Helix - Repository KhNMU: страница

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Transcript Helix - Repository KhNMU: страница

Adenegan Adesola Idowu
5th year
Kharkov National Medical University
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Lysosomes are subcellular organelles responsible for the physiologic
turnover of cell constituents. Lysosomal storage diseases describe a
heterogeneous group
of dozens of rare inherited disorders characterized by the accumulation
of undigested or
partially digested macromolecules, which ultimately results in cellular
dysfunction and
clinical abnormalities. Several studies have explored different methods
of treatment, but
only are promising and safe even though they are very expensive.
The aim of this work is to describe a few of the various lysosomal
storage disorder.
What are LSDs?
 This are a group of approximately 50 rare inherited metabolic disorders
that result from defects in lysosomal function. Lysosomal storage
diseases result when the lysosome – a specific organelle in the body's
cells – malfunctions.
 It is commonly referred to as the cell’s recycling center when the
lysosome doesn’t function normally, excess products destined for
breakdown and recycling are stored in the cell.
 Because there are numerous specific deficiencies, storage diseases are
usually grouped biochemically by the accumulated metabolite
Basic cell biology
 Lysosomes are membrane-bound organelles that
function as the "stomachs" of eukaryotic cells .
 They are surrounded by a single membrane, have
an acidic interior pH level of about 5 maintained by
a proton pump, and carry a high content of
digestive enzymes. All require an acidic
environment to function properly and are called
acid hydrolases.
 Extracellular materials to be degraded in the
lysosome are brought into the cell by either
pinocytosis or phagocytosis.
 Intracellular materials, such as old organelles, are
brought into a lysosome by a process called
Classification of LSDs
I - Defective metabolism of glycosaminoglycans
" the mucopolysaccharidoses"
(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 IX (Hyaluronidase deficiency)
Multiple Sulfatase deficiency
II - Defective degradation of glycan portion of glycoproteins
Fucosidosis, type I and II
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
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
Mucolipidosis, type II and III
VIII - Transport and trafficking defects
Danon disease
Mucolipidosis type IV
Niemann-Pick type C
Infantile sialic acid storage disease
Salla disease
Tay-Sachs Disease and Sandhoff's Disease
Tay-Sachs disease
 Deficiency of hexosaminidase A
results in accumulation of GM2 in the
brain.Autosomal recessive; the most
common mutations are carried by
1/27 normal adults of Eastern
European (Ashkenazi) Jewish origin
 Diagnosis is clinical and can be
confirmed by enzyme assay
 In the absence of effective treatment,
management is focused on screening
adults of childbearing age in high-risk
populations to identify carriers (by
way of enzyme activity and mutation
testing) combined with genetic
Gaucher's Disease
Gaucher's disease is a
sphingolipidosis resulting from
glucocerebrosidase deficiency,
causing deposition of
glucocerebroside and related
Diagnosis is by enzyme analysis of
Gaucher's cells—lipid-laden tissue
macrophages in the liver, spleen,
lymph nodes, or bone marrow that
have a wrinkled tissue-paper
appearance—are diagnostic.
Enzyme replacement with placental
or recombinant glucocerebrosidase is
effective in types I and III; there is no
treatment for type II.
Mucopolysaccharidoses (MPS)
MPS are inherited deficiencies of enzymes involved in
glycosaminoglycan breakdown. Glycosaminoglycans
(previously termed mucopolysaccharides) are
polysaccharides abundant on cell surfaces and in
extracellular matrix and structures. Enzyme deficiencies
cause extensive bone, soft tissue, and CNS changes.
manifestations include coarse facial features,
neurodevelopmental delays and regression, joint
contractures, organomegaly
Diagnosis is confirmed by enzyme analysis of cultured
fibroblasts (prenatal) or peripheral WBCs (postnatal).
Treatment of MPS type I (Hurler's disease) is enzyme
replacement with α-l-iduronidase, which effectively halts
progression and reverses all non-CNS complications of
the disease
Hematopoietic stem cell (HSC) transplantation
Fabry's Disease
Fabry's disease (angiokeratoma
corporis diffusum) is an X-linked
deficiency of the lysosomal enzyme αgalactosidase A, which is needed for
normal trihexosylceramide catabolism.
Glycolipid (globotriaosylceramide)
accumulates in many tissues (eg,
vascular endothelium, lymph vessels,
heart, kidney).
Diagnosis is by assay of galactosidase
activity—prenatally in amniocytes or
chorionic villi and postnatally in serum
or WBCs.
Treatment is enzyme replacement with
recombinant α-galactosidase A
combined with supportive measures for
fever and pain. Kidney transplantation is
effective for treating renal failure.
Materials and methods
Enzymatic diagnosis of lysosomal storage disorders
Twenty-seven different lysosomal storage disorders were diagnosed in 545
individuals. The prevalence ranged from 1 per 57,000 live births for Gaucher
disease to 1 per 4.2 million live births for sialidosis. Eighteen of 27 disorders had
more than 10 diagnosed cases. As a group of disorders, the combined
prevalence was 1 per 7700 live births.
Bone marrow transplant
Enzyme Replacement therapy
Umbilical cord transplant
Pharmacological chaperone therapy
Gene therapy
Individually, lysosomal storage disorders are rare genetic diseases.
However, as a group, they are relatively common and represent an
important health problem. Their early diagnosis is paramount since
there are increasing possible therapies even though majority are still
going through clinical trials.
Thank you for your