Gaucher disease is the most prevalent hereditary metabolic storage disorder, and the most common
genetic disease in individuals of Ashkenazic Jewish ancestry. Patients with
Gaucher disease have been classified into three clinical phenotypes. Patients with type 1 disease exhibit markedly variable hepatosplenomegaly,
anemia,
thrombocytopenia, skeletal, and, to a lesser extent, pulmonary and kidney involvement. The central nervous system does not appear to be involved. In patients with
type 2 Gaucher disease, hepatosplenomegaly and extensive central nervous system damage are apparent in infancy. These patients usually die between 1 and 2 years of age. Patients with
type 3 Gaucher disease have been subclassified into types 3a and 3b. Type 3a patients exhibit mild-to-moderate hepatosplenomegaly and slowly progressive neurologic deterioration. Recurrent
myoclonic seizures are common. Patients with type 3b
Gaucher disease exhibit
splenomegaly along with extensive
hepatomegaly that is frequently accompanied by
esophageal varices. Horizontal supranuclear gaze
paresis is the major
neurologic sign. Excessive quantities of
glucocerebroside accumulate in the organs of patients with
Gaucher disease because of a deficiency of the
enzyme glucocerebrosidase. In the vast majority of patients, the reduction of
glucocerebrosidase activity is caused by mutations in the gene that codes for
glucocerebrosidase. In a few instances,
glucocerebroside accumulates due to a lack of
saposin C, a cohydrolase that is required in addition to
glucocerebrosidase for the catabolism of
glucocerebroside. Mutations in the
glucocerebrosidase gene are discussed in the context of the severity of disease and the presence or absence of nervous system involvement.
Enzyme replacement therapy is highly beneficial for patients with
type 1 Gaucher disease.
Enzyme replacement is also being investigated for patients with type 3b
Gaucher disease. Novel procedures must be developed to deliver
glucocerebrosidase to the nervous system so that patients with type 2 and type 3a
Gaucher disease can be helped. Exploration of gene therapy for
Gaucher disease is under way.