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MECHANISM OF MACROPHAGE EXPANSION
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In Gaucher and Niemann-Pick diseases, major clinical manifestations result from accumulation of glucocerebroside and sphingomyelin, respectively, in macrophages, leading to their massive expansion in tissues (see Fig. 38–1).
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Etiology and Pathogenesis
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Glucocerebroside accumulates because of a deficiency of glucocerebrosidase (β-glucosidase).
Very rarely a neuropathic form may be caused by a deficiency of saposin, a β-glucosidase cofactor.
Inherited as an autosomal recessive disorder, with high gene frequency among Ashkenazi Jews.
More than 100 different mutations have been reported, but the 5 mutations most common in Ashkenazi Jews account for more than 95 percent of mutations in that population.
The most common mutation in the Jewish population is 1226G (N370S). It usually gives rise to mild disease in the homozygous form.
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Three types of Gaucher disease are recognized:
— Type 1 occurs in both children and adults, and is primarily caused by an accumulation of glucocerebroside-laden macrophages in liver, spleen, and marrow. Neurologic manifestations are rare and primarily affect the peripheral nervous system.
— Type 2 is exceedingly rare and is characterized by rapid neurologic deterioration and early death.
— Type 3, or juvenile Gaucher disease, is a subacute neuropathic disorder with later onset of symptoms and better prognosis than type 2.
Type 1 may be asymptomatic, or symptoms may range from minimal to severe:
— Chronic fatigue is common.
— Hepatic and/or splenic enlargement may cause significant (mechanical) problems.
— Thrombocytopenia is a common presenting finding.
— Skeletal lesions are often painful. "Erlenmeyer flask" deformity of the femur is common. Aseptic necrosis of femoral head and vertebral collapse may occur.
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Blood count may be normal, but normocytic, normochromic anemia with modest reticulocytosis is often found. Thrombocytopenia is common, particularly in patients with significant splenomegaly and may be severe.
Leukocytes are deficient in acid β-glucosidase activity.
Gaucher cells are large cells found in marrow, spleen, and liver in varying numbers. They are ...