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1122 Part VIII: Monocytes and Macrophages Chapter 72: Gaucher Disease and Related Lysosomal Storage Diseases 1123

Gal-GalNAc Figure 72–1. The catabolic pathways of
Gal-Glc-Cer [GM ] selected glycosphingolipids involved in
1
NANA
Generalized gangliosidosis some of the glycolipid storage diseases. Solid
squares depict the blocked pathways caused
by specific inherited deficiencies of enzymes,
Gal which give rise to the accumulation of the
GalNAc respective substrates. The names of the vari-
Gal-Glc-Cer [GM ] GalNAc-Gal-Gal-Glc-Cer [Globoside]
2
NANA ous diseases are shown above the names of
Tay-Sachs disease Sandhoff disease the deficient enzymes. (Reproduced with per-
mission from Lichtman’s Atlas of Hematology,
www.accessmedicine.com.)
GalNAc GalNAc
NANA-Gal-Glc-Cer [GM ] Gal-Gal-Glc-Cer
3
Fabry disease
Neuraminidase
NANA Gal
Gal-Glc-Cer

Gal
Glc-Cer
Gaucher disease

Glc

H
SO 3 2 Gal Coline-P
SO H-Gal-Cer Gal-Cer Ceramide Phosphorylcholine-Cer
3
[Sphingomyelin]
Metachromatic Krabbe disease Niemann-Pick disease
leukodystrophy Sphingomyelinase
Arylsulfatase A
Farber disease
Ceramidase

Fatty acid
Sphingosine

The high prevalence of at least two Gaucher mutation, N370S and glucocerebroside induces increased cell size and cytoplasmic striations,
84GG (and possibly R496H and others), among Ashkenazi Jews, and leading to the formation of “Gaucher cells” (see Fig. 72–1). Inherent
14
the existence of other lysosomal diseases within this ethnic group, may in subsequent lysosomal dysfunction is a dysregulation of metabolites
reflect, in addition to a founder effect, a selective advantage. However, and the consequent lack of coordination of cellular metabolism. These
a selective advantage because of greater resistance to tuberculosis or changes may explain the elaboration of various cytokines and other
15
superior intelligence has not been proven. Animal studies suggest that biomarkers because of engorgement of macrophages.
16
the selective advantage may be the higher circulating serum levels of Accumulating evidence indicates that in addition to the glucocere-
glucocerebroside that have antiinflammatory and beneficial immuno- brosidase enzyme (GBA1), a second, nonlysosomal glucocerebrosidase,
modulary effects. 17 GBA2, a cytosolic protein that tightly associates with cellular mem-
branes, may be integral to the pathogenesis of Gaucher disease, affecting
ETIOLOGY AND PATHOGENESIS its phenotype by potentially interacting with GBA1. 18–20
In rare instances, severe forms of Gaucher disease are associ-
Enzymatic Basis ated with deficiency of saposin C, a heat-stable glucocerebrosidase
During normal growth, development, and senescence, parts of or whole co-factor. 21,22
cells are continually replaced. Breakdown of complex constituents of
cells requires sequential enzymatic degradation. Such degradation
occurs largely in secondary lysosomes, organelles formed by the fusion GENETIC BASIS OF GAUCHER DISEASE
of primary lysosomes with phagocytic vacuoles containing ingested The glucocerebrosidase gene is located on chromosome 1q21. A pseudo-
material. gene, with 96 percent sequence homology, has been identified approx-
Gaucher disease is the result of a hereditary deficiency in the imately 16 kb downstream from the functional gene. Nearly 300 point
8,23
activity of a lysosomal enzyme, glucocerebrosidase, required for glyco- mutations causing Gaucher disease have been described ; most are
lipid degradation. The reduced activity of glucocerebrosidase results in point mutations, missense, nonsense, frameshift, and splice-site muta-
accumulation of glucocerebroside in macrophages engorgement with tions, but there are also insertions, deletions, and recombinant alleles.

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