Tay–Sachs and Sandhoff diseases are lysosomal storage disorders characterized by the absence of β-hexosaminidase activity and the accumulation of GM2 ganglioside in neurons. In each disorder, a virtually identical course of neurodegeneration begins in infancy and leads to demise generally by 4–6 years of age. Through serial analysis of gene expression (SAGE), we determined gene expression profiles in cerebral cortex from a Tay–Sachs patient, a Sandhoff disease patient and a pediatric control. Examination of genes that showed altered expression in both patients revealed molecular details of the pathophysiology of the disorders relating to neuronal dysfunction and loss. A large fraction of the elevated genes in the patients could be attributed to activated macrophages/microglia and astrocytes, and included class II histocompatability antigens, the pro-inflammatory cytokine osteopontin, complement components, proteinases and inhibitors, galectins, osteonectin/SPARC, and prostaglandin D2 synthase. The results are consistent with a model of neurodegeneration that includes inflammation as a factor leading to the precipitous loss of neurons in individuals with these disorders.