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Fragile X-associated tremor/ataxia syndrome

Orpha number ORPHA93256
Synonym(s) FXTAS syndrome
Prevalence 1-9 / 100 000
Inheritance
  • X-linked dominant
Age of onset Adulthood
ICD-10
  • G11.2
OMIM
UMLS -
MeSH -
MedDRA -
SNOMED CT
  • 448045004

Summary

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a rare neurodegenerative disorder characterized by adult-onset progressive intention tremor and gait ataxia.

Prevalence and incidence are unknown. The disease primarily affects males and there is a lifetime cumulated risk for men in the general population of about 1/8,000.

The age of onset of tremor and/or ataxia in males is about 60 years. The clinical presentation is heterogeneous with variable dominant manifestations including: intention tremor, progressive cerebellar gait ataxia, frontal executive dysfunction, cognitive decline, peripheral neuropathy, and dysautonomia. Other signs include mild parkinsonism and psychiatric manifestations (depression, anxiety, agitation) with possible progression to dementia. Carrier females generally have less severe manifestations than males but also have an increased risk of primary ovarian insufficiency, chronic muscle pain, and hypothyroidism.

FXTAS is caused by a CGG trinucleotide repeat expansion (55-200 repeats) in the permutation range of the FMR1 gene (Xq27.3). Approximately 1/260 females and 1/800 males in the general population are permutation carriers and penetrance is age dependent. The disease affects more than 33% of male and 10% of female carriers of the expansion. The severity of the clinical and neuropathological manifestations is correlated with the extent of the CGG expansion

Diagnosis may be difficult because of the combination of signs that are common in elderly patients. Magnetic resonance imaging (MRI) shows global loss of brain volume, in particular cerebellar and cortical atrophy and hyperintensity white matter lesions around the periventricular area and in the middle cerebellar peduncles. Molecular genetic testing is needed to confirm diagnosis.

Differential diagnoses include dementia, rare parkinsonian disorders and spinocerebellar ataxias (see these terms).

As this is an adult-onset disorder, no antenatal diagnosis is possible.

Transmission follows an X-linked dominant pattern with variable penetrance. Genetic counseling should be provided to patients and their families.

There is no specific treatment for FXTAS that targets the underlying pathological mechanism. Symptomatic treatment for the psychiatric and neurological manifestations should therefore be provided, along with specific monitoring for progression and degeneration.

The prognosis depends on the speed of progression of the disease, which is highly variable.

Expert reviewer(s)

  • Dr Ginevra ZANNI

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Detailed information

Review article
  • EN (2013)Patient Inform
Clinical practice guidelines
  • DE (2009)
Guidance for genetic testing
  • EN (2011,pdf)
Clinical genetics review
  • EN (2012)
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