Download 8. Sphingolipid DISORDERS

LIPID STORAGE
DISEASES
CLASSIFICATION :
Mucopolysaccharidoses (variable nervous system
involvement)
Mucolipidoses
Glycoproteinoses
Glycogen storage
Sphingolipidoses
Lipid storage disorders
Multiple enzyme defects
Transport defects
Batten Disease
(Red = nervous system involvement)
INBORN ERRORS OF PHOSPHOLIPID, SPHINGOLIPID
METABOLISM
• Demyelination: Sclerosis multiplex
• White matter decrease of [phospholipid], [plasmenyl
ethanolamine], [sphingolipid]
• Sphingolipidosis:
•
•
•
•
Accumulation of complex lipids
Synthesis of complex lipids is not effected
Lack of specific (hydrolytic) lysomal enzymes
All tissues are effected
• Multiple sulfatase deficiency
Biosynthesis of membrane lipids and
steroids 1
3
THE PRINCIPAL CLASSES OF STORAGE AND MEMBRANE LIPIDS
All these lipids have either glycerol or sphingosine as the backbone.
LYSOSOMAL STORAGE DISEASES ( LSDs )
Are caused by defects in lysosomal hydrolases and proteins
essential to lysosomal biogenesis/function
Defects give rise to swollen lysosomes, developmental and
degenerative defects with varying involvement of the nervous
system due to ‘storage’ of material in the lysosome.
LSDs cause death in childhood (generally) after normal infancy.
LSDs are essentially incurable, but some are treatable to varying
degrees.
LYSOSOMAL STORAGE DISEASE (Amaurotic Idiocy)
Autosomal recessive diseases
Individually rare
Collectively occur @ 1/8000 live births
Cause death in early to late childhood (after normal infancy)
Varying involvement of the nervous system
All ‘store’ material in the lysosome due to defects in
substrate degradation or biogenesis of the lysosome
GENERAL OUTLINE OF LSD DYSFUNCTION:
Mutations arising in hydrolytic enzyme, co-factor or factor essential
of enzyme delivery to lysosome
Also, factors essential for lysosome function and biogenesis
(membrane proteins, channels and proteins of unknown function)
plus factors for protein traffic to lysosome
Material (substrate) continues to be delivered to lysosome
resulting in ‘stored’ material, leads to swollen lysosomes
Developmental dysfunction and early death: symptoms v. variable,
varying involvement of different tissues
- Usually, lack of an enzyme leads to accumulation of a
particular lipid, causing symptoms such as enlarged
spleen and liver, seizures, blindness, mental retardation
and death
Synthesis of complex lipids is not effected
• All tissues are effected
Degradation of sphingolipids
 by lysosomal enzymes (deficiencies result in lysosomal storage disease =
sphingolipidoses)
SPHINGOLIPIDOSES
genetic mutations, mental retardation, death
Name
Deficient enzyme
Acccumlated lipid
Fucosidosis
α-Fucosidase
H-Isoantigen
Generalized gangliosidosis
GM1-β-Galactosidase
GM1-Ganglioside
Tay-Sachs disease
Hexosaminidase A
GM2-Ganglioside
Tay-Sachs variant
Hexosaminid. A and B
GM2-Ganglioside
Fabry disease
α-Galactosidase
Globotriaosylceramide
Ceramide lactoside lipidosis
Ceramide lactosidase
Ceramide lactoside
Metachromatic leukodystrophy Arylsulfatase A
3-Sulfogalactosylceramide
Krabbe disease
β-Galactosidase
Galactosylceramide
Gaucher disease
β-Glucosidase
Glucosylceramide
Niemann-Pick disease
Sphingomyelinase
Sphingomyelin
Farber disease
Ceramidase
Ceramide
GANGLIOSIDOSIS
A disease of the accumulation of gangliosides is called
"Gangliosidosis", which is a form of Lipid storage disorder. The
gangliosidoses are two distinct genetic groups of diseases. Both are
autosomal recessive and affect males and females equally.
•GM1 gangliosidoses
•GM2 gangliosidoses
GANGLIOSIDOSIS
•The GM1 gangliosidoses are caused by a deficiency of
beta-galactosidase, with resulting abnormal storage of acidic
lipid materials in cells of the central and peripheral nervous
systems, but particularly in the nerve cells.
•GM1 has three forms: early infantile, late infantile, and adult.
THE GM2 GANGLIOSIDOSES cause the body to store
excess acidic fatty materials in tissues and cells, most
notably in nerve cells. these disorders result from a
deficiency of the enzyme beta-hexosaminidase. the
gm2 disorders include:
Tay-Sachs (GM2-gangliosidosis)
First described in 1880’s from ‘cherry-red’ spot in fundus (retina)
(lipid deposition in bipolar ganglion cells)
Genetic defect: Hexosaminidase A (HEXA)
storage material: GM2 ganglioside, globoside, glycolipids
Tay – Sachs Disease
.
Ceramid
Glu
Gal
GalNAc
NANA
hexosaminidase
Biosynthesis of membrane lipids and
steroids 1
15
TAY-SACHS DISEASE
Tay – Sachs Disease
• Deficiency of Hexosaminidase A
• Hexosaminidase A
• hydrolyses the N-acetylgalactosamine of GM2
ganglioside
• Mental retardation
• Macrocephalia
• Death at age 2-4
• Frequency: Ashkenazi Jewish
population 1:3500
Biosynthesis of membrane lipids and
steroids 1
17
Tay-Sachs disease (also known as GM2 variant B).
