1. Sphingolipidoses: sphingolipids
    derivatives of ceramide
  2. Ceramide is formed by
    esterification of a fatty acid with the amino group sphingosine
  3. Sphingolipids localized mainly in
    the white matter of the CNS
  4. X group of sphingomyelin is
    phosphoryl choline
  5. X group of cerebroside
    galactose or glucose
  6. X group of ganglioside
    silica acid-containing oligosaccharide
  7. Sphingomyelins
    • most abundant sphingolipid found in mammalian membranes especially the plasma membrane.
    • They are found in nerve tissue and erythrocytes
  8. Cerebrosides (galactosylceramide and glucosylceramide)
    • are found predominantly in the brain and PNS
    • with high concentrations in the myelin sheath
    • major constituents of oligodendrocytes
  9. Gangliosides
    • found primarily in the ganglion cells of the CNS
    • particularly at nerve endings
    • they are concentrated in rafts in the plasma membrane (signal transduction)
    • brain has 50-500 times more gangliosides than most non-neural tissues
  10. Sulfatides
    • are cerebrosides with sulfated galactosyl residues
    • synthesized primarily in oligodendrocytes of the CNS
  11. Sphingolipidoses: General Principles
    • Generally cause neuronal or white matter disease
    • Onset typically in childhood
    • progressive fatal: course
    • no definitive treatment
    • Neuronal disease: brain and other structures to some extent
    • White matter disease: leukodystrophy
    • Loss of cells/tissue
    • Reactive gliosis
    • Atrophy of brian in later stages
    • Characteristic EM findings
  12. Neuronal Storage
    • Cytoplasm swollen: often foamy or vacuolated
    • Nucleus eccentric, because accumulation displaces the Nissl substance
    • In later stages, neurons are lost and replaced by reactive glia (gliosis)
  13. Gitter cells (macrophages)
    white matter disease associated with myelin breakdown products
  14. GM1 Gangliosidosis
    problem in GM1 conversion to GM2 (done by beta-galactoisidase)
  15. GM1 Gangliosidosis: inheritance, biochemical findings
    • Inheritance: Autosomal Recessive
    • Biochemical Findings: disease of lysosomes, beta-galactoisidase
    • GM1 ganglioside and it's derivative asialo-GM1 ganglioside (GA1) accumulate
    • also glycoprotein-derived oligosaccharides and deratan sulfate are found at elevated intracellular concentrations
  16. GM1 gangliosidosis etiology
    • rare
    • several forms
    • most common is infantile onset form
    • storage in CNS and viscera
    • symptoms noted at or shortly after birth: psychomotor retardation)difficult to Dx just on clinical) - seizures, blindness, loss of appetite, weight loss
    • Skeletal abnormalities
    • Organomegaly
    • Death by age 2!
    • GM1 gangliosidosis findings
    • Cherry red spot - though not specific
    • retinal disease
    • skeletal abnormalities
    • Frontal bossing, depressed nasal bridge
    • Low set ears
  17. GM1 pathology
    • Very diffuse neuronal storage in brain
    • Also astrocyte storage
    • Also ganglion cells in intestine
    • organomegaly, especially liver and spleen!
    • EM picture similar to Tay-Sachs disease!: vacuolated lymphocyte
  18. GM1 brain
    Neurons swollen, filled with ganglioside
  19. Tay-Sach's Disease and Sandhoff disease
    • Tay-Sach's: a problem with Hexosaminidase A; alpha/beta subunits: GM2
    • Sandhoff disease: Hexosaminidase B Beta/Beta subunits: GLOBOSIDE
  20. Tay-Sachs
    • Inheritance: autosomal recessive
    • Biochemical findings: Hexosaminidase A and Hexosaminidase B levels are elevated
  21. Sandhoff
    • Inheritance: Autosomal Recessive
    • BOTH Hexosaminidases A and B are defective
  22. Tay-Sachs disease
    • more common in eastern Europeans, Ashkenazis and French-Canadians
    • Baby normal at birth
    • Onset at 3 Months
    • Psychomotor retardation, impaired vision
    • Hyperacusis = exaggerated startle response
    • Death by age 3-4 years
  23. Tay-Sachs pathology
    • No visceral organ involvement
    • Storage in neurons
    • Retina, brain (esp. cerebellum): autonomic ganglia
    • Brain becomes enlarged: megencephaly - may be present
    • With neuronal loss, brain undergoes atrophy
    • enlarged neurons, foamy cytoplasm
    • EM shows typical inclusions in Tay-Sachs disease
  24. Eye symptoms in Tay-Sachs
    • choroid membrane in the retina is involved
    • Cherry red spot: is the vascular choroid at macula; stands in contrast to pale surrounding retina with swollen ganglion cells
  25. Sandhoff disease
    • No ethnic tendency
    • Neurologic picture similar to Tay-Sachs
    • ALSO storage in visceral organs
    • Swollen hepatocytes, pancreatic acini, renal tubules: from deposition
