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  1. 1. M.Prasad Naidu MSc Medical Biochemistry, Ph.D.Research Scholar
  2. 2.  The Lipids are a heterogeneous group of compounds which are relatively insoluble in water, but freely soluble in nonpolar organic solvents like benzene, chloroform, ether, hot alcohol, acetone,etc.  Lipids are classified based on their chemical nature
  3. 3.  Simple lipids  Compound lipids  Derived lipids  Lipids complexed to other compounds
  4. 4.  Compound lipids are esters of fatty acids containing groups in addition to an alcohol and a fatty acid.  Compound lipids are phospholipids, glycolipids and other complex lipids.
  5. 5. Glycolipids  Glycolipids are widely distributed in every tissue of the body, particularly in nervous tissue such as brain.  They occur particularly in the outer leaflet of the plasma membrane, where they contribute to cell surface carbohydrates.
  6. 6.  The major glycolipids found in animal tissues are glycosphingolipids.  They contain ceramide and one or more sugars.  Ceramide + Glucose ----- Glucocerebroside  Ceramide + Galactose ---Galactocerebroside
  7. 7. Globosides ( ceramide oligosaccharides )  They contain two or more hexoses or hexosamines, attached to a ceramide molecule.  Ceramide + Galactose + Glucose -- Lactosyl ceramide  Lactosyl ceramide is a component of erythrocyte membrane.
  8. 8. Gangliosides  They are formed when ceramide oligo-saccharides have at least one molecule of NANA ( N-acetyl neuraminic acid ) ( Sialic acid) attached to them.  Ceramide – Glucose – galactose – NANA ; this is designated as GM3 ( ganglioside M3 ).
  9. 9.  Gangliosides contribute to stability of paranodal junctions and ion channel clusters in myelinated nerve fibres.  Autoantibodies to GM1 disrupt lipid rafts, paranodal or nodal structures, and ion channel clusters in peripheral motor nerves.
  10. 10.  A specific ganglioside on intestinal mucosal cell binds to the b subunit of the Cholera toxin when the a subunit enters the cell.  It keeps the level of cellular cAMP raised by inhibition of GTPase activity of the G protein.  Gangliosides also act as receptors for other toxins like tetanus toxin, and toxins of viral pathogens.
  11. 11. Sulpholipids or sulfatides  These are formed when sulfate groups are attached to ceramide oligosaccharides. Sulphated Cerebrosides Sulphated globosides Sulphated Gangliosides  All these complex lipids are important components of membranes of nervous tissue.
  12. 12. Synthesis of Glycosphingolipids  synthesis of glycosphingolipids occurs primarily in the Golgi apparatus by sequential addition of glycosyl monomers transferred from UDP-sugar donors to the acceptor molecule.
  13. 13. Degeneration of Glycosphingolipids  Glycosphingolipids are internalized by endocytosis.  All of the enzymes required for the degrative process are present in lysosomes, which fuse with the endocytotic vesicles.  The lysosomal enzymes hydrolytically and irreversibly cleave specific bonds in the glycosphingolipid.
  14. 14.  Failure of degradation of these compounds results in accumulation of these complex lipids in CNS.  This group of inborn errors is known as lipid storage diseases.
  15. 15. Lipid storage diseases  They are called as spingolipidoses. Gaucher’s disease  most common lysosomal storage diseases  enzyme deficiency – Beta glucosidase
  16. 16.  lipid accumulating – Glucosylceramide  Clincal symptoms 3 types – adult, infantile, juvenile Hepatosplenomegaly, erosion of long bones, moderate anemia, mental retardation in infants
  17. 17. Niemann- pick disease  enzyme deficiency – sphingomyelinase  lipid accumulating – sphingomyelin  Clinical symptoms severe CNS damage, mental retardation, hepatosplenomegaly, cherry rod spot in macula neurodegenerative course ( type A ) death occurs by 2 years of age
  18. 18. Krabbe’s disease  Globoid cell dystrophy  enzyme deficiency – Beta galactosidase  lipid accumulating – Galactosylceramide  Clinical symptoms severe mental retardation, total absence of myelin in CNS, Globoid bodies in white matter
  19. 19. Metachromatic leukodystrophy  enzyme deficiency – arylsulfatase  lipid accumulating – 3-sulfogalactosylceramide  Clinical symptoms Mental retardation and psychologic disturbances in adults, demyelination, neurological deficit, difficulty in speech and optic atrophy, progressive paralysis, dementia in adult form, nerves stain yellowish-brown with cresyl violet – metachromasia
  20. 20. Fabry’s disease  enzyme deficiency – alpha galactosidase  lipid accumulating – Globotriaosylceramide  Clinical symptoms progressive renal failure, death by 5 years of age, skin rash, purplish papules appear, X – linked inheritance
  21. 21. Tay-Sachs disease  enzyme deficiency – Hexosaminidase A  lipid accumulating – GM2 Ganglioside  Clinical symptoms Incidence 1 in 6000 births mental retardation, blindness, cherry red spot in the macula, muscular weakness, progressive deterioration, death by 3-4 years
  22. 22. Generalized gangliosidoses  enzyme deficiency – Beta-galactosidase  lipid accumulating – Ganglioside (GM1)  Clinical symptoms mental retardation, hepatosplenomegaly, skeletal deformities, foam cells in bone marrow, cherry-red macula in the retina
  23. 23. Lactosyl ceramidoses  enzyme deficiency – Beta-galactosidase  lipid accumulating – Lactosyl ceramide  Clinical symptoms mainly CNS and reticulo-endothelial system affected
  24. 24. Sandhoff’s disease  enzyme deficiency – Hexosaminidase A and B  lipid accumulating – Globoside  Clinical symptoms neurological deficit, mental retardation
  25. 25. Farber disease  enzyme deficiency – Ceramidase  lipid accumulating – ceramide  Clinical symptoms hoarseness, dermatitis, subcutaneous nodules of lipid-laden cells, tissues show granulomas, skeletal deformation, painful and progressive joint deformity, mental retardation, fatal in early life
  26. 26. Laboratory diagnosis  A specific sphingolipidosis can be diagnosed by measuring enzyme activity in cultured fibroblasts or peripheral leukocytes, or by analysis of DNA.  Histologic examination of the affected tissue is also useful.
  27. 27.  Shell-like inclusion bodies are seen in Tay-Sachs disease and a wrinkled tissue paper appearance of the cytosol is seen in Gaucher disease.  All these diseases can be diagnosed prenatally by amniocentesis and culture of amniotic fluid cells.
  28. 28.  Lysosomal storage diseases are diagnosed by quantitative enzyme assay.  Carriers are best diagnosed by DNA analysis of the common mutations.
  29. 29. Treatment  Replacement of deficient enzyme has been tried in Gaucher’s disease, with limited success.  Gaucher disease and Fabry disease are treated by recombinant human enzyme replacement therapy, but the monetary cost is extremely high.
  30. 30.  Gaucher disease has also been treated by bone marrow transplantation.  Other promising approaches are substrate deprivation therapy to inhibit the synthesis of sphingolipids and chemical chaperone therapy.  Gene therapy for lysosomal disorders is also currently under investigation.
  31. 31. thank you