Joe T. R. Clarke
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).
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 161-1. Structure of ceramide (N-acyl-sphingenine).
FIGURE 161-2. Summary of the structure and catabolism of sphingolipids. 1, β-galactosidase; 2, β-hexosamini-dase A + GM2 activator protein; 3, α-neuraminidase (sialidase) + saposin B; 4, β-hexosaminidase A; 5, α-galactosi-dase + 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
All but one of the sphingolipidoses are transmitted as autosomal recessive conditions; Fabry disease is inherited as an X-linked disorder (eTable 161.2 ). With respect to genotype-phenotype correlations, some generalizations are possible, but in most situations, identifying specific mutations may be useful diagnostically but is often only poorly predictive of disease severity.
The diagnosis requires a high index of clinical suspicion. Histopathologic studies on bone marrow aspirates or on tissue obtained by biopsy often show the presence of storage cells; however, the changes are generally not specific enough (except in the case of Gaucher disease) to make the diagnosis of a specific sphingolipidosis. The positive filipin staining of cultured fibroblasts is a characteristic finding in Niemann-Pick disease, type C.
The demonstration of profound deficiency of lysosomal enzyme activity, using synthetic substrates, is adequate for establishing a specific diagnosis of most sphingolipidoses. The diagnosis of activator deficiency is best achieved by specific mutation analysis. Carrier detection by measurement of enzyme levels in serum is the basis of Tay-Sachs carrier detection and is used for large-scale carrier detection among high-risk populations, such as Ashkenazi Jews. For other sphingolipidoses, including X-linked Fabry disease, carrier detection by enzyme assay is technically difficult and unreliable. Mutation analysis is easier and more reliable. Mid-trimester prenatal diagnosis of all the sphingolipidoses is possible by appropriate enzyme assays or by molecular genetic studies on chorionic villus samples or cultured amniotic fluid cells.
Treatment by hematopoietic stem cell transplantation (HSCT) with cord blood stem cells or by allogeneic bone marrow transplantation may arrest or delay the progression of neurological deterioration in children with metachromatic leukodystrophy or late-onset Krabbe disease. HSCT using cord blood stem cells, carried out before 3 weeks of age, significantly improves the survival of infants with infantile Krabbe disease; however, its role in the long-term management of these disorders is still unclear.
Enzyme replacement therapy (ERT) has emerged as one of the most important advances in the treatment of sphingolipidoses (eTable 161.3 ).3 ERT by biweekly infusions of recom-binant human glucocerebrosidase is invariably effective in reversing the hematologic and early skeletal complications of Gaucher disease, regardless of the type.4 However, there is little or no effect on the neurological complications of types 2 and 3. ERT has also been approved to treat Fabry disease and is under development for the treatment of Niemann-Pick disease, type B.
Glycosphingolipid accumulation in Gaucher disease is decreased by treatment with miglustat, an inhibitor of the synthesis of glucosylceramide, the precursor of all the glycosphingolipids.5 Studies are under way to evaluate this approach to treating other sphinoglipidoses, such as Fabry disease and Niemann-Pick disease, type C. The drug is currently not recommended for use in children. In cases where the mutation causes the synthesis of a catalytical-ly active but highly unstable enzyme protein, treatment with a competitive inhibitor of the enzyme, a pharmacological chaperone, stabilizes it enough to correct the enzyme deficiency. Although this is a promising area of clinical investigation, it is not yet available for the treatment of any of the sphingolipidoses.