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Intranuclear inclusions in neural cells with premutation alleles in fragile X associated tremor/ataxia syndrome
  1. F Tassone1,
  2. R J Hagerman2,
  3. D Garcia-Arocena1,
  4. E W Khandjian3,
  5. C M Greco4,
  6. P J Hagerman1
  1. 1Department of Biological Chemistry, School of Medicine, University of California Davis, CA, USA
  2. 2M.I.N.D. Institute and Department of Pediatrics, University of California Davis Medical Center, Sacramento, CA, USA
  3. 3Department of Medical Biology, Laval University, Quebec, Canada
  4. 4Department of Pathology, University of California Davis Medical Center, Sacramento, CA, USA
  1. Correspondence to:
 F Tassone
 Department of Biological Chemistry, UC Davis School of Medicine, One Shields Avenue, Davis, CA 95616, USA; ftassoneucdavis.edu

https://doi.org/10.1136/jmg.2003.012518

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    Fragile X syndrome is generally considered to be a non-progressive neurodevelopmental disorder in which carriers of premutation alleles (~55 to 200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene are largely unaffected. However, we have recently identified a new syndrome among male carriers, characterised by tremor and/or ataxia, cognitive deficits, parkinsonism, and autonomic dysfunction.1,5,6,8,10 Neuroradiological findings include moderate to severe cortical atrophy (cerebral and cerebellar cortical volume loss) and characteristic hyperintensities on T2-weighted MR imaging of the deep cerebellar white matter and middle cerebellar peduncles.2,8 The disorder, termed fragile X associated tremor/ataxia syndrome,8 has been observed thus far almost exclusively in older adult male premutation carriers of more than 50 years of age.

    Eosinophilic intranuclear inclusions are broadly distributed in both neurones and astrocytes throughout the cerebrum and brain stem of all persons with fragile X associated tremor/ataxia syndrome (FXTAS) examined to date (8/8),5,7 with the greatest numbers of neuronal inclusions found in the hippocampus. No inclusions were detected in the Purkinje cells, although axonal degeneration and Purkinje cell loss were prominent findings in the cerebellum.5

    Premutation carriers generally have elevated FMR1 mRNA levels, suggesting that FXTAS could result from a toxic gain of function of the FMR1 mRNA.5,6,8 To determine whether inclusion formation and clinical involvement are associated with allelic mosaicism, we defined the size of the CGG expansion and the relative expression levels of the FMR1 gene in various regions of the brain of a male premutation carrier who died with neurological symptoms consistent with FXTAS, and whose neural cells possessed numerous intranuclear inclusions. Analysis of multiple brain regions was undertaken to demonstrate that premutation alleles were directly associated with inclusion formation, and that full mutation alleles, even if present at …

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