Fragile X-Associated Tremor / Ataxia Syndrome (FXTAS), is a progressive
neurodegenerative disease, with motor disorders, cognitive deficits and
dementia, neuropathy, and dysautonomia.
In this article, there is an overview of the main clinical features and
radiological findings, as well as a short reference on the molecular
mechanisms responsible for the disease, in order to facilitate
non-specialist doctors or nurses to early recognize FXTAS.
This is the most common form of inherited mental retardation recognized in
the late 1990s. It is caused by a permutation in the FMR1 gene on
the X chromosome.
The FMR1 gene contains a 5΄ untranslated CGG repeats region ,
from 6 to 55 triplets in length. In gene permutation, there is an expansion
of the CGG repeats between 55 to 200 triplets. With a length of more than
200 triplets (full mutation), the gene becomes non-functional . In
individuals with a full mutation of the FMR1 gene, FXTAS has never
The syndrome is characterized by tremor, ataxia, parkinsonism, cognitive
decline, dementia and neuropathy. It occurs at ages greater than 50 years
and it is estimated that one of the 259 females  and one of the 813 men
, are carriers of an FMR1 premutation. This may suggest that the
syndrome is probably one of the most common late-onset neurodegenerative
2. Molecular basis of FXTAS.
The FMR1 gene produces mRNA FMR1 which is transcribed into FMRP
protein. This protein is an RNA-binding protein which regulates translation
at the dendrites, and modulates synaptic plasticity and dendritic morphology
. In gene premutation, the reduced FMRP production causes a 2 to 10 fold
increase in the mRNA FMR1levels. This imbalance which presumably compensates
a transcriptional deficit of FMRP , is believed to cause neurotoxic
effects due to the excessive interaction of the trinucleotides’ binding
proteins and the transcription factors with the excess of mRNA FMR1 and / or
its extended CGGn contained in its molecule. This disorder could be
addressed through the ubiquitin /proteasome pathway. In case of this pathway
failure, inclusions are generated, which may be function protectively, but
may also trigger the apoptosis pathway and the neuronal death [7,8]. The
presence of intranuclear inclusions in both neurons and astrocytes but not
in oligodendrocytes throughout the brain consist the pathological hallmark
of FXTAS. The inclusions are ubiquitin-positive but negative in both TAU
protein and synuclein. In this sense, it seems that FXTAS does not belong to
any known group of neurodegenerative diseases which is characterized by the
presence of intracellular inclusions (Pick, Parkinson, MSA disease) 
Micrograph of cortical neuronal and astroglial cells bearing
intranuclear inclusions (brown, ubiquitin immunostaining). A
nucleolus (blue) in the neuronal nucleus is shown (magnification
The nuclear inclusions, which are numerous in the hippocampus, was found to
contain mRNA FMR1 and many proteins associated with numerous neuronal
functions. This means that a reduction of these factors from the cell pool,
will significantly burden the cellular processes .
3. Clinical features.
Tremor and ataxia are the first movement disorders, and the patients often
report incidents of falls. The tremor initially occurs during intentional
movements in performing daily tasks and in the course of the disease,
postural tremor may also occur. It usually affects the upper limbs, starting
with the dominant hand and then extended to the other .
Ataxia is consistent with a cerebellar subtype, having difficulty with
tandem gait and stance, whereas parkinsonian type rigidity is less obvious
Peripheral neuropathy occurs in the lower extremities, with reduced deep
tendon reflexes, reduction of touch, pain, muscular weakness and
abnormalities in the proprioceptive response .
The cognitive deficits are initially subtle. They are related to a reduction
of the executive cognitive functions and working memory, and they are not
usually assessed [15.16]. A little impairment of the primary declarative
memory and episodic recall seem to coexist. Characteristic executive
cognitive deficits are the impairment in the initiation of purposeful, and
the goal-directed activity.
The psychiatric features of FXTAS appear as anxiety, depression,
irritability, disinhibition or inappropriate behavior . Psychiatric
disorders such as cognitive deficits often appear early, before motor
deficits . Dementia in some cases occurs simultaneously with anxiety or
mood disorders , with characteristics of frontal subcortical-type
dementia and leads to a complete loss of the patient’s autonomy .
4. Radiological features.
In brain MRI, a generalized atrophy, a decrease in brain volume (mainly
parietally and frontally), pons and cerebellum is observed [20, 21]. There
are confluent areas of increased signal intensity on T2 weighted or FLAIR
acquisitions, periventricular and in the deep white matter of the cerebral
hemispheres . Spongiform intercellular edema in the middle cerebellar
peduncle (MCP), is illustrated as an increased T2 signal intensity of the
MCP, but it is found in only 60% of the patients .
The radiological findings have been confirmed by neuropathological analyses
in post- mortem brains of patients and they fully justify the clinical
features of the syndrome.
