Enzyme Deficient in Gaucher Disease
Gaucher disease is caused by a deficiency of the lysosomal enzyme acid β-glucocerebrosidase (also called glucocerebrosidase or β-glucosidase), which is encoded by the GBA gene. 1
Pathophysiology
Acid β-glucocerebrosidase normally catalyzes the hydrolysis of the sphingolipid glucocerebroside (glucosylceramide) into glucose and ceramide. 2, 3
The enzymatic deficiency causes accumulation of glucosylceramide (GL-1) primarily in the lysosomal compartment of macrophages, giving rise to foam cells or "Gaucher cells." 2
This accumulation occurs predominantly in the reticuloendothelial system, affecting the liver, spleen, bone marrow, and other organs. 2, 4
Diagnostic Confirmation
Diagnosis is confirmed by demonstrating deficient acid β-glucocerebrosidase enzymatic activity in leukocytes. 1, 5
If leukocyte GBA enzyme activity is low on repeat testing, proceed to GBA gene sequencing for molecular confirmation. 1
Identification of biallelic pathogenic variants in the GBA1 gene provides genetic confirmation and may offer prognostic information. 6, 5
Clinical Consequences of Enzyme Deficiency
Type 1 (non-neuronopathic): Hepatosplenomegaly, thrombocytopenia, anemia, and bone disease without primary neurological involvement. 1, 7
Type 2 (acute neuronopathic): Rapidly progressive with severe neurological manifestations, often fatal in early childhood. 6, 8
Type 3 (chronic neuronopathic): Variable neurological involvement including seizures, bulbar palsy, hypertonia, and supranuclear gaze palsy. 6, 8