Fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in approximately 40% of aging male (andless commonly, female) carriers of premutation expansions (55-200 CGG repeats) of the fragile X mentalretardation 1 (FMR1) gene. The overall goal of this project is to develop and utilize quantitative measures ofCNS dysfunction in premutation carriers as outcome measures for targeted treatment studies of FXTAS.Sixty premutation carriers, ages 30 to 79 yr, both affected and unaffected, and an equal number of age-,sex-, and education-matched controls will be recruited per year for the first 3 years of the project. Following amedical assessment that includes a videotaped neurological examination with quantitative standardizedmeasures, subjects will participate in several quantitative analyses of CNS dysfunction (Aim 1), includingvolumetric MRI studies, event related potentials (ERPs), psychophysiological studies (prepulse inhibition andfear potentiated startle), quantitative motor measures (CATSYS), neuropsychological measures (executivefunction and memory), and nerve conduction studies (NCS). Many of these quantitative measures will alsobe carried out in transgenic mouse models of FXTAS (Project 2), which will then be used as animalcorrelates, to better gauge the neuropathology of FXTAS and its intrinsic reversibility as a model forsuccessful therapeutic intervention. A component of this research will develop, with Project 4, an integratedMRI approach for studying volumetric changes across the lifespan of premutation carriers.Consortium Project 1 described preliminary observations for the neuroprotective effect of lithium in aneural cell model of FXTAS.
Aim 2 of this project will study the neuroprotective effects of lithium carbonate ina controlled trial of aging premutation carriers who have early symptoms of FXTAS (Aim 2). We will use thequantitative measures outlined above as outcome measures for this lithium trial in addition to psychiatricassessments of clinical .improvement, including the Neuropsychiatric Inventory, the Symptom Checklist-90(SCL-90), and the Clinical Global Impressions Scale- Improvement (CGI-I).
In Aim 3, we will also offer anopen trial, to patients who are ineligible or unwilling to participate in the lithium trial, to assess the benefit ofthe NMDA antagonist, memantine. Studies in Project 1 and 2, related to involvement of glutamate toxicity inFXTAS, will better inform this treatment trial.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Linked Research project Grant (RL1)
Project #
1RL1AG032115-01
Application #
7467621
Study Section
Special Emphasis Panel (ZRR1-SRC (99))
Program Officer
Buckholtz, Neil
Project Start
2007-09-30
Project End
2012-06-30
Budget Start
2007-09-30
Budget End
2008-06-30
Support Year
1
Fiscal Year
2007
Total Cost
$1,073,885
Indirect Cost
Name
University of California Davis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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
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
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
Seritan, Andreea L; Kim, Kyoungmi; Benjamin, Ian et al. (2016) Risk Factors for Cognitive Impairment in Fragile X-Associated Tremor/Ataxia Syndrome. J Geriatr Psychiatry Neurol 29:328-337
Schneider, A; Johnston, C; Tassone, F et al. (2016) Broad autism spectrum and obsessive-compulsive symptoms in adults with the fragile X premutation. Clin Neuropsychol 30:929-43
Yang, Jin-Chen; Rodriguez, Annette; Royston, Ashley et al. (2016) Memantine Improves Attentional Processes in Fragile X-Associated Tremor/Ataxia Syndrome: Electrophysiological Evidence from a Randomized Controlled Trial. Sci Rep 6:21719
Ram, Suresh; Devapriya, Inoka A; Fenton, Grace et al. (2015) Axonal neuropathy in female carriers of the fragile X premutation with fragile x-associated tremor ataxia syndrome. Muscle Nerve 52:234-9
Jalnapurkar, Isha; Rafika, Nuva; Tassone, Flora et al. (2015) Immune mediated disorders in women with a fragile X expansion and FXTAS. Am J Med Genet A 167A:190-7
Muzar, Zukhrofi; Lozano, Reymundo; Schneider, Andrea et al. (2015) Methadone use in a male with the FMRI premutation and FXTAS. Am J Med Genet A 167:1354-9
Careaga, Milo; Rose, Destanie; Tassone, Flora et al. (2014) Immune dysregulation as a cause of autoinflammation in fragile X premutation carriers: link between FMRI CGG repeat number and decreased cytokine responses. PLoS One 9:e94475

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