Fragile X syndrome (FXS) is the most common known inherited cause of mental retardation, but it can also manifest as a broad spectrum of behavior and learning problems in individuals with an IQ in the normal range. Preliminary studies have demonstrated less involvement cognitively and physically in fragile X individuals with mosaicism (some cells with a premutation and others with a full mutation) or partial methylation of a full mutation. Our preliminary studies have revealed significant correlations between expression of the FMRI protein (FMRP) and a) the percent of cells with a premutation in mosaic males and b) the percent of cells with an unmethylated FMR1 gene in males with a full mutation. In females, the percent of cells with the normal FMR1 gene on the active X chromosome (activation ratio) also correlates with the percent of cells producing FMRP. This project will utilize a new technique to measure FMRP expression developed by Dr. Ben Oostra in the Netherlands in addition to FMR1 DNA measures (CGG repeat number, methylation status and activation ratio). These measures will be correlated with clinical measures to investigate fragile X phenotypic variability within the context of a family study format that also accounts for the effects of background genes. This study combines the advances in the statistical modeling of quantitative pedigree data developed by the Australian team, Drs. Loesch and Huggins, with the latest molecular and protein studies to be done in Denver. Nine hundred individuals in 150 families will be evaluated at two centers, Denver and Melbourne, over a three-year period. The evaluation includes physical (including anthropometric and dermatoglyphic studies), neurocognitive (including executive function measures) and emotional measures which are sensitive to subtle effects of the FMR1 mutation. All molecular and protein studies will be carried out in Denver by Dr. Annette Taylor. This project will characterize whether involvement truly exists in individuals with the premutation and a careful search for subtle mosaicism will be carried out in blood and buccal cells in individuals with the premutation. This project will be a model for investigation of complex genotype-phenotype relationships in other disorders whose genes are now being characterized.
| Shelton, Annie L; Wang, Jun Y; Fourie, Emily et al. (2018) Middle Cerebellar Peduncle Width-A Novel MRI Biomarker for FXTAS? Front Neurosci 12:379 |
| Napoli, Eleonora; Schneider, Andrea; Wang, Jun Yi et al. (2018) Allopregnanolone Treatment Improves Plasma Metabolomic Profile Associated with GABA Metabolism in Fragile X-Associated Tremor/Ataxia Syndrome: a Pilot Study. Mol Neurobiol : |
| Loesch, Danuta Z; Tassone, Flora; Mellick, George D et al. (2018) Evidence for the role of FMR1 gray zone alleles as a risk factor for parkinsonism in females. Mov Disord 33:1178-1181 |
| Wang, Xiao-Hong; Yang, Jin-Chen; Soohoo, Robert et al. (2018) Cognitive Deficits and Associated ERP N400 Abnormalities in FXTAS With Parkinsonism. Front Genet 9:327 |
| Ligsay, Andrew; El-Deeb, Marwa; Salcedo-Arellano, Maria J et al. (2018) General Anesthetic Use in Fragile X Spectrum Disorders. J Neurosurg Anesthesiol : |
| Martínez Cerdeño, Verónica; Hong, Tiffany; Amina, Sarwat et al. (2018) Microglial cell activation and senescence are characteristic of the pathology FXTAS. Mov Disord : |
| Jacquemont, Sébastien; Pacini, Laura; Jønch, Aia E et al. (2018) Protein synthesis levels are increased in a subset of individuals with fragile X syndrome. Hum Mol Genet 27:2039-2051 |
| Shickman, Ryan; Famula, Jessica; Tassone, Flora et al. (2018) Age- and CGG repeat-related slowing of manual movement in fragile X carriers: A prodrome of fragile X-associated tremor ataxia syndrome? Mov Disord 33:628-636 |
| Martínez-Cerdeño, Verónica; Lechpammer, Mirna; Hagerman, Paul J et al. (2017) Two FMR1 premutation cases without nuclear inclusions. Mov Disord 32:1328-1329 |
| Jiraanont, Poonnada; Sweha, Stefan R; AlOlaby, Reem R et al. (2017) Clinical and molecular correlates in fragile X premutation females. eNeurologicalSci 7:49-56 |
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