakdown ("digestion") of foreign as well as endogenous substances. These substances are macromolecules such as proteins , polysaccharides , nucleic acids and lipids . The breakdown is catalyzed by a number of enzymes . The enzymes are hydrolyzing (splitting) enzymes, so-called hydrolases such as proteases , nucleases and lipases .
If the activity of one of these enzymes is significantly reduced, that is, the enzyme can no longer catalyze the breakdown of a macromolecule or can only catalyze it much more slowly, the macromolecules to be broken down first accumulate in the cell. Above a certain concentration, they can enter the extracellular matrix in an uncontrolled manner via the plasma membrane and thus accumulate in the entire organism.
The cause of decreased enzyme activity can be a regulatory problem or a defect in the genome of the affected patient. In the latter case, the coding gene can be changed by mutation in such a way that the enzyme is changed in its secondary or tertiary structure and it is less effective. The genetic defect can to the next generation passed are. Depending on the inheritance , the passing on of the genetic defect does not automatically mean that the offspring is sick. Mucopolysaccharidosis type II ( Hunter syndrome ) and Fabry disease is an X-linked , and all other autosomal - recessive inherited.
The organs liver , spleen and skin , but also the nervous system , cartilage and bones are mostly affected by the reduced enzyme activity .
In addition to the reduced enzyme activity, missing or defective membrane transporters can also lead to an accumulation (storage) of metabolic products in the cell. This is the case with about five of the previously known lysosomal storage diseases.
The single defect in the protein or membrane transporter can lead to a very complex course of the disease. In general, lysosomal storage diseases are divided into three groups: severe infantile, moderately severe juvenile and mild adult forms.
Prevalence
The total incidence of all lysosomal storage diseases is around 1 in 7500 to 8000 newborns.
therapy
It is possible, genetically produced enzymes via infusion supplied to the patient in question. The enzyme replacement therapy (ERT) is in some diseases such as Hunter syndrome ( Idursulfase ) or Gaucher's disease ( imiglucerase ) become an established method. In addition, stem cell transplantation has proven itself in some syndromes .
Enzyme replacement therapy only offers a treatment option for internal organs and connective tissue. In the case of bone tissue or in the area of the central nervous system, it fails because the blood-brain barrier represents an insurmountable barrier for enzymes. In such cases, low-molecular compounds that prevent or at least reduce the formation of new macromolecules in the lysosome can be a therapeutic approach ( substrate reduction therapy (SRT)).
Another therapeutic approach is chaperone therapy . It is intended to activate the defective enzymes in vivo . As an active ingredient, sugar-like substances are to be used that have a positive effect on the correct folding of the enzymes and thus increase the activity of the enzymes or prevent their breakdown in the proteasome as part of the protein quality control. The name is misleading in that only the function of a chaperone (a class of proteins that are also involved in the folding of polypeptide chains) is to be imitated, but iminoaldites ( pharmacological chaperones ) are actually used instead of the body's own molecular chaperones. The effectiveness of this class of active ingredients is currently being tested in Gaucher's disease and Fabry's disease ( Migalastat , in clinical phase III). There is still no approved active ingredient available.
A promising future therapeutic approach, but still largely in its infancy, is gene therapy .
