Action tremor & dementia in male carriers of fragile X

Summary

Principal Investigator: JAMES P GRIGSBY
Affiliation: University of Colorado Health Sciences Center
Country: USA
Abstract: 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.
Funding Period: 2003-09-15 - 2009-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutation
    David Hessl
    Medical Investigation of Neurodevelopmental Disorders Institute, University of California Davis Medical Center, Sacramento, CA 95817, USA
    Am J Med Genet B Neuropsychiatr Genet 139:115-21. 2005
  2. doi Fragile X syndrome with anxiety disorder and exceptional verbal intelligence
    Kathleen Angkustsiri
    M I N D Institute, University of California Davis Medical Center, Sacramento, California 95817, USA
    Am J Med Genet A 146:376-9. 2008
  3. doi Cognitive profile of fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome
    Jim Grigsby
    Department of Medicine, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045 5701, USA
    Neuropsychology 22:48-60. 2008
  4. doi A quantitative assessment of tremor and ataxia in FMR1 premutation carriers using CATSYS
    Dalila Aguilar
    Medical Investigation of Neurodevelopmental Disorders MIND Institute, University of California Davis Medical Center, Sacramento, California 95817, USA
    Am J Med Genet A 146:629-35. 2008
  5. doi A girl with fragile X premutation from sperm donation
    Juthamas Wirojanan
    MIND Institute, University of California Davis Medical Center, Sacramento, California 95817, USA
    Am J Med Genet A 146:888-92. 2008
  6. pmc Expanded clinical phenotype of women with the FMR1 premutation
    Sarah M Coffey
    Department of Pediatrics, University of California at Davis Medical Center, Sacramento, California 95817, USA
    Am J Med Genet A 146:1009-16. 2008
  7. pmc Dementia in fragile X-associated tremor/ataxia syndrome (FXTAS): comparison with Alzheimer's disease
    Andreea L Seritan
    Department of Psychiatry and Behavioral Sciences, University of California Davis, Sacramento, California 95817, USA
    Am J Med Genet B Neuropsychiatr Genet 147:1138-44. 2008
  8. pmc Abnormal nerve conduction features in fragile X premutation carriers
    Kultida Soontarapornchai
    M I N D Institute, University of California Davis Medical Center, Sacramento, CA 95817, USA
    Arch Neurol 65:495-8. 2008
  9. pmc Reduced telomere length in older men with premutation alleles of the fragile X mental retardation 1 gene
    Edmund C Jenkins
    Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA
    Am J Med Genet A 146:1543-6. 2008
  10. pmc Treatment of fragile X-associated tremor ataxia syndrome (FXTAS) and related neurological problems
    Randi J Hagerman
    MIND Institute, University of California, Davis, School of Medicine, Sacramento, CA 95817, USA
    Clin Interv Aging 3:251-62. 2008

Scientific Experts

  • Randi Hagerman
  • James Bourgeois
  • Sebastien Jacquemont
  • David R Hessl
  • Andreea L Seritan
  • Flora Tassone
  • Kathleen Angkustsiri
  • JAMES P GRIGSBY
  • M A Leehey
  • Edmund C Jenkins
  • D A Hall
  • Paul J Hagerman
  • Claudia M Greco
  • Dolores Garcia-Arocena
  • Danh V Nguyen
  • Sarah M Coffey
  • Kultida Soontarapornchai
  • Juthamas Wirojanan
  • Angela G Brega
  • Nicole Tartaglia
  • Dalila Aguilar
  • Louise W Gane
  • J S Adams
  • L Zhang
  • C DeCarli
  • P J Hagerman
  • S Cohen
  • Susan Bacalman
  • Judith R Brouwer
  • Lili Zhou
  • Allison M Sumis
  • Claudia Greco
  • Elizabeth M Berry-Kravis
  • Rob Willemsen
  • Anna Ludwig
  • Christopher G Goetz
  • Erin Howell
  • Christine Iwahashi
  • Jane E Yang
  • Luis Campos
  • Lanee S Bounds
  • Jennifer B Cogswell
  • Ann Reynolds
  • Rachael E Bennett
  • Ruiqin Pan
  • Jennifer M Yuhas
  • Jennifer Yuhas
  • Patrick E Adams
  • Ricardo Maselli
  • Kathryn E Sigford
  • Melanie Doerflinger
  • Timothy K Vartanian
  • Hannah E Bronsky
  • Grace Fenton-Farrell
  • Mariya Borodyanskaya
  • Kylee Cook
  • James A Brunberg
  • J A Brunberg
  • W Zhang
  • S M Rivera
  • K Koldewyn
  • John E Gould
  • D Nguyen
  • P E Adams
  • Kultida Soontrapornchai
  • Beth L Goodlin-Jones
  • J Cogswell
  • D Loesch
  • K Masyn
  • J Adams
  • J Brunberg
  • S Rivera
  • Jennifer Cogswell
  • Faraz Farzin

