Gaucher disease.

Gaucher disease is an inherited recessive autosomal metabolic defect due to a deficiency of the lysosomal enzyme beta-glucocerebrosidase. The enzyme substrate, glucocerebroside, accumulates in the body, predominantly in the liver, spleen, and bone marrow. Osteoarticular manifestations are often inaugural and contribute much of the morbidity and disability associated with Gaucher disease. There are three types of Gaucher disease. The most common is type 1, which can produce a broad range of presentations characterized by cytopenia and involvement of the spleen, liver, and bone marrow. Types 2 and 3 are rarest variants that manifest in infancy and cause neurologic damages. Patients with type 2 Gaucher disease usually die before 2years of age. beta-glucocerebrosidase assays and examination of bone marrow smears and biopsies ensure the diagnosis. Specific mutations in the beta-glucocerebrosidase gene are associated with specific clinical presentations: thus, the N370S mutation (heterozygous or homozygous) confers type 1 disease and the L444P mutation neurologic involvement and type 3 disease. Bone involvement is a feature in 70%-100% of cases. Abnormal bone remodeling, osteonecrosis and bony infarcts, osteopenia with fractures, and more rarely infections may occur. The other manifestations are dominated by cytopenia (thrombocytopenia, neutropenia, or anemia), hypersplenism, and liver enlargement. The risk of myeloma is increased. Parkinson-like syndromes were recently described in patients with type 1 disease. The enzyme chitotriosidase can be assayed to quantify the degree of macrophage activation. The chemokine CCL18 is another valuable marker but is not readily available in everyday practice. The treatment of Gaucher disease includes symptomatic drugs to relieve pain. Splenectomy is rarely necessary now that specific treatments are available. Enzyme replacement therapy (imiglucerase) has considerably improved the management of the highest risk patients. More recently, an enzyme inhibitor that decreases the production of the substrate (miglustat) was introduced. Chemical chaperone therapy and gene therapy hold promise for the future.