The sphingolipidoses are a group of rare, multisystemic, clinically heterogeneous lysosomal storage disorders characterized by defects in the breakdown of complex lipids. Clinical findings may include hepatosplenomegaly, bone involvement, macular cherry red spots, interstitial lung disease, hematopoietic abnormalities, and neurologic disease. Because the affected enzymes are expressed in different tissues and the degree of enzymatic impairment may vary, clinical manifestations are quite variable. There is a wide range in age of onset from prenatal nonimmune hydrops to slowly progressive adult-onset disease. All but one of the sphingolipidoses are autosomal recessive conditions; Fabry disease is inherited as an X-linked disorder.
A diagnosis of sphingolipidosis requires a high index of clinical suspicion. Either the demonstration of a deficiency of lysosomal enzyme activity or gene sequencing can establish a specific diagnosis of most sphingolipidoses. 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. Prenatal diagnosis of all the sphingolipidoses is possible through molecular genetic studies on chorionic villus samples or cultured amniotic fluid cells.
The sphingolipidoses, with their corresponding gene(s) gene and enzymatic defects, are shown in Table 156-1.
TABLE 156-1BIOCHEMICAL CLASSIFICATION AND GENETICS OF THE SPHINGOLIPIDOSES |Favorite Table|Download (.pdf) TABLE 156-1BIOCHEMICAL CLASSIFICATION AND GENETICS OF THE SPHINGOLIPIDOSES
|Disorder ||Enzyme Defect ||Gene |
|Gaucher disease, types 1, 2, and 3 ||Glucocerebrosidase (β-glucosidase) ||GBA |
|Gaucher disease with normal glucocerebrosidase ||Saposin C ||PSAP |
|Fabry disease ||α-Galactosidase A ||GLA |
|Niemann-Pick disease, types A and B ||Acid sphingomyelinase ||SMPD1 |
|Niemann-Pick disease, type C ||Intracellular cholesterol trafficking defect ||NPC1 |
|Metachromatic leukodystrophy ||Arylsulfatase A ||ARSA |
|Metachromatic leukodystrophy with normal arylsulfatase A ||Saposin B ||PSAP |
|Krabbe disease ||Galactocerebrosidase ||GALC |
|GM1 gangliosidosis ||β-Galactosidase ||GLB1 |
|Tay-Sachs disease ||β-Hexosaminidase A ||HEXA |
|GM2 activator deficiency ||GM2 activator protein ||GM2A |
|Sandhoff disease ||β-Hexosaminidase A and B ||HEXB |
|Farber lipogranulomatosis ||Ceramidase ||ASAH |
Treatments available for the sphingolipidoses include enzyme replacement therapy, substrate reduction therapy, hematopoietic stem cell transplantation, and symptomatic care.
PATHOGENESIS AND EPIDEMIOLOGY
The normal stepwise degradation of glycosphingolipids occurs in lysosomes. Sphingolipidoses are due to the accumulation of compounds containing a large lipophilic core called ceramide and either a hydrophilic oligosaccharide (glycosphingolipid) or a phosphorylcholine (sphingomyelin) (Fig. 156-1). 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 (Fig. 156-2).
Structure of ceramide (N-acylsphingenine).
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 ...