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The sphingolipidoses are a clinically heterogeneous group of disorders characterized by inherited point defects in the breakdown of complex lipids; this results in the accumulation of compounds containing a large lipophilic core called ceramide and either a hydrophilic oligosaccharide (glycosphingolipids) or a phosphorylcholine (sphingomyelin).1 Ceramide is composed of a long-chain fatty alcohol containing an amine group in amide linkage with a long-chain fatty acid (Fig. 161-1).

Figure 161-1.

Structure of ceramide (N-acylsphingenine).

The normal stepwise degradation of glycosphingolipids occurs in lysosomes (Fig. 161-2). Each step in the catabolism of the sphingolipids is catalyzed by one of a series of hydrolytic enzymes that requires the presence of activator proteins (eg, the saposins and GM2 activator protein)2 for activity in vivo. Disease variants caused by defects in prosaposin or GM2 activator protein are rare and diagnostically challenging.

Figure 161-2.

Summary of the structure and catabolism of sphingolipids. 1, β-galactosidase; 2, β-hexosaminidase A + GM2 activator protein; 3, α-neuraminidase (sialidase) + saposin B; 4, β-hexosaminidase A; 5, α-galactosidase + saposin B; 6, glucocerebrosidase + saposin C; 7, arylsulfatase A; 8, galactocerebrosidase; 9, acid sphingomyelinase; 10, acid ceramidase + saposin D and C.

Sphingolipid storage diseases may present at any age (Table 161-1); the clinical manifestations vary markedly according to the patient’s age at presentation. Gaucher disease is a particularly good example (eTable 161.1). Gaucher disease is caused by marked deficiency of lysosomal glucocerebrosidase (β-glucosidase), and it is not possible to distinguish the different variants of the disease on the basis of residue enzyme activity. When it presents in the newborn period, the disease is characterized by severe generalized ichthyosis, hepatosplenomegaly, and severe CNS impairment. Survival beyond a few weeks is rare. Type 2 (acute neuronopathic) Gaucher disease is a severe and rapidly progressive neurodegenerative condition associated with marked hepatosplenomegaly but with few of the hematologic or skeletal complications of later-onset variants of the disease. At the other extreme, patients with type 1 (non-neuronopathic) Gaucher disease, by far the most common variant, often have few if any clinical manifestations of the disorder. In most, splenomegaly and hypersplenism are the most common presenting symptoms, often associated with bone pain but without any primary neurological abnormalities. The most clinically heterogeneous group is patients with type 3 (subacute neuronopathic) disease. These individuals may present with neurological problems, with only subtle evidence of non-neurological involvement, or they may come to attention as a result of very severe, early onset hepatosplenomegaly and skeletal complications, with later development of slowly progressive neurodegeneration.

Table 161-1. Clinical Features of Sphingolipidoses (Continued)

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