Transcript The Lysosomes and lysosomal storage disorders (LSD)

The Lysosome and lysosomal
storage disorders (LSD)
Part III A
Clinical profile of the LSDs
Serge Melançon, MD
February 2009
SYNOPSIS
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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
Gaucher cell 1882
Ernest GAUCHER (1854-1919)
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
I - Defective metabolism of glycosaminoglycans
" the mucopolysaccharidoses"
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
II - Defective degradation of glycan
portion of glycoproteins
Aspartylglucosaminuria
Fucosidosis, type I and II
Mannosidosis
Sialidosis, type I and II
III - Defective degradation of glycogen
Pompe disease
IV - Defective degradation of sphingolipid
components
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
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 multienzyme complex that is required for transport cannot
form (Cathepsin A / sialidase / -galactosidase )
Biochemical and Cellular basis of LSDs…
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In the Golgi, defective glycosylation could result in
an enzyme with reduced catalytic activity
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Alternatively, defective glycosylation with mannose6-phosphate in the Golgi could produce an enzyme
that cannot reach lysosomes
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Defects in other transport steps from the Golgi
could also lead to an LSD
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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
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
Futerman AH & van Meer G (2004) 5:554-565