Gaucher disease and Niemann-Pick disease are the two
lipid storage disorders that are most likely to be encountered by
the hematologist because both may cause hepatosplenomegaly and cytopenias.
Gaucher disease is the most common autosomal recessive
lipid storage disorder. It is most prevalent in Ashkenazi Jews,
in whom the disease genotype occurs in approximately 1 in 850 births.
Deficiency of the enzyme β-glucocerebrosidase results
in accumulation of the glycolipid glucocerebroside in the cells of
the macrophage-monocyte system. Patients with the common type 1
disease have no primary neuronopathic symptoms, but there is involvement
of the central nervous system in type 2 and type 3 diseases. Diagnosis
of Gaucher disease depends on demonstration of deficiency of β-glucocerebrosidase or
identification of mutations in the β-glucocerebrosidase
gene. Disease manifestations include hepatosplenomegaly, thrombocytopenia,
anemia, osteoporosis with pathologic fractures and osteonecrosis,
and, less commonly, pulmonary infiltration. Many patients, especially those
who are homozygous for the common N370S (1226C→G)
mutation, are protected against neurologic involvement, probably
because of some residual glucocerebrosidase activity, and may manifest
a mild disease that does not require specific therapy. There has
been some concern about an increased incidence of malignancies and
parkinsonism in patients with type 1 disease. For patients who have
more severe signs and symptoms, effective enzyme replacement therapy
with imiglucerase is available. The glucocerebroside substrate reduction
therapy is also available but may cause adverse events.
Niemann-Pick disease is a heterogeneous group of autosomal
recessive disorders. Type A and type B result from deficiency of
the enzyme sphingomyelinase, whereas type C results from mutations
in the NPC1 or NPC2 genes that
appear to be involved in cholesterol trafficking, and results in
accumulation of cholesterol as well as sphingomyelin. Type A is
a severe lethal infantile form of the disease with marked progressive neurologic
involvement. Type B is a later-onset form of the disease with no
neurologic involvement but with hepatosplenomegaly in many patients.
Patients with type C disease manifest neurologic signs and hepatosplenomegaly
and may survive into adulthood. The marrow of these patients contains
typical foam cells with small droplets in the cytoplasm and sea-blue
histiocytes. Miglustat therapy was approved for patients with type
C disease in 2008 in Europe.
Acronyms and Abbreviations
Acronyms and abbreviations that
appear in this chapter include: cDNA, complementary DNA; ERT, enzyme
replacement therapy; HSGP, horizontal supranuclear gaze palsy; MRI,
magnetic resonance imaging; SRT, substrate reduction therapy.
The glycolipid storage diseases are hereditary disorders in which
one or more tissues become engorged with specific lipids, because
of deficiencies of specific lysosomal enzymes required for hydrolysis
of one of the glycosidic bonds. Figure 73–1 shows
the catabolic pathway of glycosphingolipids and lists the diseases
that are involved in impaired degradation because of specific enzyme
deficiencies. The type of lipid and its tissue distribution have
a characteristic pattern in each disorder. This chapter deals mainly
with Gaucher disease, in which glucocerebroside is stored. It is
the most ...