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Fragile X Associated Tremor and Ataxia Syndrome (FXTAS)

Fragile X Associated Tremor and Ataxia Syndrome (FXTAS). Lisa Avery Sarah Carr Aarti Patel Shveta Sharma . PHM142 Fall 2012 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson. What we ’ re going to talk about … . Fragile X Syndrome (FXS)

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Fragile X Associated Tremor and Ataxia Syndrome (FXTAS)

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  1. Fragile X Associated Tremor and Ataxia Syndrome (FXTAS) Lisa Avery Sarah Carr Aarti Patel Shveta Sharma PHM142 Fall 2012 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

  2. What we’re going to talk about … • Fragile X Syndrome (FXS) • Fragile X Associated Tremor and Ataxia Syndrome (FXTAS) • Genetics • Pathology • Biochemistry and Mechanism • Symptoms and Treatment

  3. Fragile X Syndrome (FXS) • Most common type of inherited mental retardation • X-chromosome linked recessive disorder • Males: 1:2500-4000 • Females: 1:7000-8000 • FMR1 site • Mutation vs. Premutation

  4. The X Chromosome • Fragile X Mutation: • Over 200 repeats of the CGG sequence on the fragile mental retardation 1 (FMR1) site • Partial or complete silencing of the associated protein • Premutation: • 55-200 repeats of the CGG sequence • Prone to expansion in transmission • Normal: • 5-55 repeats of the CGG sequence

  5. Fragile X associated Tremor andAtaxia Syndrome (FXTAS) • Adult onset • Premutation: common is general population • Males: 1:813 • Females: 1:259 • 1/3 of male premutation population develop FXTAS • Accompanied by Parkinson's disease, autonomic dysfunction, and cognitive decline

  6. Fragile X Syndrome (FXS) • expansion of CGG which affects the FMR1 (fragile X mental retardation 1 gene) • 200 or more CGG repeats • this leads to a failure to express FMRP (fragile X mental retardation protein) • FMRP is needed for normal neural development • absence of FMRP leads to abnormalities in brain development and function http://cibar.stanford.edu/fragx/

  7. GABAergic System and Fragile X Syndrome • GABAergic protein expression in FMR1 knockout mice forebrain vs. wild-type mice forebrain • Lowered levels of: • GABAA receptor α1, β2, and δ subunits • GABA transaminase • Succinic semialdehyde dehydrogenase • GABA = gamma- aminobutyric acid • Main inhibitory CNS neurotransmitter involved in neuronal excitability and modulation of learning, cognition, and memory Adusei, D. C., Pacey, L. K., Chen, D., & Hampson, D. R. (2010). Early developmental alterations in GABAergic protein expression in fragile X knockout mice. Neuropharmacology, 59(3), 167-171.

  8. Symptoms of FXTAS • Typically late-onset neurological symptoms in male carriers of premutation FMR1 alleles • Clinical presentation is heterogeneous • Gait ataxia • Lack of coordination in walking movements • Indicates neurological dysfunction • Progressive intention tremor

  9. Symptoms • Typically have normal intelligence compared to patients with Fragile-X Syndrome (most common cause of mental retardation) • Parkinsonism • Cognitive decline • Emotional difficulties • Disinhibition and apathy • Subtle facial abnormalities

  10. Neurological Symptoms • Cerebral and cerebellar white matter disease • Intranuclear inclusions on brain and spinal cord Major diagnostic feature MRI: atrophy and white matter lesions in cerebral hemispheres and middle cerebellar peduncles Greco et al.