The FXTAS appears to be a common progressive neurodegenerative disorder of
late age, with early symptoms which are not usually recognized but are
attributed to aging or other neurologic diseases. Since there is no
effective treatment, it is important to identify the syndrome early with a
DNA research of the Fragile X (FMR1), in order to genetically determine the
premutated carriers of the gene, to provide them with genetic counseling
1. Verkerk AJ, Pieretti M, Sutcliffe JS, et al.
Identification of a gene (FMR-1) containing a CGG repeat coincident with a
breakpoint cluster region exhibiting length variation in fragile X syndrome.
2. Pieretti M, Zhang FP, Fu YH, et al. Absence of
expression of the FMR-1 gene in fragile X syndrome. Cell 1991;66:817-822.
3. Rousseau F, Rouillard P, Morel ML, Khandjian EW, Morgan K. Prevalence of
carriers of premutation-size alleles of the FMRI gene—and implications for
the population genetics of the fragile X syndrome. Am J Hum Genet
4. Dombrowski C, Levesque ML, Morel ML, Rouillard P,
Morgan K, Rousseau F. Premutation and intermediate-size FMR1 alleles in 10
572 males from the general population: loss of an AGG interruption is a late
event in the generation of fragile X syndrome alleles. Hum Mol Genet
5. Bear MF, Huber KM, Warren ST. The mGluR theory of
fragile X mental retardation. Trends Neurosci 2004;27:370-377.
Hagerman PJ, Hagerman RJ. The fragile-X premutation: a maturing perspective.
Am J Hum Genet 2004;74:805-816.
7. Garcia-Arocena D, Iwahashi CK, Won N,
et al. Induction of inclusion formation and disruption of lamin A/C
structure by premutation CGG-repeat RNA in human cultured neural cells. Hum
Mol Genet 2005;14:3661-3671.
8. Oostra BA, Willemsen R. A fragile
balance: FMR1 expression levels. Hum Mol Genet 2003;12:249-257.
CM, Hagerman RJ, Tassone F, et al. Neuronal intranuclear inclusions in a new
cerebellar tremor/ataxia syndrome among fragile X carriers. Brain
10. Iwahashi CK, Yasui DH, An H-J, et al. Protein
composition of the intranuclear inclusions of FXTAS. Brain 2006;129:256-271.
11. Jacquemont S, Hagerman RJ, Leehey M, et al. Fragile X premutation
tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am
J Hum Genet 2003;72:869-878.
12. Rogers C, Partington MW, Turner GM.
Tremor, ataxia and dementia in older men may indicate a carrier of the
fragile X syndrome. Clin Genet 2003; 64:54-56.
13. Berry-Kravis E, Lewin
F, Wuu J, et al. Tremor and ataxia in fragile X premutation carriers:
blinded videotape study. Ann Neurol 2003; 53:616-623.
14. Hagerman RJ,
Coffey SM, Maselli R, et al. Neuropathy as a presenting feature in fragile
X-associated tremor/ataxia syndrome. Am J Med Genet A 2007;143:2256-2260.
15. Grigsby J, Brega AG, Leehey MA, et al. Impairment of executive cognitive
functioning in males with fragile X-associated tremor/ataxia syndrome. Mov
16. Grigsby J, Leehey MA, Jacquemont S, et al.
Cognitive impairment in a 65-year-old male with the fragile X-associated
tremor-ataxia syndrome (FXTAS). Cogn Behav Neurol 2006;19:165-171.
Bourgeois JA, Farzin F, Brunberg JA, et al. Dementia with mood symptoms in a
fragile X premutation carrier with the fragile X-associated tremor/ataxia
syndrome: clinical intervention with donepezil and venlafaxine. J
Neuropsychiatry Clin Neurosci 2006; 18:171-177.
18. Moore CJ, Daly EM,
Schmitz N, et al. A neuropsychological investigation of male premutation
carriers of fragile X syndrome. Neuropsychologia 2004;42:1934-1947.
Seritan AL, Nguyen DV, Farias ST, et al. Dementia in fragile X-associated
tremor/ataxia syndrome (FXTAS): comparison with Alzheimer’s disease. Am J
Med Genet B 2008;147:1138-1144.
20. Brunberg JA, Jacquemont S, Hagerman
RJ, et al. Fragile X premutation carriers: characteristic MR imaging
findings of adult male patients with progressive cerebellar and cognitive
dysfunction. Am J Neuroradiol 2002; 23:1757-1766.
21. Loesch DZ, Litewka
L, Brotchie P, Huggins RM, Tassone F, Cook M. Magnetic resonance imaging
study in older fragile X premutation male carriers. Ann Neurol
22. Storey E, Billimoria P. Increased T2 signal in the
middle cerebellar peduncles on MRI is not specific for fragile X premutation
syndrome. J Clin Neurosci 2005;12:42-43.
23. Okamoto K, Tokiguchi S,
Furusawa T, et al. MR features of diseases involving bilateral middle
cerebellar peduncles. AJNR Am J Neuroradiol 2003;24:1946-1954.