]: Rett syndrome (RS) predominantly affects girls, and is associated in most cases with mutations in the MeCP2 gene. Pathogenetic mechanisms of RS are unknown, but the investigators'studies support the overall hypothesis that the genetic defect disrupts maturation of neurons and their interconnections during rapid brain growth when synapses are formed and pruned. Five interactive projects will test this hypothesis with the ultimate goal of providing rational treatments. Project I will determine the natural history of the disease and biological basis for phenotypic variability by neurological, neuroimaging, and molecular approaches. Treatment with a NMDA/glutamate channel blocker will be instituted to prevent excitotoxicity and provide neuroprotection. Project IB will establish the status of the cholinergic system in vivo by single photon emission computerized tomography (SPECT) measurement of vesamicol binding as a function of age, and identify RS patients for treatment with anticholinesterase inhibitors. Also, the effect of ketamine-induced blocking of glutamate receptors on dopamine release will be investigated. In addition, MR-spectroscopy (MRS) will determine changes in glutamate with age, and efficacy of therapy with glutamate antagonists. Finally, longitudinal volumetric MRI analyses will assess age-related and regional changes. Project II will utilize cultured olfactory receptor neurons (ORNs) as a model of neuronal involvement in RS, in which effects of various mutations in MeCP2 and therapeutic interventions will be studied. Project III will pursue recent observations of extranuclear MeCP2 to characterize MeCP2 expression and subcellular localization in lymphocytes and brain of RS patients with and without different MeCP2 mutations, and in related animal models. Transcriptional regulator complexes in cellular and tissue samples will be characterized. Functional consequences of MeCP2 deficit in lymphocytes and brain from RS patients and animal models will also be delineated by patterns of histone acetylation. Project IV will determine the effect of altered MeCP2 expression on glutamate receptor ontogeny, cortical plasticity, and effect of altered MeCP2 expression on cerebellar development;examine morphological, neurological, and behavioral differences in mice with various MeCP2 mutations. Cortical as well as cerebellar granule neurons from mutant mice will also be cultured and methods to restore MeCP2 function will be explored.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Pediatrics Subcommittee (CHHD)
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Oster-Granite, Mary Lou
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Hugo W. Moser Research Institute Kennedy Krieger
United States
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Crosson, Jane; Srivastava, Siddharth; Bibat, Genila M et al. (2017) Evaluation of QTc in Rett syndrome: Correlation with age, severity, and genotype. Am J Med Genet A 173:1495-1501
Pidcock, Frank S; Salorio, Cynthia; Bibat, Genila et al. (2016) Functional outcomes in Rett syndrome. Brain Dev 38:76-81
O'Driscoll, Cliona M; Coulter, Jonathan B; Bressler, Joseph P (2013) Induction of a trophoblast-like phenotype by hydralazine in the p19 embryonic carcinoma cell line. Biochim Biophys Acta 1833:460-7
Kaufmann, W E; Tierney, E; Rohde, C A et al. (2012) Social impairments in Rett syndrome: characteristics and relationship with clinical severity. J Intellect Disabil Res 56:233-47
BraĊĦi?, James Robert; Bibat, Genila; Kumar, Anil et al. (2012) Correlation of the vesicular acetylcholine transporter densities in the striata to the clinical abilities of women with Rett syndrome. Synapse 66:471-82
Downs, Jennepher; Bebbington, Ami; Kaufmann, Walter E et al. (2011) Longitudinal hand function in Rett syndrome. J Child Neurol 26:334-40
Makkonen, Ismo; Riikonen, Raili; Kuikka, Jyrki T et al. (2011) Brain derived neurotrophic factor and serotonin transporter binding as markers of clinical response to fluoxetine therapy in children with autism. J Pediatr Neurol 9:1-8
Foley, Kitty-Rose; Downs, Jenny; Bebbington, Ami et al. (2011) Change in gross motor abilities of girls and women with rett syndrome over a 3- to 4-year period. J Child Neurol 26:1237-45
Blue, Mary E; Kaufmann, Walter E; Bressler, Joseph et al. (2011) Temporal and regional alterations in NMDA receptor expression in Mecp2-null mice. Anat Rec (Hoboken) 294:1624-34
Jentarra, Garilyn M; Olfers, Shannon L; Rice, Stephen G et al. (2010) Abnormalities of cell packing density and dendritic complexity in the MeCP2 A140V mouse model of Rett syndrome/X-linked mental retardation. BMC Neurosci 11:19

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