The incidence is particularly high among Eastern European and Ashkenazi
Jewish populations, as well as certain French Canadians and Louisianan
Cousins. Affected children appear to develop normally for the first few months
of life. Symptoms begin by 6 months of age and include progressive loss of
mental ability, dementia, decreased eye contact, increased startle reflex to
noise, progressive loss of hearing leading to deafness, difficulty in swallowing,
blindness, cherry-red spots in the retinas, and some paralysis. Seizures may
begin in the child’s second year. Children may eventually need a feeding tube
and they often die by age 4 from recurring infection.
No specific treatment is available. Anticonvulsant medications may initially
control seizures. Other supportive treatment includes proper nutrition and
hydration and techniques to keep the airway open. A much rarer form of the
disorder, which occurs in patients in their twenties and early thirties, is
characterized by unsteadiness of gait and progressive neurological
deterioration.
TAY-SACHS DISEASE
SANDHOFF DISEASE (VARIANT AB).
This is a severe form of Tay-Sachs disease. Onset usually occurs at
the age of 6 months and is not limited to any ethnic group.
Neurological symptoms may include progressive deterioration of
the central nervous system, motor weakness, early blindness,
marked startle response to sound, spasticity, myoclonus (shock-like
contractions of a muscle), seizures, macrocephaly (an abnormally
enlarged head), and cherry-red spots in the eye. Other symptoms
may include frequent respiratory infections, murmurs of the heart,
doll-like facial features, and an enlarged liver and spleen. There is
no specific treatment for Sandhoff disease. As with Tay-Sachs
disease, supportive treatment includes keeping the airway open
and proper nutrition and hydration. Anticonvulsant medications
may initially control seizures. Children generally die by age 3 from
respiratory infections.
A, Near end stage in a Spanish 13-year-old patient with
GM2-gangliosidosis variant B1 (photograph courtesy of
H.H. Goebel, Mainz
).
B, GM2-gangliosidosis in a 23-week-old fetus; and part of a
cortical neuron; early stage of membranous cytoplasmic bodies
(two clusters marked by crosses), i.e., lipid storing secondary
lysosomes, ×36,000 (courtesy W. Schlote, Tübingen).
• .
C, The large cells are neurons distended by lysosomal storage in
the medulla oblongata of a 1.5-year-old patient with GM1gangliosidosis. The small dark bodies are nuclei from increased
numbers
of glial cells (“reactive gliosis”).
• .
D, Cherry red macular spot in an infantile patient with GM2gangliosidosis variant B (Tay–Sachs disease). The dark red spot in
the middle of the light central area is secondary to lipid storage
in neuronal cells in this area; the storing cells have lost their
processes that normally cover the fovea centralis. The fovea
normally appears as yellow, but is changed to the red macular
spot showing the color of the choroidea behind the retina.
Sphingolipidoses
• .
Ceramide
Niemann-Pick Disease
P-Choline
sphingomyelinase
• Accumulation of sphingomyelin
Biosynthesis of membrane lipids and
steroids 1
25
Degradation of Sphingomyelin
• Sphingomyelin is degraded by
sphingomyelinase, a lysosomal enzyme that
hydrolytically removes phosphorylcholine,
leaving a ceramide.
• The ceramide is, in turn, cleaved by
ceramidase into sphingosine and a free fatty
acid
TAY-SACHS DISEASE
SPHINGOMYELIN DEGRADATION
• Niemann-Pick disease
is due to
sphingomyelinase
deficiency
• Sphingomyelin
accumulates in the
brain, spleen, and liver
NIEMANN-PICK DISEASE
Types of Niemann-Pick disease
•
•
•
•
Niemann-Pick disease (Types A and B)
Autosomal recessive disease
Inability to degrade sphingomyelin
The deficient enzyme is sphingomyelinase—a
type of phospholipase C
• Type A—less than 1% normal activity
• lipid deposit in liver and spleen  Increase
size of liver and spleen , Neuron-degeneration
• Type B—5% or more of normal activity
• little to no damage to neural tissue, but lungs,
spleen, liver, and bone marrow are affected
• Mostly commonly affect jews
Gaucher’s - disease
• Accumulation of glucocerebrosides in
reticuloendothelial cells of spleen, liver, and bone
marrow
• the most common of lysosomal storage disease
• Mental retardation
• .
Ceramide
Glu
b-glucosidase
Biosynthesis of membrane lipids and
steroids 1
32
TAY-SACHS DISEASE
Krabbe disease
• Accumulation of Galactosyl ceramide
Ceramide
Gal
• .
b-galactosidase
Biosynthesis of membrane lipids and
steroids 1
37
TAY-SACHS DISEASE
Sphingolipidoses
Ceramide
Glu
Fabry Disease
Gal
Gal
a-galactosidase
Biosynthesis of membrane lipids and
steroids 1
43
Fabry Disease
ECONOMIC COST
ERT is current most effective treatment (non neurodegenerative LSDs):
Disease
$)
Treatment
Annual Cost (per patient in
Gaucher
ERT
145,000 - 290,000
Gaucher
SRT
91,000
Fabry
ERT
156,000
Reasons:
High regulatory costs
Cost of research
Lack of competition (Orphan Drug Act 1983, US)
SUMMARY OF DEFECTS IN GANGLIOSIDE CATABOLISM THAT CONTRIBUTE TO
HUMAN DISEASE
Medical Condition
Defective Enzyme
Major
Accumulating
Metabolite
Generalized Gangliosidosis
Beta-Galactosidase
GM1
Tay-Sachs Disease
Hexosaminidase A
GM2
Gaucher’s Disease
Glucocerebrosidase
Glucosylcerebroside
Niemann-Pick Disease
Sphingomyelinase
Sphingomyelin
Sandhoff’s Disease
Hexosaminidase A&B
A Globoside*
Fabry’s Disease
Alpha-Galactosidase A
A Globoside*
*The globosides that are substrates for the defective enzymes in these diseases do not have
specific names, but are referred to by the broad term globoside.
Some
sphingolipidoses