The individual diseases
| syndrome | Enzyme / transporter | Chromosome / gene locus (gene) |
Prevalence | ICD-10 | OMIM |
| Mucopolysaccharidoses | |||||
| Hurler-Pfaundler Syndrome (MPS IH) | α-L- iduronidase | 4q 16.3 | |||
| Scheie's Disease (MPS IS) | α-L-iduronidase | 4q16.3 | |||
| Hurler-Scheie Syndrome (MPS IH / S) | α-L-iduronidase | 4q16.3 | |||
| Hunter Syndrome (MPS II) | Iduronate 2 sulfatase | Xq 27.3-28 | 1: 136,000 | E76.1 | |
| Sanfilippo Syndrome Type A (MPS IIIA) | Heparan sulfate sulfamidase (SGSH) | 17q 25.3 | 1: 114,000 | E76.2 | |
| Sanfilippo syndrome type B (MPS IIIB) | α-N- acetylglucose amidase (NAGLU) | 17q21 | 1: 211,000 | E76.2 | |
| Sanfilippo Syndrome Type C (MPS IIIC) | Acetyl-CoA α-glucosaminide-N-acetyltransferase (HGSNAT) | 8p 11.1 | 1: 1,407,000 | E76.2 | |
| Sanfilippo syndrome type D (MPS IIID) | N-acetyl-glucosamine-6-sulfate sulfatase (GNS) | 12q 14 | 1: 1,056,000 | E76.2 | |
| Morquio Syndrome Type A (MPS IVA) | N-acetyl-glucosamine-6-sulfate sulfatase | 16q 24.3 | 1: 169,000 | ||
| Morquio syndrome type B (MPS IVB) | β-galactosidase | 3p 21.3 | |||
| Morquio Syndrome Type C (MPS IVC) | |||||
| Maroteaux-Lamy Syndrome (MPS VI) | Aryl sulfatase B | 5q 11-13 (ARSB) | 1: 235,000 | ||
| Sly Syndrome (MPS VII) | β-glucuronidase | 7q 21.1-11 | 1: 2,111,000 | ||
| Mucolipidoses (ML) | 1: 325000 | ||||
| Sialidosis type II (ML type I) | Neuraminidase | 6p 21.3 | 1:> 4,200,000 | E77.1 | |
| I-cell disease (ML type IIα / β) | Phosphotransferase | 12q 23.3 (GNPTAB) | 1: 330,000 (including ML III) | E77.0 | |
| Pseudo-Hurler polydystrophy (ML type IIIα / β) | Phosphotransferase | 12q23.3 (GNPTAB) | 1: 330,000 (including ML II) | E77.0 | |
| Sialolipidosis (ML type IV) | Mucolipin-1 | 19p 13.3-p13.2 (MCOLN1) | |||
| Sphingolipidoses | |||||
| GM1 gangliosidosis type I | β-galactosidase | 3p 21.3 (GLB1) | 1: 384,000 (type I, II + III) | E75.1 | |
| GM1 gangliosidosis type II | β-galactosidase | 3p21.3 | 1: 384,000 (type I, II + III) | E75.1 | |
| GM1 gangliosidosis type III | β-galactosidase | 3p21.3 | 1: 384,000 (type I, II + III) | E75.1 | |
| Tay-Sachs syndrome | β- hexosaminidase A | 15q 23-24 (HEXA) | 1: 201,000 | E75.0 | |
| Sandhoff disease | β-hexosaminidase A & B | 5q 13 (HEXB) | 1: 130,000 | E75.0 | |
| Tay-Sachs syndrome AB variant (GM2 activator deficiency) | GM2 activator | 5q31.3-q33.1 | E75.0 | ||
| Fabry disease | α-galactosidase | Xq 22 (GLA) | 1: 117,000 | E75.2 | |
| Gaucher's disease type I | Glucocerebrosidase | 1q 22 (GBA) | 1: 57,000 (all Gaucher disease together) | E75.2 | |
| Gaucher's disease type II | Glucocerebrosidase | 1q22 (GBA) | 1: 57,000 (all Gaucher disease together) | E75.2 | |
| Gaucher's disease type III | Glucocerebrosidase | 1q22 (GBA) | 1: 57,000 (all Gaucher disease together) | E75.2 | |
| Gaucher's disease type IIIC | Glucocerebrosidase | 1q22 (GBA) | 1: 57,000 (all Gaucher disease together) | E75.2 | |
| Gaucher's disease perinatally fatal | Glucocerebrosidase | 1q22 (GBA) | 1: 57,000 (all Gaucher disease together) | E75.2 | |
| Metachromatic Leukodystrophy (MLD) | Aryl sulfatase A. | 22q 13.3 (ARSA) | 1: 92,000 | E75.2 | |
| Saposin B deficiency | Saposin B | 10q 22.1 (PSAP) | |||
| Krabbe's disease | Galactosylceramidase | 14q 31 (GALC) | 1: 201,000 | ||
| Crab's disease atypical, SAPOSIN-A deficiency | Saposin A | 10q22.1 (PSAP) | |||
| Niemann-Pick disease type A | Sphingomyelinase | 11p 15.4-p15.1 (SMPD1) | 1: 218,000 (A + B together) | E75.2 | |
| Niemann-Pick disease type B | Sphingomyelinase | 11p15.4-p15.1 (SMPD1) | 1: 218,000 (A + B together) | E75.2 | |
| Niemann-Pick disease type C1 | NPC1 protein | 18q 11-q12 (NPC1) | 1: 211,000 | E75.2 | |
