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The Cerebellum

, Volume 15, Issue 5, pp 546–551 | Cite as

A Majority of FXTAS Cases Present with Intranuclear Inclusions Within Purkinje Cells

  • Jeanelle Ariza
  • Hailee Rogers
  • Angela Monterrubio
  • Adriana Reyes-Miranda
  • Paul J. Hagerman
  • Verónica Martínez-CerdeñoEmail author
Original Paper

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder that affects carriers of a FMR1 premutation. Symptoms include cerebellar ataxia, tremor, and cognitive deficits. The most characteristic pathology of FXTAS is the presence of eosinophilic ubiquitin-positive intranuclear inclusions in neurons and astrocytes throughout the nervous system and non-nervous tissues. Inclusions are present in neurons throughout the brain but are widely believed not to be present in the Purkinje cells (PCs) of the cerebellum. However, we analyzed 26 postmortem cases of FXTAS and demonstrated that 65 % of cases presented with inclusions within PCs of the cerebellum. We determined that the presence or absence of inclusions in PCs is correlated with age and that those cases with PC inclusions were overall 11 years older than those with no PC inclusions. Half of the cases with PCs with inclusions presented with twin nuclear inclusions. This novel finding demonstrating the presence of inclusions within PCs provides an insight into the understanding of the FXTAS motor symptoms and provides a novel target for the development of therapeutic strategies.

Keywords

FXTAS FRMP Ubiquitin Purkinje cells Cerebellum 

Notes

Acknowledgments

This work was supported by the National Institute of Health grants MH094681 (Dr. Martínez-Cerdeño), HD040661 (Dr. P Hagerman), HD036071 (covered brain collection), and by the Department of Pathology and Laboratory Medicine at UC Davis and the Shriners Hospitals.

Compliance with Ethical Standards

All tissue samples were obtained through consented autopsies with institutional review board approval.

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Hagerman PJ, Hagerman RJ. Fragile X-associated tremor/ataxia syndrome. Ann N Y Acad Sci. 2015;1338:58–70.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Iwahashi CK, Yasui DH, An HJ, Greco CM, Tassone F, Nannen K, et al. Protein composition of the intranuclear inclusions of FXTAS. Brain J Neurol. 2006;129(Pt 1):256–71.Google Scholar
  3. 3.
    Gokden M, Al-Hinti JT, Harik SI. Peripheral nervous system pathology in fragile X tremor/ataxia syndrome (FXTAS). Neuropathol Off J Jpn Soc Neuropathol. 2009;29(3):280–4.CrossRefGoogle Scholar
  4. 4.
    Greco CM, Berman RF, Martin RM, Tassone F, Schwartz PH, Chang A, et al. Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain J Neurol. 2006;129(Pt 1):243–55.Google Scholar
  5. 5.
    Greco CM, Hagerman RJ, Tassone F, Chudley AE, Del Bigio MR, Jacquemont S, et al. Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain J Neurol. 2002;125(Pt 8):1760–71.CrossRefGoogle Scholar
  6. 6.
    Louis ED, Vonsattel JP, Honig LS, Lawton A, Moskowitz C, Ford B, et al. Essential tremor associated with pathologic changes in the cerebellum. Arch Neurol. 2006;63(8):1189–93.CrossRefPubMedGoogle Scholar
  7. 7.
    Hagerman PJ, Hagerman RJ. The fragile-X premutation: a maturing perspective. Am J Hum Genet. 2004;74(5):805–16.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Jacquemont S, Hagerman RJ, Leehey MA, Hall DA, Levine RA, Brunberg JA, et al. Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA. 2004;291(4):460–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Willemsen R, Hoogeveen-Westerveld M, Reis S, Holstege J, Severijnen LA, Nieuwenhuizen IM, et al. The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndrome. Hum Mol Genet. 2003;12(9):949–59.CrossRefPubMedGoogle Scholar
  10. 10.
    Louis ED. Essential tremor. Lancet Neurol. 2005;4(2):100–10.CrossRefPubMedGoogle Scholar
  11. 11.
    Martinez-Cerdeno V, Lechpammer M, Lott A, Schneider A, Hagerman R. Fragile X-associated tremor/ataxia syndrome in a man in his 30s. JAMA Neurol. 2015;72(9):1070–3.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Louis ED, Faust PL. Purkinje cell loss in essential tremor. Mov Dis Off J Mov Dis Soc. 2014;29(10):1329–30.CrossRefGoogle Scholar
  13. 13.
    Babij R, Lee M, Cortes E, Vonsattel JP, Faust PL, Louis ED. Purkinje cell axonal anatomy: quantifying morphometric changes in essential tremor versus control brains. Brain J Neurol. 2013;136(Pt 10):3051–61.CrossRefGoogle Scholar
  14. 14.
    Muzar Z, Lozano R, Schneider A, Adams PE, Faradz SM, Tassone F, et al. Methadone use in a male with the FMRI premutation and FXTAS. Am J Med Genet A. 2015;167(6):1354–9.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Hunsaker MR, Wenzel HJ, Willemsen R, Berman RF. Progressive spatial processing deficits in a mouse model of the fragile X premutation. Behav Neurosci. 2009;123(6):1315–24.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Hashem V, Galloway JN, Mori M, Willemsen R, Oostra BA, Paylor R, et al. Ectopic expression of CGG containing mRNA is neurotoxic in mammals. Hum Mol Genet. 2009;18(13):2443–51.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hukema RK, Buijsen RA, Schonewille M, Raske C, Severijnen LA, Nieuwenhuizen-Bakker I, et al. Reversibility of neuropathology and motor deficits in an inducible mouse model for FXTAS. Hum Mol Genet. 2015;24(17):4948–57.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Jeanelle Ariza
    • 1
  • Hailee Rogers
    • 1
  • Angela Monterrubio
    • 1
  • Adriana Reyes-Miranda
    • 1
  • Paul J. Hagerman
    • 2
    • 3
  • Verónica Martínez-Cerdeño
    • 1
    • 2
    Email author
  1. 1.Department of Pathology and Laboratory Medicine, Institute for Pediatric Regenerative Medicine and Shriners Hospitals for Children of Northern CaliforniaUC Davis School of MedicineSacramentoUSA
  2. 2.MIND InstituteUC Davis Medical CenterSacramentoUSA
  3. 3.Department of Biochemistry and Molecular MedicineUC Davis School of MedicineSacramentoUSA

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