Gaucher Disease

Gaucher disease is the most common lysosomal storage disease, caused by autosomal recessive mutations in the GBA1 gene (chromosome 1q21) encoding the lysosomal enzyme beta-glucocerebrosidase (acid beta-glucosidase). This enzyme normally cleaves glucocerebroside (glucosylceramide) — a glycosphingolipid intermediate generated during the catabolism of cell membrane glycolipids, particularly from red blood cell and white blood cell membrane turnover — into glucose and ceramide within lysosomes. When beta-glucocerebrosidase activity falls below 15% of normal, undegraded glucocerebroside accumulates progressively within tissue macrophages, transforming them into pathognomonic 'Gaucher cells' — enlarged macrophages (20-100 μm) with a characteristic 'crinkled tissue paper' or 'wrinkled silk' cytoplasmic appearance on light microscopy, caused by the striated pattern of tubular glucocerebroside deposits within distended lysosomes. These lipid-engorged Gaucher cells infiltrate the reticuloendothelial system: the spleen (causing massive splenomegaly, often 15-75x normal, with resultant hypersplenism producing pancytopenia), liver (hepatomegaly with potential fibrosis), bone marrow (displacing normal hematopoiesis, causing bone pain, avascular necrosis from marrow infarction, and the characteristic Erlenmeyer flask deformity of the distal femur from failed bone remodeling), and occasionally lungs (pulmonary hypertension, particularly post-splenectomy). Three clinical types are recognized:...