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Online mutation report
Spastic paraparesis, cerebellar ataxia, and intention tremor: a severe variant of FXTAS?
  1. S Jacquemont1,
  2. A Orrico2,
  3. L Galli2,
  4. P K Sahota3,
  5. J A Brunberg4,
  6. C Anichini5,
  7. M Leehey6,
  8. S Schaeffer7,
  9. R J Hagerman1,
  10. P J Hagerman3,
  11. F Tassone3
  1. 1MIND Institute, University of California Davis Medical Center, Sacramento, CA, USA
  2. 2Molecular Medicine, Azienda Ospedaliera Universitaria Senese, Siena, Italy
  3. 3Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Davis, CA, USA
  4. 4Department of Radiology, School of Medicine, UC Davis Medical Center, Sacramento, CA, USA
  5. 5Department of Pediatrics, University of Siena, Siena, Italy
  6. 6Department of Neurology, University of Colorado Health Science Center, CO, USA
  7. 7Service de Neurologie, Centre Hospitalier Universitaire de Caen, France
  1. Correspondence to:
 Dr F Tassone
 UC Davis, Medicine, Biochemistry and Molecular Medicine, One Shields Avenue, Davis, CA 95616, USA; ftassoneucdavis.edu

https://doi.org/10.1136/jmg.2004.024190

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    Fragile X associated tremor/ataxia syndrome (FXTAS) is a recently identified neurodegenerative disorder affecting older adult males with pre-mutation alleles of the fragile X mental retardation 1 (FMR1) gene.1–3 These male carriers, in their fifties and older, develop progressive intention tremor, cerebellar ataxia, progressive cognitive difficulties, and variable features including peripheral neuropathy, lower limb proximal muscle weakness, and autonomic dysfunction.

    Radiological signs include global brain atrophy and white matter disease characterised by hyperintensities in the middle cerebellar peduncles (MCP) on T2 sequence with scattered periventricular disease, corresponding to spongiform changes and demyelination on neuropathological studies.2

    Here we report three pre-mutation carriers (two sisters and one sporadic case) presenting with spastic paraparesis, cerebellar ataxia, and intention tremor, and having neuroimaging features suggestive of a severe variant of FXTAS. A random X inactivation pattern was found in the two affected sisters. The third female sibling was unaffected and her inactivation pattern was significantly skewed. This suggests that the X inactivation ratio may be responsible for the incomplete penetrance of the neurological symptoms in this family.

    CASE DESCRIPTIONS

    Case 1 (II-2)

    The first sister developed spasticity and balance difficulty in the third decade of her life. During this time, she underwent neurological evaluation. She was well oriented, with intact speech and cognitive function. Examination of the lower extremity showed paraparesis, mild spasticity, and positive Babinski. The upper extremities showed diminished co-ordination and intention tremor. EEG, ECG fundoscopy, electromyography (EMG), and nerve conduction studies were normal. Cerebrospinal fluid (CSF) was normal, with absence of oligoclonal bands. Muscle biopsy showed a chronic neurogenic process. She had anxiety and mild depression.

    Case 2 (II-3)

    The other sister gradually developed spasticity with dragging of the toes while walking, lower limb weakness, and difficulty with balance. Neurological evaluation at 35 years of age showed normal cognitive functions. Examination of the lower extremities, showed paraparesis, …

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    Footnotes

    • Competing interests: none declared