sphingolipid

STRUCTURE AND SYNTHESIS - Synthesis begins in the ER with serine + palmitoyl-CoA (rate-limiting enzyme: serine palmitoyltransferase, requires vitamin B6/PLP) to form sphingosine. Acylation with a fatty acid forms CERAMIDE, the precursor for all sphingolipids. - Ceramide + phosphocholine (from phosphatidylcholine) = SPHINGOMYELIN (the only sphingolipid that is also a phospholipid; abundant in myelin sheath). - Ceramide + sugar(s) = glycosphingolipids: cerebrosides (ceramide + glucose or galactose), globosides (ceramide + 2 or more sugars), gangliosides (ceramide + oligosaccharide with sialic acid/NANA), and sulfatides (sulfated galactocerebroside). - Functions: membrane structure (outer leaflet of plasma membrane, lipid rafts), myelin insulation, cell recognition and signaling (ceramide and sphingosine-1-phosphate are involved in apoptosis, proliferation, lymphocyte trafficking), and blood group antigens (ABO is based on glycosphingolipids).

DEGRADATION AND DISEASE (SPHINGOLIPIDOSES) Lysosomal storage diseases caused by deficiency of specific hydrolases. Most are autosomal recessive; Fabry is X-linked recessive.

High-yield table (disease: enzyme deficiency: accumulated substrate: key features) - Tay-Sachs: hexosaminidase A: GM2 ganglioside: neurodegeneration, cherry-red macula, onion-skin lysosomes, NO hepatosplenomegaly, Ashkenazi Jews. - Sandhoff: hexosaminidase A and B: GM2 ganglioside + globoside: like Tay-Sachs but WITH hepatosplenomegaly. - Fabry: alpha-galactosidase A: ceramide trihexoside (globotriaosylceramide): X-linked; peripheral neuropathy/acroparesthesias, angiokeratomas, hypohidrosis, renal failure, cardiomyopathy/stroke. Treatment: enzyme replacement (agalsidase), migalastat for amenable variants. - Gaucher (most common): glucocerebrosidase (beta-glucosidase): glucocerebroside: hepatosplenomegaly, pancytopenia, bone crises/avascular necrosis, Erlenmeyer flask deformity, crinkled-paper macrophages (Gaucher cells). Treatment: enzyme replacement (imiglucerase) or substrate reduction (eliglustat). - Niemann-Pick (types A and B): sphingomyelinase: sphingomyelin: hepatosplenomegaly, cherry-red macula, foam cells, neurodegeneration (type A, severe, Ashkenazi). Type C is a defect in cholesterol transport (NPC1), not sphingomyelinase. - Krabbe: galactocerebrosidase: galactocerebroside (and psychosine): peripheral neuropathy, optic atrophy, developmental delay, globoid cells (multinucleated). - Metachromatic leukodystrophy: arylsulfatase A: cerebroside sulfate: central and peripheral demyelination, ataxia, dementia. - Farber disease (ceramidase deficiency) and GM1 gangliosidosis (beta-galactosidase) are less common.

MNEMONIC "Tay-SaCHs: no hepatosplenomegaly (Cherry-red spot, Hexosaminidase A)." "Fabry = Fabulous X, kidneys/skin/pain." Cherry-red macula: Tay-Sachs, Niemann-Pick (also seen in central retinal artery occlusion). Hepatosplenomegaly present: Gaucher, Niemann-Pick, Sandhoff. Absent: Tay-Sachs, Fabry, Krabbe, MLD.

OTHER ASSOCIATIONS - Multiple sclerosis involves myelin (rich in sphingolipids), but it is autoimmune rather than a sphingolipidosis. - Fingolimod (S1P receptor modulator) is used in MS; it traps lymphocytes in lymph nodes. Related drugs include siponimod, ozanimod, and ponesimod. - Cholera toxin binds GM1 ganglioside on enterocytes. - Diagnosis of the lysosomal diseases: leukocyte or fibroblast enzyme assays, genetic testing. Management is largely supportive, with enzyme replacement or substrate reduction therapy available for Gaucher and Fabry.