Glycosphingolipids are a
polysaccharide chain between 1 and 40
carbohydrate residues long glycosidically linked to
ceramide (a long-chain aliphatic amino-alcohol or sphingoid) that is embedded in the cell plasma membrane with the
carbohydrate moiety on the outside. The sphingoid imparts rigidity to the membrane and the
carbohydrate tails protect the cell surface and have functions in relation to cell adhesion, growth, regulation, differentiation, cell interaction, recognition and signalling. They provide adhesion sites for pathogens and change during oncogenic transformation.
Ceramide is also a component of
sphingomyelin.
Glycosphingolipids are degraded by lysosomal hydrolysis. The
sphingolipidoses are a series of diseases in which mutations affecting the
enzymes catalysing the last 11 steps of this process causing abnormal compounds proximal to the metabolic block to accumulate intralysosomally. Thus, they are a sub-group of the
lysosomal storage diseases. The degradation of
sphingolipids containing three or less
carbohydrate residues requires a
sphingolipid activator
protein and mutations affecting these
proteins also cause abnormal
glycosphingolipid storage. With one exception (
Fabry disease, which is X linked) the
sphingolipidoses are inherited autosomally. The phenotypic manifestations of the individual
sphingolipidoses are variable although the more severe variants are usually the better known. They have generally been regarded as untreatable but notable therapeutic advances are being made by
enzyme replacement therapy and regulating the rate of
glycosphingolipid synthesis by inhibiting
UDP-glucose-N-acylsphingosine D-glucosyl
transferase (CerGlcT), which is the first reaction on the pathway of
glycosphingolipid synthesis. The compounds used are N-alkylated iminosugars whose
glucose and
galactose stereochemistries inhibit CerGlcT. Prenatal and carrier state diagnosis, genetic counselling and the abortion of affected foetuses are reducing the incidence of some of the most severe
sphingolipidoses in certain high-incidence populations.