title: Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines.
abstract: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder with core features of action tremor and cerebellar gait ataxia. Frequent associated findings include parkinsonism, executive function deficits and dementia, neuropathy, and dysautonomia. Magnetic Resonance Imaging studies in FXTAS demonstrate increased T2 signal intensity in the middle cerebellar peduncles (MCP sign) in the majority of patients. Similar signal alterations are seen in deep and subependymal cerebral white matter, as is general cortical and subcortical atrophy. The major neuropathological feature of FXTAS is the presence of intranuclear, neuronal, and astrocytic, inclusions in broad distribution throughout the brain and brainstem. FXTAS is caused by moderate expansions (55-200 repeats; premutation range) of a CGG trinucleotide in the fragile X mental retardation 1 (FMR1) gene, the same gene which causes fragile X syndrome when in the full mutation range (200 or greater CGG repeats). The pathogenic mechanism is related to overexpression and toxicity of the FMR1 mRNA per se. Although only recently discovered, and hence currently under-diagnosed, FXTAS is likely to be one of the most common single-gene disorders leading to neurodegeneration in males. In this report, we review information available on the clinical, radiological, and pathological features, and prevalence and management of FXTAS. We also provide guidelines for the practitioner to assist with identifying appropriate patients for DNA testing for FXTAS, as well as recommendations for genetic counseling once a diagnosis of FXTAS is made.
authors.affiliation: Department of Pediatrics, Rush University Medical Center, Chicago, Illinois 60612, USA. Elizabeth_m_berry-kravis@rush.edu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Berry-Kravis
authors.forename: Liane
authors.initials: L
authors.lastname: Abrams
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Coffey
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Hall
authors.forename: Claudia
authors.initials: C
authors.lastname: Greco
authors.forename: Louise W
authors.initials: LW
authors.lastname: Gane
authors.forename: Jim
authors.initials: J
authors.lastname: Grigsby
authors.forename: James A
authors.initials: JA
authors.lastname: Bourgeois
authors.forename: Brenda
authors.initials: B
authors.lastname: Finucane
authors.forename: Sebastien
authors.initials: S
authors.lastname: Jacquemont
authors.forename: James A
authors.initials: JA
authors.lastname: Brunberg
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Janet
authors.initials: J
authors.lastname: Lin
authors.forename: Flora
authors.initials: F
authors.lastname: Tassone
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hagerman
authors.forename: Randi J
authors.initials: RJ
authors.lastname: Hagerman
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Leehey
mesh_terms: D001259:Ataxia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005192:Family Health; D005260:Female; D005600:Fragile X Syndrome / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005820:Genetic Testing; D017408:Guidelines as Topic / Q000592:standards*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D012737:Sex Factors; D014202:Tremor / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology