Rett syndrome (RS) is a disorder that affects young girls and is characterized by progressive loss of cognitive function and ability to communicate, apraxia of hand movements, seizures, respiratory disturbances, ataxia, corticospinal tract involvement, and characteristic hand-wringing movements. It affects only females with an incidence of 1:10,000-1:15,000. Diagnosis depends upon the presence of a characteristic and remarkably consistent constellation of symptoms and signs. There is no diagnostic marker. It is proposed, but not proven, that RS is an X-linked dominant, lethal in males and reproductively lethal in females, with most cases representing new mutations. The present application is submitted 25 months after the initiation of P01 HD 23540, and requests support for an additional 3 years of multidisciplinary clinical and basic research studies designed to elucidate the pathogenesis of RS and to initiate therapy. It includes four highly interrelated components. Project 1 will conduct multidisciplinary evaluations of clinical features and therapeutic interventions in 100 patients with documented """"""""classical"""""""" RS, and will carry out investigations to help clarify the genetic basis of RS. The other three projects are designed to test and extend a pathogenetic hypothesis developed during the 25 months of the current grant period; namely, that RS is a neurodegenerative disorder that affects most severely dopaminergic neurons in the substantia nigra and basal ganglia and cholinergic neurons in the basal forebrain. This hypothesis will be evaluated by the techniques of neuropathology (Projects 2a and 2b), neurochemistry (Project 3), Positron Emission Tomography (Project 4a) and Magnetic Resonance Imaging (Project 4b). This approach may clarify the pathogenesis of RS, but also will serve as a model of how a neonatal neurodegenerative process differs from disorders such as Alzheimer and Parkinson disease that affect at least in part the same neurons later in life. During this grant period, a series of therapeutic interventions will be sought and implemented.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Mental Retardation Research Committee (HDMR)
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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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