Rett syndrome (RS) is a common cause of neurologic dysfunction in females for which the etiology has not been identified. Routine pathologic examinations provide no clue as to the pathogenesis of Rett syndrome. The brains are small, and have decreased melanin in the substantia nigra. These alterations do not appear to be the result of a degenerative process. Quantitative Golgi analyses have identified reduced lengths of dendrites in selected cortical pyramidal neurons, and because the alterations in size do not appear to be the result of atrophy and are independent of age, a possible interpretation is that complete growth has not occurred; i.e., there is a selective arrest of brain maturation. Two other observations support such an idea; the girls have generalized growth retardation, and preliminary studies of the heart demonstrate an immature appearing conduction system. Because there is some evidence that the biogenic amines, which are known to act as neurotrophic factors, are decreased in RS, our pathologic studies are organized to explore this aspect of neurotransmitter function and to test the following Hypothesis: that in Rett Syndrome there is a selective arrest of brain, cardiac conduction system and somatic growth, related to decreased biogenic amines or peptide activity. The objective of our anatomic studies will be to examine organs at autopsy for morphologic evidence of a developmental arrest and for alterations in their chemoarchitecture which could reflect an immaturity and/or an alteration in essential trophic factors which may have an etiologic significance RS.
The specific aims of the project are: 1) To characterize microscopic features in Rett brains which could signify developmental arrest using a) Golgi techniques to further study cortical pyramidal neurons; b) immunocytochemistry to characterize the presence and maturity of selected neuronal types, particularly dopaminergic and GABAergic neurons; and c) counting techniques to estimate regional cell populations. 2) To quantify neurotransmitter receptor binding densities in Rett brains and hearts and in animal models of Rett neuropathology from Project 3. 3) To assess the morphologic maturity of the cardiac conduction system in RS and in animal models of Rett neuropathology from Project 3. 4) To continue to collect data about other organ growth by expanding the autopsy registry. These studies will provide important baseline data pertaining to the normal development of the brain and heart and may define a selective immaturity in RS which could explain some of its enigmatic pathophysiology.
Showing the most recent 10 out of 23 publications
