Sphingolipid formation

brain PNS- high [ ] in myelin

major constituents of oligodendrocytes

Most abundant-mammalian membranes

nerve tissue and erythrocytes

ganglion cells of CNS - nerve endings

Rafts in plasma membrane - signal transduction

20-500X more in brain than non-neural tissues

GM1 Gangliosidosis

Biochem

(GM1) GAL-NAGA-GAL-GLC-CER-NANA--->NAGA-GAL-GLC-CER-NANA(GM2)

 blocked due to lack of Beta-Galactosidase

(auto recessive)

Gal from GM1 cannot be removed

Accumulation of GM1 Ganglioside and 

Asialo-GM1 Ganglioside (GA1)

Also elevated glycoprotein derived oligosacharides and keratan sulfate

GM1 Gangliosidosis

Clinical/path

Clinical-infantile onset- storage in CNS and Viscera

symptoms just after birth- psychomotor retardation, seizures, blindness, loss appetite, wt loss, skeletal abnorm, organomegaly, death by 2y

Path-cherry red spot, widening of bones/metaphyses, depressed nasal bridge

-diffuse neuronal storage, atrocyte storage, ganglion cells in intestine, hepato/splenomagaly, EM like Tay-sachs, Neurons swollen, filled with ganglioside

Tay-Sachs 

Biochem

(GM2) NAGA-GAL-GLC-CER-NANA--->GAL-GLC-CER-NANA

Defect in Alpha unit of Hexosaminidase 

(A is alphabeta, B is betabeta)

Hexosaminidase A is absent, Hexosaminidase B elevated

Prevents removal of NAGA from GM2

Sandhoff

Biochem

(GM2) NAGA-GAL-GLC-CER-NANA--->GAL-GLC-CER-NANA

(Globoside) NAGA-GAL-GAL-GLC-CER--->GAL-GAL-GLC-CER

Beta unit of Hexosaminidase defective

-Hexosaminidase A and B defective/absent

-Prevents NAGA removal from GM2 and Globoside

TaySachs

Clinical/Path

Clinical-normal at birth, onset 3mths, psychomotor retardation, impaired vision, hyperacusis- death 3-4y --> E. euros, Ashkenazis, Fr. Canadians

Path-No visceral, storage in neurons (retina, brain-cerebellum, autonomic ganglion, megancephaly followed by atrophy

-enlarged neurons, foamy cytoplasm

-meganeurites-swollen processes filled w/ganglioside

-EM-typical Membranous Cytoplasmic bodies

Sandhoff

Clinical/Path

Clinical-similar to taysachs + visceral involvement

-neuro picture similar to TS

-swollen hepatocytes, pancreatic acini, renal tubules

-foamy macros in spleen, LN's, marrow, lungs

Gaucher

biochem

Glucosyl-CER--->Ceramide

Absent Beta-Glucosidase (a hydrolase)

-Can't remove Glucosyl from Glucosyl-Ceramide (glucocerebroside)

auto recessive

Gaucher

clinical/path

Clinical-adult form most common-50% ashkenazi

-no CNS symptoms-onset late childhood, early adult

-Hepatosplenomegaly-hypersplenism+pancytopenia

-live well into adulthood-variable prognosis

Path-cerebroside stored in macros (histiocytes)

-derived from breakdown of blood cells

-eccentric nucleus, wrinkled tissue cytoplasm

-EM=membrane bound tubules

-bone lesions-lytic/osteopenic->erlenmeyer flask

Infantile-same as above + CNS- onset 3-6m, psychomotor retardation- death 1-2y

Niemann-Pick

Biochem

Sphingomyelin--->CERAMIDE

Defect in sphingomyelinase

can't convert sphingomyelin to Ceramide

A and B- sphingomyelin accumulates in lysosomes

C-defect in cholesterol trafficking-more common

Niemann-Pick

clinical/path

Clinical-A is classical-neuro disease+organomegaly

-cherry red spot-death by 3y

-Adult form-no CNS

Path-HUGE spleen- protuberant abdomen

-monocyte/macrophage system lime gaucher

-Signature=SEA BLUE HISTIOCYTE (Wrights)

-EM- myelin like inclusion

Metachromatic Leukodystrophy

Biochem

So3H-GAL-CER---->GAL-CER

Arylsulfatase A defect

blocks sulfatide removal, preventing cerebroside formation

Results in sulfatide accumulation

MLD/Greenfield's

Clinical/Path

Clinical-late infantile most common, juve and adult forms

-motor symptoms early-hypotonia, weakness, gait

-peripheral neuropathy, death 2-10y

Path-bilateral diffuse brain lesions-white matter firm and cavitated

-LFB-myelin loss w/sparing of U-Fibers

-metachromatic gitter cells filled with sulfatide

-EM lamellar inclusions

-Metachromatic stain in peripheral nerves

Krabbe

Biochem

GAL-CER-->CERAMIDE

Defective Beta-Galactosidase

prevents removal of galactose preventing formation of Ceramide

Does not cause GAL-CER accumulation

Causes accumulation of Psychosine

Krabbe

Clinical/Path

Clinical-t1-infantile, t2 late infantile, t3 juvenile, t4 adult

-onset 3-6m

-psychomotor retardation-irritable, stiff, fever

-rapid progression-CNS and PNS, death 2y

Path-Myelin loss, loss of oligodendroglia (psychosine poisoned)- neurons spared

-Globoid cells-clusters of foamy/fat macrophages around blood vessels