The classic studies of the neuropathology of Rett Syndrome have failed to define any specific morphologic marker which is pathognomonic of the disease. None of the characteristic pathologic processes of degeneration, storage, neoplasia and malformation are recognizable in Rett Syndrome, so that the explanation for the profound defects in cognitive, motor and emotional function in Rett girls remains elusive. There are numerous problems in attempting to study the morphologic """"""""changes""""""""; early clinical diagnosis of Rett syndrome, at a stage when the """"""""process"""""""" which interrupts brain function appears to begin is difficult to establish; the girls evolve through four clinical stages, and each may have a particular morphology; the girls may die at any stage of their disease; and the number of girls available for study at each center is limited. The prolonged evolution of the clinical syndrome has hampered our understanding of the essential or primary, morphologic and chemical features of the syndrome. Nevertheless, in some cases there have been numerous irregularities of morphology observed at all levels of the peripheral and central nervous system, microcephaly, peripheral nerve degenerations, cerebellar atrophy, spinal cord degeneration, mitochondrial alterations, lipid accumulations, and decreased neuronal dendritic branching. the most consistent observation is the decreased brain size of Rett girls. The purpose of this project is to continue with the classic examination of all cases of Rett syndrome which are referred to our center for autopsy, with a consideration of the findings of the whole autopsy, as well as the neuropathology. An autopsy registry of reports and slides from autopsies of Rett girls who are known to the International Rett Association will be established. This will provide a source of material from girls of all ages, and hopefully enable us to form a more complete concept of the morphologic effects of Rett Syndrome on all systems, at various stages of the disease. The neuropathological studies include classical neuropathologic examinations of all cases, as well as studies directed towards several specific questions. Golgi studies will be continued in attempts to identify whether there is a preferential site of the decreased dendritic branching which we have observed in Rett syndrome. Neuronal counts will be made in selected areas of cortex in attempts to define further the character of the microcephaly in Rett Syndrome and the selective functional deficits. Neurotransmitter receptor binding will be measured in order to provide more data about altered neurotransmitters (catecholaminergic, cholinergic, serotoninergic, and opioid). Mitochondria will be studied morphologically and biochemically. The pineal gland will be studied as a possible site of abnormality in Rett Syndrome.
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