Detail Information

Publications30

  1. ncbi Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutation
    David Hessl
    Medical Investigation of Neurodevelopmental Disorders Institute, University of California Davis Medical Center, Sacramento, CA 95817, USA
    Am J Med Genet B Neuropsychiatr Genet 139:115-21. 2005
    ....
  2. doi Fragile X syndrome with anxiety disorder and exceptional verbal intelligence
    Kathleen Angkustsiri
    M I N D Institute, University of California Davis Medical Center, Sacramento, California 95817, USA
    Am J Med Genet A 146:376-9. 2008
    ..Women with FXS can present primarily with learning and emotional problems, and clinicians should consider FXS in these women regardless of their IQ...
  3. doi Cognitive profile of fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome
    Jim Grigsby
    Department of Medicine, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045 5701, USA
    Neuropsychology 22:48-60. 2008
    ..Longitudinal research currently underway will provide insight into the progression of the disorder...
  4. doi A quantitative assessment of tremor and ataxia in FMR1 premutation carriers using CATSYS
    Dalila Aguilar
    Medical Investigation of Neurodevelopmental Disorders MIND Institute, University of California Davis Medical Center, Sacramento, California 95817, USA
    Am J Med Genet A 146:629-35. 2008
    ..0016). These results demonstrate that the quantitative measures of the CATSYS system can document significant differences in intention tremor and postural sway in patients with FXTAS compared to controls...
  5. doi A girl with fragile X premutation from sperm donation
    Juthamas Wirojanan
    MIND Institute, University of California Davis Medical Center, Sacramento, California 95817, USA
    Am J Med Genet A 146:888-92. 2008
    ..We suggest fragile X DNA screening in gamete donor candidates to decrease the chance of fragile X involvement in their offspring...
  6. pmc Expanded clinical phenotype of women with the FMR1 premutation
    Sarah M Coffey
    Department of Pediatrics, University of California at Davis Medical Center, Sacramento, California 95817, USA
    Am J Med Genet A 146:1009-16. 2008
    ..The remarkable degree of thyroid dysfunction (17% in the non-FXTAS group and 50% in the FXTAS group) warrants consideration of thyroid function studies in all female premutation carriers, particularly those with core features of FXTAS...
  7. pmc Dementia in fragile X-associated tremor/ataxia syndrome (FXTAS): comparison with Alzheimer's disease
    Andreea L Seritan
    Department of Psychiatry and Behavioral Sciences, University of California Davis, Sacramento, California 95817, USA
    Am J Med Genet B Neuropsychiatr Genet 147:1138-44. 2008
    ..Further research is needed to outline the neuropsychiatric profile in FXTAS and the correlation of genetic markers with the progression and severity of cognitive loss...
  8. pmc Abnormal nerve conduction features in fragile X premutation carriers
    Kultida Soontarapornchai
    M I N D Institute, University of California Davis Medical Center, Sacramento, CA 95817, USA
    Arch Neurol 65:495-8. 2008
    ..Distal neuropathy is part of the clinical phenotype in most males with the fragile X-associated tremor/ataxia syndrome (FXTAS) caused by the 55 to 200 CGG repeat expansion...
  9. pmc Reduced telomere length in older men with premutation alleles of the fragile X mental retardation 1 gene
    Edmund C Jenkins
    Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA
    Am J Med Genet A 146:1543-6. 2008
    ..Thus, telomere shortening may serve as a biomarker for cellular dysregulation that may precede the development of the symptoms of FXTAS...
  10. pmc Treatment of fragile X-associated tremor ataxia syndrome (FXTAS) and related neurological problems
