Rett syndrome (RS), which affects approximately 1 in 10,000 young females, is characterized by cognitive deterioration, ataxia, apraxia, rigidity, and stereotyped hand movements. Neuropathological features include reduction in brain size and hypopigmentation of neurons of the substantia nigra pars compacta (SNpc). Neurochemical and imaging studies support nigrostriatal involvement. The results of our preliminary studies show abnormalities in neurons of the substantia nigra (SN), including decreased numbers of neurons, ubiquitin-stained neuronal inclusion bodies, decreased immunostaining for transmitter markers, and evidence of cell death using terminal deoxynucleotidyl transferase (TDT)-mediated dUTP-biotin nick end labeling (TUNEL), which labels fragmented intranucleosomal DNA. These preliminary data represent the first evidence for cell death in RS.