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Role of lysosomes?
- Key component in the intercellular digestive tract.
- Contain many hydrolytic enzymes.
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Route of production of lysosomal enzymes?
- Synthesized the the endoplasmic reticulum
- Transported to the golgi.
- In the golgi they undergo many post transcriptional modifications, attachment of mannose-6-phosphate to some oligosaccharide side chains.
- The mannose, address labels, bind to receptors on the internal golgi membrane and are segregated from other enzymes. They then are pinched off in vesicles and moved to lysosomes.
- The mannose-6-phosphate receptors are shuttled back to the golgi.
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Function of lysosomal acid hydrolyses?
- catalyze the breakdown of a variety of macromolecules.
- Can be derived from the turnover of intercellular organelles or acquired form outside the cell.
- With a deficiency of any of these enzymes the partially degraded by products can collect in the cell and inhibit normal cell function.
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5 routes of difunctional lysosomal enzymes?
- 1. synthesis of a catalytically inactive protein that will cross link with normal enzyme. Immunoassays will look normal but functional enzyme will be low.
- 2. Defect in post translational processing.
- 3. Lack of enzyme activator protein.
- 4. Lack of substrate activator protein. Proteins that bind with the substrate and facilitate its hydrolysis.
- 5. Lack of transport protein required to remove material from the lysosome.
- -Lysosomal storage disorders can result from the lack of any preteen essential for the normal function of lysosomes.
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What organs are effected?
- 1. The tissue where most of the material to be degraded is found.
- 2. The location of degradation.
- Ex. The brain is rich in gangliosides and hence defective hydrolysis of gangliosides results primarily in the storage within neurons and neurologic symptoms.
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7 subgroups of lysosomal storage diseases.
- 1. glycogenosis
- 2. Spingolipidoses
- 3. Sulfatidoses
- 4. Mucopolysaccharidoses MPS
- 5. Mucolipidoses
- 6. Other complex carb diseases.
- 7. Other lysosomal storage diseases.
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Pompe disease
- Type 2 glycogenosis
- a-1,4-glucosidase
- glycogen
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GM1 gangliosidosis
- type 1 infantile, generalized
- Tyoe 2 Juvenile
- GM1 ganglioside b-galactosidase
- GM1 galctoside, galactose containing oligosaccharides
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Tay-sachs
- GM2 ganglisidosis
- Hexasaminidase alpha
- GM2 gangliside
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Sandhoff disease
- GM2 gangliosidosis
- Hexasaminidase beta
- GM2 ganglioside
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Metachromatic leukodystrophy
- Sulfatidoses
- arylsulfatase A
- sulfatide
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Multiple sulfatase deficiency
- Sulfatidoses
- arylsulfitase A,B,C; steroid sulfatase; iduronate sulfatase; heparin N-sulfatase
- sulfide, steroid sulfide, heparin sulfide, dermatan sulfide
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Krabbe disease
- Sulfatidoses
- Galactosylceramidase
- galactocerebroside
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Fabry disease
- sulfatidoses
- a-galctosidase A
- ceramide trihexoside
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Gaucher disease
- Sulfatidoses
- glucocrebrosidase
- glucocerebroside
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Niemann-pick
- Sulfatidoses
- sphingomyelinase
- sphingomyelin
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Hurler
- MPS1
- a-L-iduronidase
- Dermatan sulfate, heparin sulfate
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Hunter
- MPS2
- L-iduronosulfate sulfatase
- Dermatan sulfate, heparin sulfate
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Mucolipidoses ML
- deficiency of phosphoralating enzymes essential for the synthesis of mannose-6-phosphate recognition marker. Enzymes are secreted extracellularly.
- Mucopolysaccharides, glycolipids
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Frucosidosis
- a-fucosidase
- fucose containing sphingolipids
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Mannosidosis
- a-mannosidase
- mannose containing oligpsaccharides
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wolman disease
- Acid lipase
- Cholesterol esters, triglycerides
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Acid phosphate deficiency
- Lysosomal acid phosphate
- Phosphate esters
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Degradation of GM2 gangliodides?
requires three polypeptides.
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Morphology of tay sachs
- GM2 accumulates in many tissues, heart, liver, spleen.
- Clinical dominance is the involvement of neurons of the central and autonomic nervous system and retina.
- Neurons are ballooned with cytoplasmic vacuoles
- Stains for fats are positive
- Whorled onion skin layers of membranes in lysosomes.
