The Lysosome and lysosomal The Lysosome and lysosomal storage disorders (LSD)storage disorders (LSD)

Part III A Part III A

Clinical profile of the LSDsClinical profile of the LSDs

Serge Melançon, MDSerge Melançon, MDFebruary 2009February 2009

SYNOPSIS

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

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

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.

HISTORY OF THE LSDs

Ernest GAUCHER (1854-1919)

Gaucher cell 1882

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)

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.

LSD Sub-Categories

LSD Sub-Categories

• 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.

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

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

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"

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

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

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

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

Biochemical and Cellular basis of lysosomal storage disorders

Biochemical and Cellular basis of lysosomal storage disorders

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 )

Biochemical and Cellular basis of LSDs…

5 In the Golgi, defective glycosylation could result in an enzyme with reduced catalytic activity

6 Alternatively, defective glycosylation with mannose-6-phosphate in the Golgi could produce an enzyme that cannot reach lysosomes

7 Defects in other transport steps from the Golgi could also lead to an LSD

8 Defects in integral lysosomal membrane proteins with transporter roles

9 Defects in proteins that are involved in other vital regulatory events of lysosomal function (LAMP2, lysosomal associated membrane protein 2)

Biochemical and Cellular basis of LSDs

Futerman AH & van Meer G (2004) 5:554-565Futerman AH & van Meer G (2004) 5:554-565

1 catalytic activity1 catalytic activity2 activator2 activator3 misfolding3 misfolding4 multienzyme complex4 multienzyme complex5 glycosylation5 glycosylation

6 M-6-P targetting6 M-6-P targetting7 other transport steps7 other transport steps8 membrane transporters8 membrane transporters9 membrane regulators9 membrane regulators