Review article| Volume 23, SUPPLEMENT 1, S72-S76, December 2001

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Rett syndrome neuropathology review 2000


      This paper will review the study of the neuropathology of Rett syndrome as it has evolved through several phases. In the 1986 the first descriptions of the Rett brain, by Seitelberger and Jellinger, identified that the brains were small, and that there was quantitatively less melanin in the pars compacta of the substantia nigra than in non-Rett brains. There were reports of non- specific gliosis and cell loss in the spinal cords and in the cerebellum, but with traditional neuropathology techniques there were no pathognomonic features that defined a specific neuropathology for Rett syndrome. This apparent absence of pathology was enigmatic in view of the profound clinical phenotype which involved dysfunction of cortex, basal ganglia, the limbic. autonomic and peripheral nervous systems. In the 1990’s evaluation of the accumulating and careful reports of the clinical, functional, anatomic and chemical features of Rett syndrome suggested that the basis of Rett syndrome could be an interruption of brain development. MRI and autopsy examinations revealed that the brain in Rett syndrome was small, and that, unlike the brain in a degenerative disease, it did not become progressively smaller over time. Moreover, only the brain, and no other organ was small, emphasizing the susceptibility of the nervous system in the Rett disorder. Using Golgi studies a selective alteration in the size of dendrites of pyramidal neurons in the frontal, motor and temporal lobes was defined. Regional decreases of dendritic spines were also observed and immunocytochemical studies defined alterations in synaptic sites, early response gene activity and interneurons. MAP-2 immunoreactivity was found to be altered in selected neuronal populations. Studies of neurotransmitters using various techniques in various brain regions and CSF defined alterations (increases or decreases) in most systems, with only, according to Wenk, the studies of the cholinergic system being consistently decreased. The hypothesis that there are decreased neurotransmitters in Rett syndrome remains attractive, for it explains many of the functional deficits in Rett syndrome, and suggests a mechanism for defective brain maturation. However, the measurement of neurotransmitters and the interpretation of the results is problematic; the studies have included girls and women at various stages of the Rett disorder, using numerous techniques and various Rett tissues. In 2000 Rett families and researchers rejoiced at the long awaited identification of a mutated gene in Rett syndrome. Now MeCP2 is the focus of research into the neuropathology of Rett syndrome. An understanding of how this DNA methylating protein contributes to normal brain development should allow us to understand the deficits in Rett syndrome. Most importantly, it may allow us to devise strategies for therapy.


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