  11. Mechanism of FXTAS • Currently: • Pathogenic mechanism is not known • Individuals with the premutation normally have atrophy of certain areas of the brain. • The most consistent finding in FMR1 premutation carriers is the presence of intranuclear brain inclusions

  12. Brain Inclusions • Defined as a non-living mass • Found primarily in the cerebrum and brainstem • Inclusions are not found in people with Fragile X syndrome but in individuals with the Fragile X premutation. • Over 20 proteins have been identified in the involvement of inclusion formation • FMR1 mRNA has been identified as a component of the inclusions

  13. Proposed Mechanism of FXTAS • Toxic RNA gain-of-function • Because tremor and ataxia are not associated with Fragile X syndrome, it is believed that the functional FMR1 protein and mRNA must be present for these symptoms to exist. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2787679/

  14. http://wizard1.ucdavis.edu

  15. Treatment • No established treatment for neurological features of the disease • A variety of drugs have been prescribed depending on symptoms • Usually medications associated with Parkinsons and tremors are prescribed • Most patients benefit from medications • Physical therapy http://www.osteoarthritisblog.com/category/osteo-arthritis-treatment-option/physical-therapy-2/ http://maennergesundheit.blogspot.ca/2011/02/wenn-der-harndrang-nervt-mit-botox.html

  16. Summary • FXS: Fragile X Syndrome • Associated with 200+ repetitions of CGG on the FMR1 gene • FXTAS: Fragile X associated Tremor and Ataxia Syndrome • Neurodegenerative disease associated with 55-200 repetitions of CGG on the FMR1 gene (premutation) • Major symptoms include gait ataxia and progressive intention tremor • Pathogenic affect thought to be caused by intranuclear inclusions (protein aggregations) in the brain. • It is believed that the repetitions of CGG causes over expression of FMR1 mRNA which has a negative affect on the cell. http://wizard1.ucdavis.edu

  17. References Adusei, D. C., Pacey, L. K., Chen, D., & Hampson, D. R. (2010). Early developmental alterations in GABAergic protein expression in fragile X knockout mice. Neuropharmacology, 59(3), 167-171. Iwahashi, C. K., Yasui, D. H., An, H. J., Greco, C. M., Tassone, F., Nannen, K., ... & Hagerman, P. J. (2006). Protein composition of the intranuclear inclusions of FXTAS. Brain, 129(1), 256-271. Tassone, F., Iwahashi, C., & Hagerman, P. J. (2004). FMR1 RNA within the intranuclear inclusions of fragile X-associated tremor/ataxia syndrome (FXTAS). RNA biology, 1(2), 103-105. Hagerman, P. J., & Hagerman, R. J. (2004). Fragile X‐associated Tremor/Ataxia Syndrome (FXTAS). Mental retardation and developmental disabilities research reviews, 10(1), 25-30. http://www.fragilex.org http://wizard1.ucdavis.edu Raske, C., & Hagerman, P. J. (2009). Molecular Pathogenesis of FXTAS. Journal of investigative medicine: the official publication of the American Federation for Clinical Research, 57(8), 825. Greco, C. M., Berman, R. F., Martin, R. M., Tassone, F., Schwartz, P. H., Chang, A., ... & Hagerman, P. J. (2006). Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain, 129(1), 243-255.  Hagerman, P. J., & Hagerman, R. J. (2004). Fragile X‐associated Tremor/Ataxia Syndrome (FXTAS). Mental retardation and developmental disabilities research reviews, 10(1), 25-30.  Hall, D. A., Berry‐Kravis, E., Hagerman, R. J., Hagerman, P. J., Rice, C. D., & Leehey, M. A. (2006). Symptomatic treatment in the fragile X–associated tremor/ataxia syndrome. Movement disorders, 21(10), 1741-1744. Jacquemont, S., Hagerman, R. J., Leehey, M., Grigsby, J., Zhang, L., Brunberg, J. A., ... & Hagerman, P. J. (2003). Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. The American Journal of Human Genetics, 72(4), 869-878.  Leehey, M. A. (2009). Fragile X-associated Tremor/Ataxia Syndrome (FXTAS): Clinical Phenotype, Diagnosis and Treatment. Journal of investigative medicine: the official publication of the American Federation for Clinical Research, 57(8), 830.

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