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  Disease summary:

  
  
  
  
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    Gaucher disease is a lysosomal storage disease (LSD) which results from the deficient activity of the degradative enzyme, acid β-glucosidase, and the lysosomal accumulation of its glycosphingolipid substrate, glucosylceramide (GL-1), primarily in the monocyte-macrophage system.

    
    
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    Three major clinical subtypes of Gaucher disease have been described. Type 1 is the most common, and is differentiated from type 2 and type 3 by a lack of primary central nervous system involvement.

    
    
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    Type 1 Gaucher disease is most common in the Ashkenazi Jewish population (∼1 in 1000 affected; 1 in 15 is a carrier) and is characterized by hepatosplenomegaly, pancytopenia, and bone disease.

    
    
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    Type 2 Gaucher disease is characterized by onset in infancy and progressive psychomotor retardation with death by age 2. Individuals with type 3 diseases may have onset in infancy with a slowly progressive neurologic course and may survive into the third or fourth decade of life.

  
  
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  Hereditary basis:

  
  
  
  
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    Gaucher disease (all subtypes) is inherited as an autosomal recessive trait. Heterozygous carriers are asymptomatic, and when both parents are carriers there is a 25% risk for an affected child with each pregnancy.

  
  
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  Differential diagnosis (Table 87-1):

  
  
  
  
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    LSDs and mucopolysaccharidosis: Hepatosplenomegaly, which is seen in Gaucher disease, is present in other lysosomal storage diseases including types A and B Niemann-Pick disease and the mucopolysaccharidoses types I, II, III, VI, and VII. The presence of other clinical features as well as biochemical testing distinguishes these.

    
    
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    Saposin C deficiency: Patients with saposin C deficiency can present with symptoms similar to severe neuronopathic Gaucher disease. However, they have normal acid β-glucosidase activity.

Diagnostic Criteria

Diagnosis is established by

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  Determining the acid β-glucosidase enzyme activity in peripheral blood leucocytes is diagnostic for all subtypes. Affected individuals will have activity which is markedly decreased to less than 10% of normal mean activity. Enzyme activity does not differentiate the subtypes or predict disease severity.

  
  
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  Mutation analysis of the five most common mutations (N370S, L444P, 84GG, IVS2+1, and R496H) in the acid β-glucosidase gene will detect over 95% of mutations in Ashkenazi Jewish patients and around 50% to 60% in non-Jewish patients. DNA sequencing of the acid β-glucosidase gene will identify other mutations, and mutation analysis can predict disease subtype and prognosis.

  
  
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  Bone marrow examination may show the presence of “Gaucher cells” which have a characteristic morphologic appearance. However, similar cells are seen in hematologic malignancies called “pseudo-Gaucher” cells. The bone marrow biopsy is not diagnostic, and determining the acid β-glucosidase enzymatic activity or acid β-glucosidase-specific mutations is required for the diagnosis.

Clinical Characteristics

Type 1 Gaucher disease patients have significant phenotypic heterogeneity. Patients may present with early-onset symptomatic disease in childhood or remain asymptomatic through life. Clinical characteristics of type 1 Gaucher disease include anemia, thrombocytopenia, hepatosplenomegaly, clinical or radiographic evidence of bone disease, and rarely, lung involvement. It is distinguished from types 2 or 3 disease by the absence of primary neurologic involvement. Commonly reported symptoms include easy bruising, bleeding, fatigue, bone or joint pain, abdominal pain, and fullness. More recently, Type 1 Gaucher disease has been associated with an increased risk for Parkinson. Types 2 and 3 disease have primary neurologic involvement, and can present with psychomotor retardation, oculomotor apraxia, and hypertonia.