Lysosomal β-hexosaminidase consists of 2 subunits, α and β. Mutations in the α-subunit gene cause Tay-Sachs disease, while mutations in the β-subunit gene cause Sandhoff disease. Mice generated by targeted disruption of either the α- or β-subunit genes displayed the pathological features of Tay-Sachs disease or Sandhoff disease, respectively. In this repon we describe the pathologic features of mice that carry both disrupted genes and that are deficient in all forms of β-hexosaminidase activity. These mice displayed physical dysmorphia and extensive neuro-visceral storage. Neurons in the CNS and PNS contained pleomorphic inclusions in addition to membranous cytoplasmic bodies characteristic of gangliosidosis. Diffuse hypomyelination was also apparent in the CNS. Vacuolated cytoplasm was a conspicuous feature of chondrocytes, osteocytes and renal tubular epithelium on routine hematoxylin and eosin (H&E) -stained sections. Numerous vacuolated cells were also noted in the connective tissue, cornea, heart valves, arterial walls, liver, spleen, skin and throughout other visceral organs. These vacuolated cells stained positive with PAS, colloidal iron and alcian blue, indicating an accumulation of glycosaminoglycans. Furthermore, cultured fibroblasts showed a defect in the degradation of glycosaminoglycans, and glycosaminoglycans were excreted in the urine of these mice (1). Thus, morphological and biochemical features in these mice are consistent with those of mucopolysaccharidosis and demonstrate an essential role of β-hexosaminidase in the degradation of glycosaminoglycans.