The addition of a sulfate group to the galactose in a galactocerebroside forms the sulfatide galactocerebroside 3-sulfate. This process is facilitated by a sulfotransferase and involves the use of the sulfate carrier 3ʹ-phosphoadenosine-5ʹphosphosulfate (PAPS). PAPS is also involved in glycosaminoglycan synthesis and steroid hormone catabolism. The synthesis of sphingolipids can be understood through Figure 17.18.

Glycosphingolipids are degraded through a process similar to glycosaminoglycans. The degradation occurs in lysosomes, which fuse with phagosomes after the internalization of glycosphingolipids via phagocytosis. Lysosomal enzymes hydrolytically cleave specific bonds in glycosphingolipids. The degradation follows the "last on, first off" rule, where the last group added during synthesis is the first group removed during degradation. Defects in the degradation of the polysaccharide chains in glycosphingolipids, glycosaminoglycans, and glycoproteins can lead to lysosomal storage diseases.

When the synthesis and degradation of glycosphingolipids are balanced, the amount of these compounds remains constant in membranes. However, if there is a deficiency in a specific lysosomal acid hydrolase required for degradation, a sphingolipid will accumulate. These deficiencies result in sphingolipidoses, which are lysosomal lipid storage diseases. Neurologic deterioration can be seen in nerve tissue, potentially leading to early death. The pathway of sphingolipid degradation and descriptions of some sphingolipidoses are provided in Figure 17.20. Some sphingolipidoses can also occur due to defects in lysosomal activator proteins, such as the saposins, which facilitate the access of hydrolases during degradation.

In the classic form of each disorder, a specific lysosomal hydrolytic enzyme is deficient, leading to the accumulation of a single sphingolipid in the affected organs. The rate of biosynthesis of the accumulating lipid is normal. These disorders are progressive and can be fatal in childhood, but there is extensive phenotypic variability, resulting in different clinical types. Various mutations within a single gene can cause a given disorder, leading to genetic variability. The sphingolipidoses are autosomal-recessive disorders, except for Fabry disease, which is X-linked. The incidence of sphingolipidoses is generally low, except for Gaucher and Tay-Sachs diseases, which are more prevalent in the Ashkenazi Jewish population. Tay-Sachs also has a high frequency in Irish American, French Canadian, and Louisiana Cajun populations.
A sulfate group from the sulfate carrier 3ʹ-phosphoadenosine-5ʹphosphosulfate ([PAPS], Fig. 17.16) is added by a sulfotransferase to the 3ʹ-hydroxyl group of the galactose in a galactocerebroside, forming the sulfatide galactocerebroside 3-sulfate (Fig. 17.17). [Note: PAPS is also the sulfur donor in glycosaminoglycan synthesis (see p. 162) and steroid hormone catabolism (see p. 240).] An overview of the synthesis of sphingolipids is shown in Figure 17.18.
C. Glycosphingolipid degradation
Glycosphingolipids are internalized by phagocytosis as described for the glycosaminoglycans (see p. 163). All of the enzymes required for the degradative process are present in lysosomes, which fuse with the phagosomes. The lysosomal enzymes hydrolytically and irreversibly cleave specific bonds in the glycosphingolipid. As seen with the glycosaminoglycans and glycoproteins (see p. 170), degradation is a sequential process following the rule “last on, first off,” in which the last group added during synthesis is the first group removed in degradation. Therefore, defects in the degradation of the polysaccharide chains in these three glycoconjugates result in lysosomal storage diseases.
D. Sphingolipidoses
In a normal individual, synthesis and degradation of glycosphingolipids are balanced, so that the amount of these compounds present in membranes is constant. If a specific lysosomal acid hydrolase required for degradation is partially or totally missing, a sphingolipid accumulates. Lysosomal lipid storage diseases caused by these deficiencies are called sphingolipidoses. The result of a specific acid hydrolase deficiency may be seen dramatically in nerve tissue, where neurologic deterioration can lead to early death. Figure 17.20 provides an outline of the pathway of sphingolipid degradation and descriptions of some sphingolipidoses. [Note: Some sphingolipidoses can also result from defects in lysosomal activator proteins (for example, the saposins) that facilitate access of the hydrolases to short carbohydrate chains as degradation proceeds.] 1.
Common properties: A specific lysosomal hydrolytic enzyme is deficient in the classic form of each disorder. Therefore, usually, only a single sphingolipid (the substrate for the deficient enzyme) accumulates in the involved organs in each disease. [Note: The rate of biosynthesis of the accumulating lipid is normal.] The disorders are progressive and, although many are fatal in childhood, extensive phenotypic variability is seen leading to the designation of different clinical types, such as types A and B in Niemann-Pick disease. Genetic variability is also seen because a given disorder can be caused by any one of a variety of mutations within a single gene. The sphingolipidoses are autosomal-recessive disorders, except for Fabry disease, which is X linked. The incidence of the sphingolipidoses is low in most populations, except for Gaucher and Tay-Sachs diseases, which, like Niemann-Pick disease, show a high frequency in the Ashkenazi Jewish population. [Note: Tay-Sachs also has a high frequency in Irish American, French Canadian, and Louisiana Cajun populations.] 2.