-
Sphingolipidoses: sphingolipids
derivatives of ceramide
-
Ceramide is formed by
esterification of a fatty acid with the amino group sphingosine
-
Sphingolipids localized mainly in
the white matter of the CNS
-
X group of sphingomyelin is
phosphoryl choline
-
X group of cerebroside
galactose or glucose
-
X group of ganglioside
silica acid-containing oligosaccharide
-
Sphingomyelins
- most abundant sphingolipid found in mammalian membranes especially the plasma membrane.
- They are found in nerve tissue and erythrocytes
-
Cerebrosides (galactosylceramide and glucosylceramide)
- are found predominantly in the brain and PNS
- with high concentrations in the myelin sheath
- major constituents of oligodendrocytes
-
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
-
Sulfatides
- are cerebrosides with sulfated galactosyl residues
- synthesized primarily in oligodendrocytes of the CNS
-
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
-
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)
-
Gitter cells (macrophages)
white matter disease associated with myelin breakdown products
-
GM1 Gangliosidosis
problem in GM1 conversion to GM2 (done by beta-galactoisidase)
-
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
-
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
-
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
-
GM1 brain
Neurons swollen, filled with ganglioside
-
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
-
Tay-Sachs
- Inheritance: autosomal recessive
- Biochemical findings: Hexosaminidase A and Hexosaminidase B levels are elevated
-
Sandhoff
- Inheritance: Autosomal Recessive
- BOTH Hexosaminidases A and B are defective
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
Infantile Gaucher disease
- Rare
- Onset 3-6 months
- Psychomotor retardation
- Hepatosplenomegaly + CNS involvement
- Poor prognosis with death in 1-2 years
-
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
-
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
-
Cherry red spot appears in what sphingolipidoses?
- GM1
- GM2
- Niemann-Pick disease
-
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
-
Metachromatic Leukodystrophy
- Arylsulfatase A: defective
- Inheritance: autosomal recessive
- Biochemical findings: Accumulation of Sulfatide
-
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
-
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
-
MLD Neuropathy
Metachromatic staining in nerve: can be used for diagnosis or for screening
-
Krabbe Disease
GAL-CER converted to Ceramide (and alternatively to Psychosine)
-
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
-
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
-
Krabbe Disease Onset 3-6 months
- Marked psychomotor retardation: irritable, stiffness, fever
- Rapid progression
- CNS and PNS involved: Average survival 2 years
-
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
|
|
