The purpose of this application is to define the clinical features of a newly identified, progressive neurologic disorder consisting of intention tremor, ataxia, and dementia, with generalized brain atrophy and inclusion bodies, among older men with the fragile X premutation. Fragile X syndrome (FXS) is a developmental disorder involving a trinucleotide repeat expansion (CGG) in the fragile X mental retardation 1 gene (FMR1). The full mutation is associated with mental retardation among males and milder impairment of cognition among females. Carriers of the FXS gene are said to possess the premutation, a smaller trinucleotide expansion (55 to 200 CGG repeats). The premutation generally has been associated with a normal or nearly normal cognitive and anatomic phenotype, but recent data suggest the premutation phenotype may include subtle developmental anomalies. Our research over the past two years suggests that a subgroup of adult males with the premutation develop a neurologic disorder resembling some of the spinocerebellar ataxias. It is first clinically apparent when the men are in their fifties or sixties, and is characterized by action tremor and other motor findings, dementia, and generalized brain atrophy. The prevalence of this disorder has not been definitively established, but our data suggest it may be between 20 and 78 per I00,000 males, which is common enough that it would represent an important public health problem. Since our previous submission of this application, we have obtained neurologic, radiologic, neuropsychological, and neuropathologic data on a number of additional patients, and the condition has become the focus of study for other investigators in the United States. and abroad. The proposed study will compare a sample of FXS carrier males with this tremor-ataxia disorder to an age- and education-matched sample of carrier males without tremor or other signs of neurologic disorder, and a matched group of healthy men without FXS involvement. The measures used include a comprehensive standardized neurological evaluation, neuropsychological examination, functional assessment, MRI of the brain, and basic molecular studies. Data will be collected at baseline, and at 18-month and 36-month follow-up points. Data analysis will include between-groups and repeated measures methods. The results of this study will provide important information on the clinical features of this previously unidentified disorder, including its rate of progression and its relationship to the FXS premutation. Further knowledge of the nature of this phenotype, and of its association with the FMR1 gene, is of substantial clinical importance for the differential diagnosis, management, and appropriate treatment of movement disorders among older males.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Biobehavioral and Behavioral Processes 3 (BBBP)
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Riddle, Robert D
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University of Colorado Denver
Internal Medicine/Medicine
Schools of Medicine
United States
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Grigsby, Jim; Brega, Angela G; Bennett, Rachael E et al. (2016) Clinically significant psychiatric symptoms among male carriers of the fragile X premutation, with and without FXTAS, and the mediating influence of executive functioning. Clin Neuropsychol 30:944-59
Grigsby, Jim (2016) The fragile X mental retardation 1 gene (FMR1): historical perspective, phenotypes, mechanism, pathology, and epidemiology. Clin Neuropsychol 30:815-33
Hessl, David; Grigsby, Jim (2016) Fragile X-associated tremor/ataxia syndrome: another phenotype of the fragile X gene. Clin Neuropsychol 30:810-4
Grigsby, Jim; Cornish, Kim; Hocking, Darren et al. (2014) The cognitive neuropsychological phenotype of carriers of the FMR1 premutation. J Neurodev Disord 6:28
Seritan, Andreea; Cogswell, Jennifer; Grigsby, Jim (2013) COGNITIVE DYSFUNCTION IN FMR1 PREMUTATION CARRIERS. Curr Psychiatry Rev 9:78-84
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Jenkins, Edmund C; Tassone, Flora; Ye, Lingling et al. (2012) Reduced telomere length in individuals with FMR1 premutations and full mutations. Am J Med Genet A 158A:1060-5
Hunsaker, Michael R; Greco, Claudia M; Spath, Marian A et al. (2011) Widespread non-central nervous system organ pathology in fragile X premutation carriers with fragile X-associated tremor/ataxia syndrome and CGG knock-in mice. Acta Neuropathol 122:467-79
Bourgeois, James A; Seritan, Andreea L; Casillas, E Melina et al. (2011) Lifetime prevalence of mood and anxiety disorders in fragile X premutation carriers. J Clin Psychiatry 72:175-82
Hunsaker, Michael R; Greco, Claudia M; Tassone, Flora et al. (2011) Rare intranuclear inclusions in the brains of 3 older adult males with fragile x syndrome: implications for the spectrum of fragile x-associated disorders. J Neuropathol Exp Neurol 70:462-9

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