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. Soft tissue masses, Gaucheromas, can occur anywhere in the body.
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.
Patients with Gaucher disease and heterozygous carriers of a mutation in GBA are at increased risk for early-onset Parkinson disease and dementia with Lewy bodies.
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 pathogenic variants cause Gaucher disease and some are highly predictive of the neuronopathic forms. Thus, genetic testing especially in a young person, is of potential value. Only four pathogenic variants 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 of Ashkenazi Jewish descent, 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.
Several recombinant forms of the enzyme glucocerebrosidase 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 ...