Clinical Information

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme, beta-glucosidase, which facilitates the lysosomal degradation of glucosylceramide (glucocerebroside) and glucopsychosine (glucosylsphingosine: lyso-GL1). Gaucher disease is caused by disease-causing variants in the GBA gene and presents with a markedly variable phenotype, ranging from a perinatal lethal disorder to mildly symptomatic. It has historically been categorized into 3 types (GD1, GD2 and GD3) based on the presence and progression of neuropathic features. All types of Gaucher disease include hepatosplenomegaly and hematological abnormalities.

Gaucher disease type I is the most common form, representing more than 90% of cases. It is generally characterized by bone disease, hepatosplenomegaly, anemia and thrombocytopenia, coagulation abnormalities, lung disease, but no central nervous system involvement. Gaucher disease types II and III are characterized by the presence of primary neurologic disease, although in practice, assigning a type in infancy can sometimes be challenging due to overlapping clinical features. In addition, type II typically presents with limited psychomotor development, hepatosplenomegaly, and lung disease, resulting in death usually between 2 and 4 years of age. Individuals with Gaucher disease type III may present prior to 2 years of age, but the progression is not as rapid, and patients may survive into the third and fourth decade. Additional subtypes of Gaucher disease include a perinatal lethal form associated with skin abnormalities and nonimmune hydrops fetalis, and a cardiovascular form presenting with calcification of the aortic and mitral valves, mild splenomegaly, corneal opacities, and gaze impairment.

Treatment is available in the form of enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) for types I and III. Some patients with chronic and progressive neurologic symptoms despite ERT or SRT may be candidates for bone marrow transplant or a multifaceted approach. Currently, only supportive therapy is available for type II because of the inability of enzyme provided by replacement therapy to cross the blood-brain barrier.

The incidence of GD is variable, with a higher occurrence in populations with known founder variants such as the Ashkenazi Jewish population.

A diagnostic workup for GD may demonstrate the characteristic finding of Gaucher cells on bone marrow examination, other hematologic abnormalities, and hepatosplenomegaly. The diagnosis can be confirmed by the demonstration of reduced or absent acid beta-glucosidase activity in leukocytes (GBAW / Beta-Glucosidase, Leukocytes) or dried blood spots (PLSD / Lysosomal and Peroxisomal Disorders Screen, Blood Spot) and molecular genetic analysis of the GBA gene (GBAZ / Gaucher Disease, Full Gene Analysis, Varies). Lyso GL-1 is a sensitive and specific biomarker for Gaucher disease, and an elevation of lyso GL-1 in blood supports the diagnosis. Lyso GL-1 has also been shown to be helpful in monitoring mildly symptomatic individuals for disease progression and in determining treatment response.