## Gaucher Disease: Enzyme Defect and Substrate **Key Point:** Gaucher disease is caused by deficiency of glucocerebrosidase (also called β-glucosidase or acid β-glucosidase), a lysosomal hydrolase that cleaves glucose from glucocerebroside. ### Pathophysiology Glucocerebroside (also called glucosylceramide) is a sphingolipid that normally is broken down by glucocerebrosidase. When this enzyme is deficient: 1. Glucocerebroside accumulates within lysosomes 2. Macrophages become engorged with the substrate, forming characteristic "Gaucher cells" 3. These lipid-laden macrophages infiltrate the reticuloendothelial system (spleen, liver, bone marrow, lymph nodes) ### Clinical Manifestations - **Type 1 (non-neuronopathic)**: Most common; hepatosplenomegaly, bone disease, anemia, thrombocytopenia - **Type 2 (acute neuronopathic)**: Severe neurological involvement in infancy; rapidly progressive - **Type 3 (chronic neuronopathic)**: Intermediate severity with progressive neurological decline **High-Yield:** Gaucher disease is the most common lysosomal storage disorder worldwide, with an estimated incidence of 1 in 40,000–60,000 in most populations. ### Diagnosis - Decreased glucocerebrosidase activity in leukocytes or fibroblasts - Elevated acid phosphatase and chitotriosidase levels (biomarkers) - Genetic testing for GBA gene mutations **Clinical Pearl:** Gaucher cells are pathognomonic — they appear as large macrophages with a characteristic "wrinkled tissue paper" or "crinkled silk" cytoplasm on bone marrow examination. [cite:Robbins 10e Ch 5]
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