| Niemann-Pick disease type C2 | NPC2 protein | 14 24.3 (NPC2) | E75.2 | ||
| Gaucher's disease saposin C deficiency | Saposin C | 10q22.1 (PSAP) | |||
| Farber Syndrome | acid ceramidase | 8p 22-p21.3 (ASAH) | |||
| Multiple sulfatase deficiency | Fgly-Generating Enzymes | 3p26 (SUMF1) | 1: 407,000 | ||
| Oligosaccharidoses | |||||
| α-mannosidosis | α-mannosidase | 19cen -q12 (MAN2B1) | 1: 1,056,000 | E77.1 | |
| β-mannosidosis | β-mannosidase | 4q 22-q25 (MANBA) | E77.1 | ||
| Fucosidosis | α-fucosidase | 1p 34 (FUCA1) | 1: 2,000,000 | E77.1 | |
| Aspartyl glucosaminuria | Aspartyl glucosaminidase | 4q32-33 (AGA) | 1: 2,111,000 | E77.1 | |
| Schindler's disease type I | α- galactosaminidase | 22q 11 (NAGA) | 1: 528,000 | ||
| Sialic Acid Storage Disease Infantile (ISSD) | Sialic acid transporter ( sialin ) | 6q 14-15 (SLC17A5) | 1: 500,000 | ||
| Sialic Acid Storage Disease adult (Salla Disease) | Sialic acid transporter (sialin) | 6q14-15 (SLC17A5) | 1: 500,000 | ||
| Galactosialidosis (Goldberg Syndrome) | Protective protein | 20q 13.1 (GLB2) | |||
| Neural ceroid lipofuscinosis | |||||
| Neuronal ceroid lipofuscinosis 1 | Palmitoyl thioesterase | 1p 32 (CLN1) | |||
| Neural ceroid lipofuscinosis 2 | Tripeptidyl peptidase 1 | 11p 15.5 (TPP1) | |||
| Neural ceroid lipofuscinosis 3 (Batten syndrome) | 16p 12.1 (CLN3) | ||||
| Ceroid neural lipofuscinosis 4A | |||||
| Neuronal ceroid lipofuscinosis 4B | |||||
| Neural ceroid lipofuscinosis 5 | 13q 21.1-q32 (CLN5) | ||||
| Neural ceroid lipofuscinosis 6 | 15q 21-q23 (CLN6) | ||||
| Neural ceroid lipofuscinosis 7 | 4q 28.1-q28.2 (MFSD8) | ||||
| Neural ceroid lipofuscinosis 8 | 8p 23 (CLN8) | ||||
| Neuronal ceroid lipofuscinosis 8 (Nordic epilepsy) | 8p23 (CLN8) | ||||
| Neural ceroid lipofuscinosis 9 | |||||
| Neural ceroid lipofuscinosis 10 | 11p15.5 (CTSD) | ||||
| Other | |||||
| Pycnodysostosis | Cathepsin K | 1q 21 (CTSK) | 1: 146,000 | ||
| Pompe disease | Lysosomal α-glucosidase | 17q 25.2-3 (ATM) | 1: 192,000 | E74.0 | |
| Cystinosis , nephropathic | Cystine transporter | 17p13 (CTNS) | 1: 528,000 | E72.0 | |
| Cystinosis, adult, not nephropathic | Cystine transporter | 17p13 (CTNS) | 1: 528,000 | E72.0 | |
| Wolman Disease / CESD | lysosomal acid lipase | 10q 23.2–23.3 (LIPA) | 1: 700,000 | E75.5 |
Individual evidence
- ↑ a b H. I. Huppertz: What opportunities does enzyme replacement therapy open up? In: Zeitschrift für Rheumatologie , Volume 65, 2006, pp. 44–45.
- ↑ a b B. Kösters: Preparative two-dimensional separation of membrane proteins using the example of the human lysosomal proteome. Dissertation, Philipps University Marburg, 2001
- ^ A b E. Paschke: Investigations for the early diagnosis and prognosis of the phenotype in lysosomal storage diseases. ( Memento of December 23, 2007 in the Internet Archive ) Project description, accessed on January 1, 2009
- ↑ M. Beck chaperone therapy with M. Gaucher. ( Memento of the original from August 16, 2010 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. (PDF; 788 kB) In: Newsletter Villa Metabolica 3, 2008
- ↑ Clinical study (phase III): Study of the Effects of Oral AT1001 (Migalastat Hydrochloride) in Patients With Fabry Disease at Clinicaltrials.gov of the NIH
- ↑ unknown: hope in genetic storage diseases. ( Page no longer available , search in web archives ) Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice. In: Doctors Week 41, 2003
- ↑ Source for the prevalences of the table: T. Gerstner: Page no longer available , search in web archives: Lysosomal storage diseases. University of Heidelberg
- ^ Hurler syndromes. In: Online Mendelian Inheritance in Man . (English).
