Gaucher’s disease is caused by a deficiency of:
Gaucher disease, the most common lysosomal storage disorder with incidence about 1 in 40,000 to 60,000 in general population and 1 in 800 among Ashkenazi Jews, arises from autosomal recessive mutations in GBA1 gene on chromosome 1q21 encoding lysosomal glucocerebrosidase, also called acid beta-glucosidase or glucosylceramide beta-glucosidase. This membrane-associated enzyme normally cleaves glucosylceramide, a major membrane glycosphingolipid intermediate, into ceramide and glucose within lysosomes of macrophages that recycle membranes from phagocytosed senescent erythrocytes and leukocytes. Deficiency leads to accumulation of undegraded glucosylceramide and glucosylsphingosine in lysosomes, producing engorged macrophages, Gaucher cells, with fibrillar wrinkled tissue paper cytoplasm due to lipid-laden lysosomes in spleen, liver, bone marrow and sometimes brain. Three clinical subtypes exist: Type 1 non-neuronopathic adult chronic with hepatosplenomegaly, anemia, thrombocytopenia and bone crises; Type 2 acute neuronopathic infantile rapidly lethal; and Type 3 chronic neuronopathic with horizontal gaze palsy and progressive neurological decline. Diagnosis measures leukocyte enzyme activity and GBA sequencing. Therapies include enzyme replacement with recombinant glucocerebrosidase imiglucerase and velaglucerase and substrate reduction with miglustat and eliglustat inhibiting glucosylceramide synthase.
Ref: Scriver et al., The Metabolic and Molecular Bases of Inherited Disease, Chapter 146: Gaucher Disease – Glucocerebrosidase.