ESSENTIALS OF DIAGNOSIS
Deficiency of beta-glucocerebrosidase.
Anemia and thrombocytopenia.
Enlargement of the liver and spleen.
Gaucher disease has an autosomal recessive pattern of inheritance. A deficiency of beta-glucocerebrosidase causes an accumulation of sphingolipid within phagocytic cells throughout the body. Anemia and thrombocytopenia are common and may be symptomatic; both are due primarily to hypersplenism, but marrow infiltration with Gaucher cells may be a contributing factor. The abdomen can become painfully distended due to enlargement of the liver and spleen. Cortical erosions of bones, especially the vertebrae and femur, are due to local infarctions, but the mechanism is unclear. Episodes of bone pain (termed “crises”) are reminiscent of those in sickle cell disease. A hip fracture in a patient of any age with a palpable spleen—especially in a Jewish person of Eastern European origin—suggests the possibility of Gaucher disease. Peripheral neuropathy may develop in patients.
Two uncommon forms of Gaucher disease, called type II and type III, involve neurologic accumulation of sphingolipid and a variety of neurologic problems. Type II is of infantile onset and has a poor prognosis. Heterozygotes for Gaucher disease are at increased risk for developing Parkinson disease.
Bone marrow aspirates reveal typical Gaucher cells, which have an eccentric nucleus and periodic acid–Schiff (PAS)-positive inclusions, along with wrinkled cytoplasm and inclusion bodies of a fibrillar type. In addition, the serum acid phosphatase is elevated. Definitive diagnosis requires the demonstration of deficient glucocerebrosidase activity in leukocytes. Hundreds of mutations have been found to cause Gaucher disease and some are highly predictive of the neuronopathic forms. Thus, mutation detection, especially in a young person, is of potential value. Only four mutations in glucocerebrosidase account for more than 90% of the disease among Ashkenazi Jews, in whom the carrier frequency is 1:15.
Gaucher disease is the most common lysosomal storage disorder. Most clinical complications can be prevented by early institution of enzyme replacement therapy. Carrier screening, especially among Ashkenazi Jews, detects those couples at 25% risk of having an affected child. Prenatal diagnosis through mutation analysis is feasible. Because of an increased risk of malignancy, especially plasma cell myeloma and other hematologic cancers, regular screening of adults with Gaucher disease is warranted.
A recombinant form of the enzyme glucocerebrosidase (imiglucerase) for intravenous administration on a regular basis reduces total body stores of glycolipid and improves orthopedic and hematologic manifestations. Unfortunately, the neurologic manifestations of types II and III have not improved with enzyme replacement therapy. The major drawback is the exceptional cost of imiglucerase, which can exceed $300,000 per year for a severely affected adult patient. Eliglustat tartrate is an oral inhibitor of glucosylceramide synthase and reduces the compound that accumulates; while still quite expensive, this approach eliminates the need ...