    Randi J Hagerman
    MIND Institute, University of California, Davis, School of Medicine, Sacramento, CA 95817, USA
    Clin Interv Aging 3:251-62. 2008
    ..The current review summarizes what is currently known regarding the symptomatic treatment, or potential for treatment, of FXTAS...
  11. pmc Clinical and neuropathologic findings in a woman with the FMR1 premutation and multiple sclerosis
    Claudia M Greco
    Department of Pathology, University of California, Davis, Health System, Sacramento, CA 95817, USA
    Arch Neurol 65:1114-6. 2008
    ..Multiple sclerosis (MS) and fragile X-associated tremor/ataxia syndrome (FXTAS) have overlapping clinical signs and symptoms...
  12. doi Functional status of men with the fragile X premutation, with and without the tremor/ataxia syndrome (FXTAS)
    Angela G Brega
    Department of Medicine, University of Colorado Denver, Aurora, CO 80217 3364, USA
    Int J Geriatr Psychiatry 24:1101-9. 2009
    ....
  13. pmc A review of fragile X premutation disorders: expanding the psychiatric perspective
    James A Bourgeois
    Department of Psychiatry and Behavioral Sciences, University of California Davis Medical Center, Sacramento, CA 95817, USA
    J Clin Psychiatry 70:852-62. 2009
    ..Remarkable advances at the molecular level have enhanced our understanding of fragile X premutation disorders...
  14. pmc FMR1 CGG repeat length predicts motor dysfunction in premutation carriers
    M A Leehey
    Department of Neurology, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262, USA
    Neurology 70:1397-402. 2008
    ..This study determines whether CGG repeat length correlates with severity and type of motor dysfunction in premutation carriers...
  15. ncbi Neuropathy as a presenting feature in fragile X-associated tremor/ataxia syndrome
    Randi J Hagerman
    Department of Pediatrics, University of California at Davis Medical Center, Sacramento, California 95817, USA
    Am J Med Genet A 143:2256-60. 2007
    ....
  16. ncbi Psychiatric phenotype of the fragile X-associated tremor/ataxia syndrome (FXTAS) in males: newly described fronto-subcortical dementia
    Susan Bacalman
    M I N D Institute, and Departments of Psychiatry and Behavioral Sciences, UCDavis Medical Center, University of California Davis, 2230 Stockton Boulevard, Sacramento, CA 95817, USA
    J Clin Psychiatry 67:87-94. 2006
    ..The authors describe and quantify the neuropsychiatric symptoms present in a cohort of males with the fragile X mental retardation 1 (FMR1) premutation allele who have developed fragile X-associated tremor/ataxia syndrome (FXTAS)...
  17. ncbi Lessons from fragile X regarding neurobiology, autism, and neurodegeneration
    Randi J Hagerman
    Department of Pediatrics, M I N D Institute, University of California Davis Health System, Sacramento, California 95817, USA
    J Dev Behav Pediatr 27:63-74. 2006
    ..The neurobiology and pathophysiology of FXS and FXTAS are described in detail...
  18. ncbi Symptomatic treatment in the fragile X-associated tremor/ataxia syndrome
    Deborah A Hall
    Department of Neurology, University of Colorado Health Sciences Center at Denver, Denver, Colorado 80262, USA
    Mov Disord 21:1741-4. 2006
    ..This study suggests that patients with FXTAS can derive improvement from medication treatment for some of their symptoms...
  19. ncbi Impairment in the cognitive functioning of men with fragile X-associated tremor/ataxia syndrome (FXTAS)
    Jim Grigsby
    Department of Medicine, University of Colorado Health Sciences Center, Aurora, CO 80045, USA
    J Neurol Sci 248:227-33. 2006
    ..The results provide evidence that FXTAS involves marked impairment of executive cognitive abilities...
  20. ncbi Cognitive impairment in a 65-year-old male with the fragile X-associated tremor-ataxia syndrome (FXTAS)
