Diseases of glycosphingolipid degradation

In contrast to the few diseases of glycosphingolipid biosynthesis known, several diseases of glycosphingolipid degradation are well documented.  These diseases, often referred to as gangliosidosis, belong to the family of lysosomal storage diseases. The corresponding defects of hexosaminidase, sialidase (neuraminidase), galactosidase and glucosidase activities are also known as Tay-Sachs, Sandhoff, Fabry and Gaucher diseases. Alteration of lysosomal glycosidase activities impairs the degradation of glycosphingolipids, which accumulate within cells. The main symptoms are severe neuro­pathies, which are often lethal in infancy. Some types of gangiosidosis can be treated by administration of the UDP-Glc ceramide glucosyltrans­ferase inhibitor Miglustat or by enzyme replacement therapy. Recombinant hexosaminidases or galactosidases carrying Man-6-P epitopes are taken up by cells after intravenous administration. The Man-6-P signal enables the targeting of the recombinant enzymes to the lysosomes, where accumulating gangliosides can be degraded. The problem or better said the curse of these enzyme replacement therapies is not medical but rather financial. Indeed, the annual cost of treatment for a patient usually exceeds US$ 100’000. Although lysosomal storage diseases are rare and only few patients require these expensive treatments, several countries lack regulations on the coverage of such treatments by health insurances. For example, the Swiss Federal Court had to rule on a case where a health insurance company refused to cover the annual treatment for a lysosomal storage disease patient (see BGE 136 V 395, decision of 23 November 2010). With far reaching consequences, the Court confirmed in its ruling that therapies exceeding annual costs of CHF 100’000 can be rejected by health insurances!

FIG: OVERVIEW GSL DEGRADATION DISEASES

Some forms of gangliosidosis are caused by defects in saposins (Sap), which are sphingolipid activator proteins capturing glycosphingolipids from membranes and exposing them to the degrading lysosomal enzymes. The four saposins Sap-A to -D and the GM2-activator protein are required for the efficient degradation of glycosphingolipids, but they also contribute to the presentation of glycolipid antigens by the CD1 complex (see chapter Glycoimmunology).

FIG: SAPOSIN FUNCTIONS

The saposins and the GM2-activator protein show different binding specificities for glycosphingolipids. For example, Sap-B and the GM2-activator protein preferentially bind long sialylated gangliosides. The other saposins recognize short glycosphingolipids and aglycosylated ceramide; Sap-A, Sap-C and Sap-D bind galactosylceramide, glucosylceramide and ceramide, respectively.