- ↑ Scheie Syndromes. In: Online Mendelian Inheritance in Man . (English).
- ↑ Hurler-Scheie Syndromes. In: Online Mendelian Inheritance in Man . (English).
- ↑ MUCOPOLYSACCHARIDOSIS TYPE II. In: Online Mendelian Inheritance in Man . (English).
- ↑ MUCOPOLYSACCHARIDOSIS TYPE IIIA. In: Online Mendelian Inheritance in Man . (English).
- ↑ MUCOPOLYSACCHARIDOSIS TYPE IIIB. In: Online Mendelian Inheritance in Man . (English).
- ↑ MUCOPOLYSACCHARIDOSIS TYPE IIIC. In: Online Mendelian Inheritance in Man . (English).
- ↑ MUCOPOLYSACCHARIDOSIS TYPE IIIC. In: Online Mendelian Inheritance in Man . (English).
- ↑ Morquio SYNDROME A. In: Online Mendelian Inheritance in Man . (English).
- ↑ MORQUIO SYNDROME B. In: Online Mendelian Inheritance in Man . (English).
- ↑ Morquio SYNDROME C. In: Online Mendelian Inheritance in Man . (English).
- ↑ MUCOPOLYSACCHARIDOSIS TYPE VI. In: Online Mendelian Inheritance in Man . (English).
- ↑ MUCOPOLYSACCHARIDOSIS TYPE VII. In: Online Mendelian Inheritance in Man . (English).
- ↑ NEURAMINIDASE DEFICIENCY. In: Online Mendelian Inheritance in Man . (English).
- ↑ MUCOLIPIDOSIS II ALPHA / BETA. In: Online Mendelian Inheritance in Man . (English).
- ↑ MUCOLIPIDOSIS III ALPHA / BETA. In: Online Mendelian Inheritance in Man . (English).
- ↑ Mucolipidosis IV. In: Online Mendelian Inheritance in Man . (English).
- ↑ GM1-GANGLIOSIDOSIS, TYPE I. In: Online Mendelian Inheritance in Man . (English).
- ↑ GM1-GANGLIOSIDOSIS, TYPE II. In: Online Mendelian Inheritance in Man . (English).
- ↑ GM1-GANGLIOSIDOSIS, TYPE III. In: Online Mendelian Inheritance in Man . (English).
- ↑ TAY-SACHS DISEASE; TSD. In: Online Mendelian Inheritance in Man . (English).
- ↑ SANDHOFF DISEASE. In: Online Mendelian Inheritance in Man . (English).
- ↑ TAY-SACHS DISEASE, FROM VARIANT. In: Online Mendelian Inheritance in Man . (English).
- ↑ FABRY DISEASE. In: Online Mendelian Inheritance in Man . (English).
- ↑ GAUCHER DISEASE TYPE I. In: Online Mendelian Inheritance in Man . (English).
- ↑ GAUCHER DISEASE TYPE II. In: Online Mendelian Inheritance in Man . (English).
- ↑ GAUCHER DISEASE, TYPE III. In: Online Mendelian Inheritance in Man . (English).
- ↑ GAUCHER DISEASE, TYPE IIIC. In: Online Mendelian Inheritance in Man . (English).
- ↑ GAUCHER DISEASE, PERINATAL LETHAL. In: Online Mendelian Inheritance in Man . (English).
- ↑ METACHROMATIC LEUKODYSTROPHY. In: Online Mendelian Inheritance in Man . (English).
- ↑ METACHROMATIC LEUKODYSTROPHY DUE TO SAPOSIN B DEFICIENCY. In: Online Mendelian Inheritance in Man . (English).
- ↑ CRAB DISEASE. In: Online Mendelian Inheritance in Man . (English).
- ↑ KRABBE DISEASE, ATYPICAL, DUE TO SAPOSIN A DEFICIENCY. In: Online Mendelian Inheritance in Man . (English).
- ↑ NIEMANN-PICK DISEASE, TYPE A. In: Online Mendelian Inheritance in Man . (English).
- ↑ NIEMANN-PICK DISEASE, TYPE B. In: Online Mendelian Inheritance in Man . (English).
- ↑ NIEMANN-PICK DISEASE, TYPE C1; NPC1. In: Online Mendelian Inheritance in Man . (English).
- ↑ NIEMANN-PICK DISEASE, TYPE C1. In: Online Mendelian Inheritance in Man . (English).
- ↑ GAUCHER DISEASE, ATYPICAL, DUE TO SAPOSIN C DEFICIENCY. In: Online Mendelian Inheritance in Man . (English).
