1. The Lysosome and lysosomal storage disorders (LSD) Part III A Clinical profile of the LSDs Serge Melançon, MD February 2009

2. SYNOPSIS Introduction History of the LSDs LSD Sub-Categories Biochemical and Cellular basis of LSD Prevalence Presentation and progression Symptoms Management

3. Introduction Tay-Sachs disease was the first lysosomal storage disorder (LSD) described, in 1881 Gaucher disease was the second, in 1882 The first link between an enzyme deficiency and a LSD (  -glucosidase and Pompe disease) was published in 1963 by Hers The successful treatment of a LSD, Gaucher disease with β-glucosidase, became available in the early 1990s

4. Introduction It is now recognized that LSDs are not simply a consequence of pure storage, but result from perturbation of complex cell signaling mechanisms These in turn give rise to secondary structural and biochemical changes, which have important implications for disease progression and therapy. Significant challenges remain, particularly targetting treatment to the central nervous and skeletal systems.

5. HISTORY OF THE LSDs Ernest GAUCHER (1854-1919) Gaucher cell 1882

6. History of the LSDs Symptoms of some LSDs were described as early as the 1880s, Many had been described and classified before the lysosome was discovered in 1955 and before their biochemical and genetic basis was fully understood This is why they received common names (i.e.: Gaucher disease, name of discovering physician). Later, an additional, more clinically descriptive name often came into use (glucocerebrosidase deficiency)

7. History of the LSDs By the 1960s the role of lysosomes in cellular digestion and substrate management was well understood, Pompe became the first disease formally recognized as a lysosomal storage disorder. By the 1970s scientists had recognized many more LSDs as such and had begun identifying and classifying the specific enzymatic problems.

8. LSD Sub-Categories

9. Every LSD results from a problem with the lysosomal process by which enzymes rid cells of substrate. Lysosomes contain about 40 different hydrolytic enzymes, produced in cell cytoplasm and each responsible for breaking down a particular substrate.

10. LSD Sub-Categories When a lysosomal enzyme (or another protein that directs it) is deficient or malfunctioning, the substrate it targets accumulates, interfering with normal cellular activity. Healthy cell vs. LSD cell with accumulated substrate

11. LSD Sub-Categories Sub-categories are based on the type of enzymatic defect and/or stored substrate product. For example, the mucopolysaccharidoses (MPS) are grouped together because each results from an enzyme deficiency that causes accumulation of particular glycosaminoglycan (GAG) substrates. and diseases that fall under them

12. MPS I (Hurler, Hurler-Scheie, Scheie) MPS II (Hunter) MPS III (San filipo Types A,B,C and D) MPS IV (Morquio type A and B) MPS VI (Maroteaux-Lamy) MPS VII (Sly) MPS IX (Hyaluronidase deficiency) Multiple Sulfatase deficiency I - Defective metabolism of glycosaminoglycans " the mucopolysaccharidoses"

13. Aspartylglucosaminuria Fucosidosis, type I and II Mannosidosis Sialidosis, type I and II II - Defective degradation of glycan portion of glycoproteins III - Defective degradation of glycogen Pompe disease

14. Acid sphingomyelinase deficiency (Niemann-Pick A & B) Fabry disease Farber disease Gaucher disease, type I, II and III GM1 gangliosidosis, type I, II and III GM2 gangliosidosis (Tay-Sachs type I, II, III and Sandhoff Krabbe disease Metachromatic leukodystrophy, type I, II and III IV - Defective degradation of sphingolipid components

15. V - Defective degradation of polypeptides Pycnodysostosis VI - Defective degradation or transport of cholesterol, cholesterol esters, or other complex lipids Neuronal ceroid lipofuscinosis, type I, II, III and IV

16. VII - Multiple deficiencies of lysosomal enzymes Galactosialidosis Mucolipidosis, type II and III VIII - Transport and trafficking defects Cystinosis Danon disease Mucolipidosis type IV Niemann-Pick type C Infantile sialic acid storage disease Salla disease

17. Biochemical and Cellular basis of lysosomal storage disorders

18. 1.Most mutations result in the delivery of a defective enzyme with a reduced catalytic activity to lysosomes 2.Another (activator) protein required for optimal hydrolase activity is defective or absent 3.A mutation that causes misfolding results in defective transport of a lysosomal hydrolase out of the endoplasmic reticulum 4.Alternatively, defective transport of a lysosomal hydrolase out of the ER occurs because a multi- enzyme complex that is required for transport cannot form (Cathepsin A / sialidase /  -galactosidase )

19. Biochemical and Cellular basis of LSDs… 5In the Golgi, defective glycosylation could result in an enzyme with reduced catalytic activity 6Alternatively, defective glycosylation with mannose- 6-phosphate in the Golgi could produce an enzyme that cannot reach lysosomes 7Defects in other transport steps from the Golgi could also lead to an LSD 8Defects in integral lysosomal membrane proteins with transporter roles 9Defects in proteins that are involved in other vital regulatory events of lysosomal function (LAMP2, lysosomal associated membrane protein 2)

20. Biochemical and Cellular basis of LSDs Futerman AH & van Meer G (2004) 5:554-565 1 catalytic activity 2 activator 3 misfolding 4 multienzyme complex 5 glycosylation 6 M-6-P targetting 7 other transport steps 8 membrane transporters 9 membrane regulators