15. Gaucher's Disease

GAUCHER'S DISEASE (in the differential diagnosis of the marrow findings)

  • The most common lysosomal storage disease; the most common genetic disorder among Ashkenazi Jews
  • Pathophysiology: deficiency of beta-glucocerebrosidase. This enzyme facilitates the intralysosomal catabolism of glucocerebroside, which is derived from phagocytosed cell membranes. Deficiency results in accumulation of glucocerebroside in macrophages of the reticuloendothelial system (Kupffer cells, splenic and bone marrow macrophages)
  • 3 types
    1. adult type, the most common, no CNS involvement, median age at dx: 21yrs
    2. infantile, severe CNS involvement, early death
    3. mild CNS involvement
  • Clinical and laboratory features: widely variable
    hepatomegaly, splenomegaly: very common
    bone pain, acute bone crisis, bone infarcts, pathologic fractures, osteonecrosis
  • Anemia, thrombocytopenia, leukopenia (hypersplenism, splenic sequestration, bone marrow infiltration)
  • monoclonal gammopathy, abnormal LFTs, � alk. Phosphatase, � acid phosphatase
  • clinical or radiological skeletal involvement: 70-100% of cases. Best monitoring method: femoral MRI
  • Diagnosis:
    1. assay of beta-glucocerebrosidase activity from peripheral blood leukocytes or cultured fibroblasts from skin biopsy: 10-30% of normal values, levels are predictive of severity
    2. lipid laden macrophages with onion skin-like cytoplasm. Pseudo-Gaucher cells in non-Hodgkin's lymphomas and CML
    3. Mutation analysis (chromosome 1q2.1), associated with severity
  • Treatment:
    Enzyme replacement treatment (ERT)
    Purified macrophage -targeted human placenta derived beta-glucocerebrosidase
    Recombinant beta-glucocerebrosidase
    Recovery of hematologic cytopenias is among the earliest and most sensitive indicators of response to ERT

(Arch Intern Med 1998; 158:1754-1760)