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).
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.
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) ||Download (.pdf)
Table 161-1. Clinical
Features of Sphingolipidoses (Continued)
|Disease||Enzyme Deficiency or Biochemical Defect||Clinical Features||Diagnosis|
|GM1 gangliosidosis, ...|