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CHAPTER 72 patients contains typical foam cells with small droplets in the cytoplasm and

GAUCHER DISEASE AND sea-blue histiocytes. Substrate reduction therapy was approved for patients
with type C disease in 2008 in Europe; pharmacologic chaperone therapy is
RELATED LYSOSOMAL being attempted.
Fabry disease, Wolman/cholesteryl ester storage disease (CESD), and
STORAGE DISEASES GM -gangliosidoses are other lipid storage diseases characterized by hepato-
1
splenomegaly; GM -gangliosidosis by hepatomegaly only. CESD patients may
2
result in anemia and have sea-blue histiocytes. They are usually not cared for
by hematologists and will not be discussed in this chapter.
Ari Zimran and Deborah Elstein
DEFINITION OF GLYCOLIPID STORAGE
SUMMARY DISEASES

Gaucher disease and Niemann-Pick disease are the two lipid storage disorders The glycolipid storage diseases are hereditary disorders in which one
that are most likely to be encountered by the hematologist because both may or more tissues become engorged with specific lipids, because of defi-
cause hepatosplenomegaly and cytopenias. ciencies of the lysosomal enzymes required for hydrolysis of one of the
Gaucher disease is a common autosomal recessive lipid storage disorder, glycosidic bonds. Figure 72–1 shows the catabolic pathway of glyco-
with an increased prevalence among Ashkenazi Jews, in whom the estimated sphingolipids and lists the diseases that are involved in impaired deg-
birth occurrence is 1 in 850. Deficiency of the enzyme β-glucocerebrosidase radation because of specific enzyme deficiencies. The type of lipid and
results in accumulation of the sphingolipid glucocerebroside in the cells its tissue distribution have a characteristic pattern in each disorder. This
of the macrophage-monocyte system. Patients with the most prevalent chapter deals mainly with Gaucher disease, in which glucocerebroside
form, type 1, have no primary neuronopathic symptoms, whereas there is is stored. It is a common lysosomal storage disorder and also the one
with the most hematologic features. The second storage disorder with
involvement of the central nervous system in type 2 and type 3. Diagnosis of some hematologic features is Niemann-Pick disease, in which the accu-
Gaucher disease depends on demonstration of decreased enzymatic activity of mulated material is sphingomyelin and/or cholesterol. The remaining
β-glucocerebrosidase combined with identification of mutations in the lysosomal diseases (Fabry disease, Wolman/cholesteryl ester storage
β-glucocerebrosidase gene at the DNA level, usually with elevation of disease, and GM - and GM -gangliosidoses), in which there is hepato-
1
2
biomarkers, such as chitotriosidase as ancillary confirmation and means of splenomegaly but few hematologic abnormalities, are not reviewed in
followup. Disease manifestations include hepatosplenomegaly, thrombo- this chapter.
cytopenia, anemia, osteopenia/osteoporosis with pathologic fractures and
osteonecrosis, and, less commonly, pulmonary infiltration. Many patients,
especially those homozygous for the common N370S mutation, are putatively GAUCHER DISEASE
protected against neurologic involvement, albeit there is evidence of a genetic HISTORY AND DEFINITION
risk factor for Parkinson disease. Generally, many patients with type 1 may
be asymptomatic or so mildly affected that they may not present until their Gaucher disease was first described by P.C.E. Gaucher in 1882, who
fifth or sixth decade and do not require disease-specific therapy, whereas for thought that the large splenic cells of a young woman seen postmor-
1
those with more severe signs and symptoms, enzyme replacement therapy tem were evidence of a primary neoplasm. The term Gaucher disease
appeared first in 1905, when the autosomal recessive genetic nature of
(currently three infusible enzymes) is available. Substrate reduction therapy the disorder was elucidated. In 1934, it was shown that glucocerebroside
2
is an oral modality but is associated with a more problematic safety profile. is the storage material in Gaucher disease, and in 1965, the primary
3
Pharmacological chaperones and oral enzyme are being tested. defect was recognized as a deficiency of glucocerebrosidase resulting in
Niemann-Pick disease is a heterogeneous group of autosomal recessive dis- an impairment of degradation of glucocerebroside. Enzymatic purifi-
4,5
orders. Type A and type B result from deficiency of the enzyme sphingomyeli- cation ultimately led to the cloning of the gene in 1985, unraveling of
6,7
nase, whereas type C results from mutations in the NPC1 or NPC2 gene, which its structure, and identification of many glucocerebrosidase mutations.
8
appears to be involved in cholesterol trafficking and resulting in accumulation Disease-specific enzyme replacement therapy (ERT) was first intro-
of cholesterol as well as sphingomyelin. Type A is a lethal infantile form with duced in 1991. 9
marked progressive neurologic involvement. Type B is a later-onset form
with no neurologic involvement but hepatosplenomegaly in many patients.
Patients with type C disease manifest progressive neurologic involvement and EPIDEMIOLOGY
hepatosplenomegaly, but may survive into adulthood. The marrow of these Gaucher disease is inherited as an autosomal recessive disorder.
Although panethnic, type 1 is most common among the Ashkenazi
Jews, with a carriership prevalence of 1 in 17 and an expected frequency
of the disease in 1 in 850 livebirths. Two distinct forms of Gaucher
10
disease, type 3b and type 3c, are also relatively common in Norrbottnia
Acronyms and Abbreviations: cDNA, complementary DNA; ERT, enzyme in northern Sweden, and near the Palestinian town of Jenin, respec-
11
replacement therapy; MRI, magnetic resonance imaging; PC, pharmacologic tively. In the general population, the estimated frequency (based on
12
chaperone; SRT, substrate reduction therapy. large-scale neonatal screening projects in three countries is in the range
of 1 in 50,000 to 1 in 100,000 persons. 13

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