    • Foamy macrophages in spleen, Lymph nodes, marrow and lungs
  26. Gaucher disease
    • Glucosyl-CER
    • converted to Ceramide by Beta-glucosidase
    • problem in this conversion
    • Inheritance: Autosomal Recessive
    • Biochemical findings: beta-glycosidase deficiency
    • Glucosyl-CER (glucocerebroside) accumulates
  27. Gaucher disease etiology and clinical presentation
    • Several forms of disease
    • 1882 - Gaucher described a "tumor" of spleen
    • Adult form most common: spleen
    • 50% cases in Ashkenazi Jews
    • Usually no CNS symptoms
    • Onset in late childhood or adulthood
    • Hepatosplenomegaly: hypersplenism with pancytopenia, have bone marrow involvement
    • live well into adulthood with variable prognosis: NOT uniformly fatal
  28. Gaucher pathology
    • Cerebroside stored maily in macrophages (histiocytes)
    • Derived in large part from breakdown of blood cells
    • Gaucher cell has eccentric nucleus, WRINKLED TISSUE PAPER CYTOPLASM
    • EM shows membrane-bound tubules
    • Bone lesions: often involve the femur, look lytic or osteopenic; has been described as falsk deformity
    • CNS: perivascular macrophages and Gaucher cells
  29. Infantile Gaucher disease
    • Rare
    • Onset 3-6 months
    • Psychomotor retardation
    • Hepatosplenomegaly + CNS involvement
    • Poor prognosis with death in 1-2 years
  30. Niemann-Pick Disease
    • Sphingomyelin turned into Ceramide by Sphingolyelinase
    • Inheritance: Autosomal recessive
    • Biochemical findings: in Types A and B sphyngomyelin accumulates in lysosomes
    • In Type C there is a defect in cholesterol trafficking
    • Type C: more common thatn types A and B
  31. Niemann-Pick disease
    • Heterogeneous group of diseases: some are not sphingolipidoses
    • Infantile form (type A) is classical type:
    • about 75% of cases
    • Severe neurology disease + organomegaly - spleen and hepatomegaly
    • Early death by age 3 years
    • Adult form (type B) usually without CNS symptoms: Patients survive into adulthood - increased longevity and decreased CNS involvement
  32. Cherry red spot appears in what sphingolipidoses?
    • GM1
    • GM2
    • Niemann-Pick disease
  33. Niemann-Pick disease pathology
    • widespread involvement of monocyte/macrophage system
    • like Gaucher disease
    • Bubbly histiocytes: round, almost membrane-like things
    • Signature cell: sea value histiocyte - not diagnostic, but indicative; seen with Wright's stain
    • EM shows myelin-like inclusions, similar to Tay-Sachs, GM1 and Niemann-Pick
  34. Metachromatic Leukodystrophy
    • Arylsulfatase A: defective
    • Inheritance: autosomal recessive
    • Biochemical findings: Accumulation of Sulfatide
  35. Metachromatic Leukodystrophy (Greenfield's disease)
    • Late infantile form most common: several types including juvenile and adult type
    • Motor symptoms predominate early: hypotonia, weakness, gait disturbances
    • peripheral neuropathy
    • Death within 2-10 years
  36. MLD
    • lesions are bilateral and diffuse: mottled appearance of the white matter
    • White matter is firm, gray, caveated
    • LFB stain shows marked loss of myelin and sparing of U fibers
    • Metachromati staining in white matter
    • Gitter cells filled with sulfated: metachromatic material stains a different color from origin stain (purple)
    • Lamellar inclusions: stacked lamellae are visible
  37. MLD Neuropathy
    Metachromatic staining in nerve: can be used for diagnosis or for screening
  38. Krabbe Disease
    GAL-CER converted to Ceramide (and alternatively to Psychosine)
  39. Krabbe's Disease (KD) clinical subtypes
    • Type 1 - infantile
    • Type 2 - late infantile
    • Type 3 - juvenile
    • Type 4 adult
    • Late and adult onset forms are more common in Southern Europe
    • Infantile globoid cell leukodystropy (GLD): rapidly progressive; invariably fatal disease of infants
  40. Krabbe Disease
    • Inheritance: Autosomal Recessive
    • Biochemical findings: Defect in Beta-galactosidase
    • Psychosine is implicated: in the disease - it inhibits cytogeneses
    • Gal-Cer levels are NOT elevated in the brain
    • Psychosine is galactosyl sphingosine
  41. Krabbe Disease Onset 3-6 months
    • Marked psychomotor retardation: irritable, stiffness, fever
    • Rapid progression
    • CNS and PNS involved: Average survival 2 years
  42. Krabbe Disease Pathology
    • Myelin loss
    • Loss of oligodendroglia: have been poisoned
    • Neurons are spared! also see sparing of U fibers
    • Globoid cells (macrophages): almost look granulomatous, a diagnostic feature of Krabbe's disease; clusters of fat macrophages, often around blood vessels, are the Dx feature of Krabbe disease
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