Which enzyme is deficient in Gaucher disease, and what substrate accumulates as a result?

Explanation

## Gaucher Disease — Enzyme Defect and Substrate **Key Point:** Gaucher disease is caused by deficiency of the lysosomal enzyme **glucocerebrosidase** (also called β-glucosidase or acid β-glucosidase), leading to accumulation of **glucocerebroside** (also called glucosylceramide) in macrophages throughout the reticuloendothelial system. ### Pathophysiology Glucocerebrosidase normally cleaves glucose from glucocerebroside. When deficient: - Glucocerebroside cannot be degraded - Accumulates in lysosomes of macrophages, creating characteristic **Gaucher cells** ("wrinkled tissue paper" appearance on light microscopy) - Storage occurs in bone marrow, liver, spleen, and brain (in neuronopathic forms) ### Clinical Manifestations by Type | Type | Age of Onset | CNS Involvement | Key Features | |------|--------------|-----------------|---------------| | Type 1 (Non-neuropathic) | Childhood–adulthood | No | Hepatosplenomegaly, bone disease, anemia | | Type 2 (Acute neuropathic) | Infancy | Severe, rapid | Neurodegeneration, death by age 2 | | Type 3 (Chronic neuropathic) | Childhood | Progressive | Intermediate severity | **High-Yield:** Type 1 is the most common form (~90% of cases) and does NOT involve the CNS, making it more amenable to enzyme replacement therapy (imiglucerase) or substrate reduction therapy (eliglustat, miglustat). ### Diagnosis - Decreased glucocerebrosidase activity in leukocytes or fibroblasts - Elevated acid phosphatase and chitotriosidase - Genetic testing for GBA gene mutations **Clinical Pearl:** Gaucher cells are pathognomonic — they appear as large, pale macrophages with a characteristic "wrinkled silk" or "crumpled tissue paper" cytoplasm due to storage of glucocerebroside. [cite:Robbins 10e Ch 5]