In the previous project period, our Genotype-Phenotype study of Fragile X families characterized the spectrum of phenotypic involvement in fragile X syndrome and in those with the premutation, leading to over 60 publications in the past five years. The combination of detailed clinical phenotyping, in the context of families spanning three generations, led to the finding of elevated FMR1-mRNA in those with the premutation (55-200 CGG repeats) and the subsequent discovery of Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) in 2001. FXTAS, which is characterized by tremor, ataxia, brain atrophy, and cognitive decline, has changed the fragile X field regarding clinical care and genetic counseling, and has promulgated a new mechanism of involvement, an RNA gain-of-function toxicity model. Our preliminary data documents problems in childhood related to the premutation, in addition to a broad array of neurological and neuropsychiatric problems in adults. Although FXTAS is more common in males with the premutation, aging females demonstrate a spectrum of neurological, neuropsychiatric, and hormonal problems that we propose to study further.
Our aims i n this competitive renewal are to explore both the neurodevelopmental and neurodegenerative effects of the premutation in both children and adults with the premutation. Our total numbers in this renewal will include 500 adults and 150 children with the premutation and controls with a focus on two specific age groups. We will study boys with the premutation between the ages of 8 to 16 years, as our preliminary data demonstrate problems with both Attention Deficit Hyperactivity Disorder and social deficits, including Autism Spectrum Disorders, in that age range. In addition, males and females over 40 years, from both premutation carrier and age- /education-matched control populations, will be included in our study of aging-related changes. We will utilize a detailed neurological examination and quantitative measurement of movement problems using the CATSYS system. In addition, we will employ psychiatric measures, neuropsychological testing, and MRI quantitative imaging to assess involvement in carriers. Our productive collaboration between California and Australia will continue during the proposed project period. We have found that the large combined data set has increased the power of our analyses, stimulated awareness of involvement of premutation carriers and FXTAS on both continents, and enhanced our knowledge of premutation involvement in diverse racial groups. ? ? ?
| 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 |
| 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; 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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