1. Role of lysosomes?
    • Key component in the intercellular digestive tract.
    • Contain many hydrolytic enzymes.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. Pompe disease
    • Type 2 glycogenosis
    • a-1,4-glucosidase
    • glycogen
  8. GM1 gangliosidosis
    • type 1 infantile, generalized
    • Tyoe 2 Juvenile
    • GM1 ganglioside b-galactosidase
    • GM1 galctoside, galactose containing oligosaccharides
  9. Tay-sachs
    • GM2 ganglisidosis
    • Hexasaminidase alpha
    • GM2 gangliside
  10. Sandhoff disease
    • GM2 gangliosidosis
    • Hexasaminidase beta
    • GM2 ganglioside
  11. Metachromatic leukodystrophy
    • Sulfatidoses
    • arylsulfatase A
    • sulfatide
  12. Multiple sulfatase deficiency
    • Sulfatidoses
    • arylsulfitase A,B,C; steroid sulfatase; iduronate sulfatase; heparin N-sulfatase
    • sulfide, steroid sulfide, heparin sulfide, dermatan sulfide
  13. Krabbe disease
    • Sulfatidoses
    • Galactosylceramidase
    • galactocerebroside
  14. Fabry disease
    • sulfatidoses
    • a-galctosidase A
    • ceramide trihexoside
  15. Gaucher disease
    • Sulfatidoses
    • glucocrebrosidase
    • glucocerebroside
  16. Niemann-pick
    • Sulfatidoses
    • sphingomyelinase
    • sphingomyelin
  17. Hurler
    • MPS1
    • a-L-iduronidase
    • Dermatan sulfate, heparin sulfate
  18. Hunter
    • MPS2
    • L-iduronosulfate sulfatase
    • Dermatan sulfate, heparin sulfate
  19. Mucolipidoses ML
    • deficiency of phosphoralating enzymes essential for the synthesis of mannose-6-phosphate recognition marker. Enzymes are secreted extracellularly.
    • Mucopolysaccharides, glycolipids
  20. Frucosidosis
    • a-fucosidase
    • fucose containing sphingolipids
  21. Mannosidosis
    • a-mannosidase
    • mannose containing oligpsaccharides
  22. wolman disease
    • Acid lipase
    • Cholesterol esters, triglycerides
  23. Acid phosphate deficiency
    • Lysosomal acid phosphate
    • Phosphate esters
  24. Degradation of GM2 gangliodides?
    requires three polypeptides.
  25. 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
  26. 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.
  27. 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.
  28. 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.
  29. 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.
  30. Where to measure glucocerebrosidase?
    leukocytes of cultured skin fibroblasts
  31. What is a mucopolysaccharide?
    long chain complex carb linked with a protein to form a proteoglycan
  32. What GAGs accumulate in MPS
    dermatan sulfate, heparin sulfate, keratan sulfate, and chondrotin sulfate
  33. 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
  34. 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.
  35. Glycogen storage diseases
    • enzymes involved in the synthesis or degradation of glycogen
    • different enzyme in each tissue
  36. 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
  37. 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
  38. 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.
  39. 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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Path chapter 5