    Jim Grigsby
    Department of Medicine, University of Colorado Health Sciences Center, Aurora, CO 80045 5701, USA
    Cogn Behav Neurol 19:165-71. 2006
    ..This is the first case report of a comprehensive neuropsychologic examination of an older man with the fragile X-associated tremor-ataxia syndrome (FXTAS)...
  21. ncbi Molecular and imaging correlates of the fragile X-associated tremor/ataxia syndrome
    S Cohen
    Department of Human Development, University of California Davis Medical Center, 2825 50 St, Sacramento, CA 95817, USA
    Neurology 67:1426-31. 2006
    ..To assess changes in regional brain volumes associated with the fragile X-associated tremor/ataxia syndrome (FXTAS) and the molecular correlates of these changes...
  22. ncbi Progression of tremor and ataxia in male carriers of the FMR1 premutation
    Maureen A Leehey
    Department of Neurology, University of Colorado at Denver and Health Sciences Center, Denver, Colorado 80262, USA
    Mov Disord 22:203-6. 2007
    ..Preliminary data on life expectancy are variable, with a range from 5 to 25 years...
  23. ncbi Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1
    Sebastien Jacquemont
    Service de Genetique, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
    Lancet Neurol 6:45-55. 2007
    ..A similar mechanism is probably involved in premature ovarian failure, which affects up to 20% of female carriers of an altered FMR1 gene...
  24. ncbi Impairment of executive cognitive functioning in males with fragile X-associated tremor/ataxia syndrome
    Jim Grigsby
    Department of Medicine, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045 5701, USA
    Mov Disord 22:645-50. 2007
    ....
  25. ncbi Testicular and pituitary inclusion formation in fragile X associated tremor/ataxia syndrome
    Claudia M Greco
    Department of Pathology, University of California Davis School of Medicine, Sacramento, California 95817, USA
    J Urol 177:1434-7. 2007
    ..Clinical manifestations of premutation status are distinct from those of the full mutation, which is the cause of the fragile X syndrome...
  26. ncbi CGG repeat length correlates with age of onset of motor signs of the fragile X-associated tremor/ataxia syndrome (FXTAS)
    Flora Tassone
    Department of Biochemistry and Molecular Medicine, University of California, School of Medicine, Davis, California 95616, USA
    Am J Med Genet B Neuropsychiatr Genet 144:566-9. 2007
    ..001) and ataxia (P = 0.002), as well as overall onset (P < 0.0001). Our findings indicate that the CGG repeat number is a potential predictor of the age of onset of core motor features of FXTAS...
  27. ncbi Cognitive, anxiety and mood disorders in the fragile X-associated tremor/ataxia syndrome
    James A Bourgeois
    Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California Davis, Sacramento, CA 95817, USA
    Gen Hosp Psychiatry 29:349-56. 2007
    ..We evaluated patients with fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder associated with a CGG repeat expansion in the premutation range in the fragile X mental retardation 1 (FMR1) gene...
  28. ncbi Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS)
    J S Adams
    M I N D Institute, University of California, Davis, CA, USA
    Neurology 69:851-9. 2007
    ..Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder occurring in male and rare female carriers of a premutation expansion (55 to 200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene...
  29. pmc Fibroblast phenotype in male carriers of FMR1 premutation alleles
    Dolores Garcia-Arocena
    Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA 95616, USA
    Hum Mol Genet 19:299-312. 2010
    ..Fibroblast studies may also prove useful in screening and testing the efficacy of therapeutic interventions...