Fragile X syndrome (FXS) is an inherited abnormality responsible for mild to moderate mental retardation among individuals with expanded DNA material (greater than 230 CGG repeats) on the FMR-1 gene. Prevalence in the general population is problematic since one in 250 females are carriers of FXS. The purpose of this research project is to investigate the impact of FXS on early neurocognitive development among infants, toddlers and preschoolers. Neurophysiological, molecular and behavioral measures will be integrated in this study to explain, in part, biobehavioral dysfunction responsible for the decline in cognitive functioning during the first five years of life. For the first time, event-related brain potentials (ERPs) will be recorded from infants and children with FXS. Unaffected and premutation siblings of subjects with FXS and (unrelated) subjects without known risk of developmental delay will serve as comparison groups. Subjects with Down syndrome (DS) will likewise serve as a contrast study group. Studies within this project will investigate syndrome-specific strengths and weaknesses related to attention, expectancy, stimulus encoding, sequential information processing, visual recognition memory and social gaze. Results will therefore provide new knowledge concerning genotypic-specific neural organization of early cognitive development among subjects with FXS (as compared to subjects with DS). Specific ERP components will thereafter be correlated to CGG repeat region size, FMRP (FMR-1 gene protein), percent methylation, mRNA and, among females, the X activation ratio. The integration of neurophysiological, molecular and behavioral measures through Hierarchical Linear Modeling will assess the impact of FXS upon human neurocognitive development. At the conclusion of our projects, measures developed within our studies will provide new methodologies in the assessment of the effectiveness of early intervention. Outcome measures will likewise provide the means to critique subsequent pharmacotherapy and gene therapy specific to FXS. Results of this study will provide a time course of onset of neuropathology due to deficiencies of FMRP during early development and, accordingly, provide a more precise target of the ideal age at which FMRP protein replacement should be applied among children with FXS.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
7R01HD038049-05
Application #
6920584
Study Section
Special Emphasis Panel (ZRG1-BBBP-6 (01))
Program Officer
Vitkovic, Ljubisa
Project Start
2000-07-01
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
5
Fiscal Year
2003
Total Cost
$229,500
Indirect Cost
Name
University of Victoria
Department
Type
DUNS #
209567957
City
Victoria
State
BC
Country
Canada
Zip Code
V8 5-C2