The role of neurogenetics in Gaucher disease
R. O. Brady, N. W. Barton and G. A. Grabowski
Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md.
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.
