Olfactory biopsies demonstrate a defect in neuronal development in Rett's syndrome

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Abstract
Rett's Syndrome (RTT) is a neurodevelopmental disorder resulting from mutation in the mecp2 gene that encodes methyl CpG binding protein 2, a transcriptional repressor. Because this disease primarily affects neurons, tissue is not available during active disease. We used the olfactory system as a model to investigate abnormalities in neuronal development in RTT, because olfactory receptor neurons (ORNs) are replaced throughout life by ongoing postnatal neurogenesis. Thus, even in the adult, the olfactory epithelium contains neurons at various developmental stages. We obtained biopsies of nasal epithelium containing ORNs from RTT patients and age‐matched controls to study the status of the neuronal population using antibodies to stage‐specific developmental markers. There were no postprocedure complications. Compared with age‐matched controls, there were far fewer mature ORNs, as defined by olfactory marker protein expression, and significantly greater numbers of immature neuron‐specific tubulin–positive ORNs present. In RTT biopsies, olfactory marker protein–positive neurons displayed abnormal structure. These results suggest that dysfunction of MeCP2 results in decreased survival of mature ORNs with a compensatory increase in neurogenesis, or a failure of immature neurons to mature. Our study indicates that olfactory biopsies provide a method to study neuronal developmental diseases in adults and children. Ann Neurol 2003