Gaucher disease: from fundamental research to effective therapeutic interventions

Gaucher disease type I is the most common lysosomal storage disorder, with a prevalence of 1:50,000 in most countries. It is caused by an autosomally recessive inherited deficiency of the lysosomal enzyme glucocerebrosidase, leading to the accumulation of glucocerebroside in the macrophages. The lipid-laden macrophages are called Gaucher cells and can be found in the liver, spleen and bone marrow. Gaucher disease type I should be considered in any patient with an unexplained splenomegaly with or without bleeding diathesis, skeletal manifestations or hepatomegaly. The diagnosis is made by showing decreased glucocerebrosidase activity in peripheral blood leucocytes or by demonstrating previously defined DNA mutations. Detailed knowledge about the molecular defect has provided a rationale for therapeutic interventions and attempts have been made to correct the defect at gene level, protein level and by manipulation of metabolism. Clinical trials of gene therapy have been conducted but so far have not resulted in successful intervention. For moderate to severely affected patients, intravenous enzyme supplementation therapy is the treatment of choice, resulting in substantial clinical improvement in the majority of patients. For individuals with mild Gaucher disease, an oral substrate inhibitor can also be considered if intravenous treatment is a less attractive option.