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GENATLAS PHENOTYPE
last update : 19-08-2010
Symbol FXTAS
Location Xq27.3
Name fragile-X tremor ataxia syndrome
Corresponding gene FMR1
Main clinical features
  • late-onset neurodegenerative disorder
  • progressive intention tremor, cerebellar ataxia and cognitive decline
  • at IRM, increased T2 signal intensity in the middle cerebellar peduncles and adjacent cerebellar white matter, intranuclear inclusions (neuronal and astrocytic)
  • neuropathological hallmark is an intranuclear inclusion, present in both neurons and astrocytes throughout the CNS
  • diminished brain activation in the amygdala and several brain areas that mediate social cognition while viewing fearful faces; reduced amygdala activation in the premutation group was significantly associated with self-report of psychological symptoms
  • neuropathological characteristics are significant cerebral and cerebellar white matter disease, associated astrocytic pathology with dramatically enlarged inclusion-bearing astrocytes prominent in cerebral white matter and the presence of intranuclear inclusions in both brain and spinal cord
    • Genetic determination other
    Function/system disorder neurology
    psychiatric disorder
    Type disease
    Mechanism(s)
    Gene mutationChromosome rearrangementEffectComments
    repeat expansion   abnormal RNA repeat expansion 55-200 (premutation), toxic 'gain-of-function' of the expanded CGG-repeat, found in the neuronal and astrocytic intranuclear inclusions associated with lamin A/C dysregulation
    Remark(s)
  • the elevated number of FMR1 transcripts present in premutation carriers suggest an RNA toxic gain-of-function mechanism
  • KHDRBS1-responsive splicing is altered in FXTAS patients,(through an RNA gain-of-function mechanism in which KHDRBS is partially sequestered within CGG aggregates and consequently loses its regulatory function in neurons from FXTAS patients) (Sellier 2010)
  • a possible late outcome of an RNA-associated pathogenic process that actually begins very early in life, and which dictates not only the later degeneration of neural cells, but also their formation, development and long-term function (Garcia-Arocena 2010)
  • decreased NAD- and FAD-linked oxygen uptake rates and uncoupling between electron transport and synthesis of ATP were observed in fibroblasts from premutation carriers, but also mitochondrial dysregulation (e.g. decreased Complex I function)
    • in carriers of small CGG-repeat expansions may predispose such individuals to other disorders (Parkinson's disease/parkinsonism) (PMID: 2051323 )
    Genotype/Phenotype correlations observed mostly in male carriers of the fragile X premutation, described less frequently and with a less severe phenotype in premutation female carriers; signs of FXTAS are detected in 16.5% of female premutation carriers and in 45.5% of premutated males older than 50 years (Rodriguez-Revenga,2009)