- Progressive distraction of neurons
- Retina ganglion cells are swollen with GM2, a cherry red spot appears in the macula.
- Appears normal at birth and begins to manifest symptoms at 6 months.
- motor and mental deterioration
- death at 2-3
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Niemann-Pick disease: Types A and B
- A: severe infantile form eight extensive neurological involvement, marked visceral accumulation of sphingomylen, progressive wasting and death within 3 years.
- B: Organomegaly but no CNS involvement
- Symptoms evident by 6 months: protuberant abdomen because of hepatosplenomegly.
- Once manifestations appear, they are followed by failure to thrive, vomiting, fever and lymphadenopathy.
- sphingomyelinase activity is in the liver and bone marrow.
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Morphology of Neimann-Pick
- accumulation of sphingomylin in lysosomes, particularly on the mononuclear phagocyte system.
- enlarged cells with sphingomyelin and cholesterol in them
- Stain positive for fat
- lysosomes take the form of parallel palisaded, zebra bodies
- spleen, live, lymph nodes, bone marrow, tonsils, gastrointestinal tract, and lungs.
- Large spleen and slightly large liver.
- 1/2 of patients have cherry red spot.
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Neimann-pick type C
- most common
- NPC-1 gene
- protein involved in cholesterol trafficking, cholesterol accumulates within the cell
- present in astrocytes, terminal axons and dendrites degenerate.
- Can present at hydrous fetal and still birth, neonatal hepatitis, chronic progressive neurologic disease.
- Childhood ataxia, suprnuclear palsy, psychomotor regression, hepatosplenomegaly and dysarthria.
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Gauchers
- Glucocerebrosidase
- Most common lysosomal storage disorder.
- Cleaves glucose molecules from ceramide
- accumulates in phagocytic cells
- glucocerebrosides are continually formed from the catabolism of glycolipids derived mainly from the cell membranes of senescent leukocytes and erythrocytes.
- detectible but low enzyme
- Gaucher cells look like tissue paper, fibrous
- Storage of lipids is toxic
- Expansion of marrow space leads to bone pain.
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Where to measure glucocerebrosidase?
leukocytes of cultured skin fibroblasts
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What is a mucopolysaccharide?
long chain complex carb linked with a protein to form a proteoglycan
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What GAGs accumulate in MPS
dermatan sulfate, heparin sulfate, keratan sulfate, and chondrotin sulfate
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General features of MPS
- includes liver spleen and blood vessels and heart
- coarse fascial features, clouding of cornea, joint stiffness, mental retardation
- mucopolysaccharide is often excreted in the urine.
- Hepatospleenomegaly 6-24 months
- Hunters, type 2, differs from hurlers in that it is X linked and has clear corneas
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MPS morphology
- mucopolysaccharide are found accumulated in mononuclear cells, endothelial cells, smooth muscle cells, and fibroblasts.
- spleen, liver, heart, and blood vessels
- cells are distended and have clearing of cytoplasm to create balloons.
- Zebra bodies in neurons
- Hepatospleenomegaly, skeletal deformaties, valvular lesions, subendothelial arterial depostits (leads to MI) brain lesions.
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Glycogen storage diseases
- enzymes involved in the synthesis or degradation of glycogen
- different enzyme in each tissue
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Formation of glycogen
- glucose to glucose-6-phosphate by hexokinase
- G6p to G1P by phosphoglucomutase
- G1P TO URIDINE DIPHOSPHATE, highly branched polymer
- aplpha 1,4 linkage
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breakdown of glycogen
- G1P is split in the liver and muscle by distance phosphorylases until about 4 glucoses remain, limit dextran
- then need a debranching enzyme
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Three principle types of glycogenoses
- 1. Hepatic type
- Von Gierke disease, Type 1, glucose-6-phosphatase, hepato and reno-megaly.
- convolutions, failure to thrive hypoglycemia, gout
- 2. Myopathic type
- McArdle syndrom Type V, muscle phosphorylase, skeletal muscle accumulates glycogen
- painful cramps with strenuous activity
- 3, misc type
- Pompe type II, acid maltase, heart muscle and liver.
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Alkaptonuria
- lack of hemogentisis oxadase
- build up of hemogentisis acid
- black urine
- deposit of pigment in articular cartilage of joints. Cartilage becomes brittle and fibrillated.
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