- ↑ COLOR LIPOGRANULOMATOSIS. In: Online Mendelian Inheritance in Man . (English).
- ↑ MULTIPLE SULFATASE DEFICIENCY; MSD. In: Online Mendelian Inheritance in Man . (English).
- ↑ MANNOSIDOSIS, ALPHA B, LYSOSOMAL. In: Online Mendelian Inheritance in Man . (English).
- ↑ MANNOSIDOSIS, BETA A, LYSOSOMAL. In: Online Mendelian Inheritance in Man . (English).
- ↑ FUCOSIDOSIS. In: Online Mendelian Inheritance in Man . (English).
- ↑ ASPARTYL GLUCOSAMINURIA. In: Online Mendelian Inheritance in Man . (English).
- ↑ SCHINDLER DISEASE, TYPE I. In: Online Mendelian Inheritance in Man . (English).
- ↑ INFANTILE SIALIC ACID STORAGE DISORDER. In: Online Mendelian Inheritance in Man . (English).
- ↑ SIALURIA, FINNISH TYPE. In: Online Mendelian Inheritance in Man . (English).
- ↑ NEURAMINIDASE DEFICIENCY WITH BETA-GALACTOSIDASE DEFICIENCY. In: Online Mendelian Inheritance in Man . (English).
- ↑ CEROID LIPOFUSCINOSIS, NEURONAL, 1; CLN1. In: Online Mendelian Inheritance in Man . (English).
- ↑ CEROID LIPOFUSCINOSIS, NEURONAL, 2; CLN2. In: Online Mendelian Inheritance in Man . (English).
- ↑ NEURONAL CEROID LIPOFUSCINOSIS, JUVENILE; JNCL. In: Online Mendelian Inheritance in Man . (English).
- ↑ CEROID LIPOFUSCINOSIS, NEURONAL, 4A, AUTOSOMAL RECESSIVE; CLN4A. In: Online Mendelian Inheritance in Man . (English).
- ↑ CEROID LIPOFUSCINOSIS, NEURONAL, 4B, AUTOSOMAL DOMINANT; CLN4B. In: Online Mendelian Inheritance in Man . (English).
- ↑ CEROID LIPOFUSCINOSIS, NEURONAL, 5; CLN5. In: Online Mendelian Inheritance in Man . (English).
- ↑ CEROID LIPOFUSCINOSIS, NEURONAL, 6; CLN6. In: Online Mendelian Inheritance in Man . (English).
- ↑ CEROID LIPOFUSCINOSIS, NEURONAL, 7; CLN7. In: Online Mendelian Inheritance in Man . (English).
- ↑ CEROID LIPOFUSCINOSIS, NEURONAL, 8; CLN8. In: Online Mendelian Inheritance in Man . (English).
- ↑ CEROID LIPOFUSCINOSIS, NEURONAL, 8, NORTHERN EPILEPSY VARIANT. In: Online Mendelian Inheritance in Man . (English).
- ↑ CEROID LIPOFUSCINOSIS, NEURONAL, 9; CLN9. In: Online Mendelian Inheritance in Man . (English).
- ↑ CEROID LIPOFUSCINOSIS, NEURONAL, 10; CLN10. In: Online Mendelian Inheritance in Man . (English).
- ↑ PYCNODYSOSTOSIS. In: Online Mendelian Inheritance in Man . (English).
- ↑ glycogen STORAGE DISEASE II. In: Online Mendelian Inheritance in Man . (English).
- ↑ CYSTINOSIS, NEPHROPATHIC; CTNS. In: Online Mendelian Inheritance in Man . (English).
- ↑ CYSTINOSIS, ADULT NONNEPHROPATHIC. In: Online Mendelian Inheritance in Man . (English).
- ↑ WOLMAN DISEASE. In: Online Mendelian Inheritance in Man . (English).
literature
- A. Mehta, M. Beck, A. Linhart, G. Sunder-Plassmann, U. Widmer: History of lysosomal storage diseases: an overview. Oxford PharmaGenesis, 2006, PMID 21290707
- EJ Bonten, et al. a .: Targeting macrophages with baculovirus-produced lysosomal enzymes: implications for enzyme replacement therapy of the glycoprotein storage disorder galactosialidosis. In: FASEB journal: official publication of the Federation of American Societies for Experimental Biology. Volume 18, Number 9, June 2004, pp. 971-973, ISSN 1530-6860 . doi : 10.1096 / fj.03-0941fje . PMID 15084520 .
Web links
- http://www.icld-hamburg.de/ International Center for Lysosomal Storage Diseases (ICLD) in Hamburg