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Acta Neuropathologica

, Volume 122, Issue 1, pp 99–110 | Cite as

The most common type of FTLD-FUS (aFTLD-U) is associated with a distinct clinical form of frontotemporal dementia but is not related to mutations in the FUS gene

  • Julie S. Snowden
  • Quan Hu
  • Sara Rollinson
  • Nicola Halliwell
  • Andrew Robinson
  • Yvonne S. Davidson
  • Parastoo Momeni
  • Atik Baborie
  • Timothy D. Griffiths
  • Evelyn Jaros
  • Robert H. Perry
  • Anna Richardson
  • Stuart M. Pickering-Brown
  • David Neary
  • David M. A. MannEmail author
Original Paper

Abstract

Frontotemporal lobar degeneration (FTLD) is clinically, pathologically and genetically heterogeneous. Recent descriptions of a pathological sub-type that is ubiquitin positive, TDP-43 negative and immunostains positive for the Fused in Sarcoma protein (FUS) raises the question whether it is associated with a distinct clinical phenotype identifiable on clinical grounds, and whether mutations in the Fused in Sarcoma gene (FUS) might also be associated with FTLD. Examination of a pathological series of 118 cases of FTLD from two centres, showing tau-negative, ubiquitin-positive pathology, revealed FUS pathology in five patients, four classified as atypical FTLD with ubiquitin inclusions (aFTLD-U), and one as neuronal intermediate filament inclusion disease (NIFID). The aFTLD-U cases had youthful onset (22–46 years), an absence of strong family history, a behavioural syndrome consistent with frontotemporal dementia (FTD) and severe caudate atrophy. Their cognitive/behavioural profile was distinct, characterised by prominent obsessionality, repetitive behaviours and rituals, social withdrawal and lack of engagement, hyperorality with pica, and marked stimulus-bound behaviour including utilisation behaviour. They conformed to the rare behavioural sub-type of FTD identified previously by us as the “stereotypic” form, and linked to striatal pathology. Cognitive evaluation revealed executive deficits in keeping with subcortical-frontal dysfunction, but no cortical deficits in language, perceptuospatial skills or praxis. The patient with NIFID was older and exhibited aphasia and dyspraxia. No patient had clinical evidence of motor neurone disease during life, or a mutation in the FUS gene. In the complementary clinical study of 312 patients with clinical syndromes of FTLD, genetic analysis revealed a 6 bp deletion in FUS in 3 patients, of questionable significance. One presented a prototypical picture of FTD, another expressive language disorder, and the third semantic dementia. None showed the early onset age or distinctive ‘stereotypic’ picture of patients with aFTLD-U. We conclude that aFTLD-U is associated with a distinct clinical form of frontotemporal dementia, potentially allowing identification of such patients in life with a high degree of precision. Whether mutations in the FUS gene cause some cases of FTLD remains unresolved.

Keywords

Frontotemporal lobar degeneration FUS gene FUS protein Clinical phenotype Histopathology 

Notes

Acknowledgments

We thank all staff at the Neuropathology Department, Newcastle General Hospital, and Histopathology Department, Salford Royal Hospitals NHS Foundation Trust, for technical assistance, particularly Andrew Brown and Janet Thompson at Newcastle for cutting and staining of the sections and Lynne Ramsay for the TDP43 staining. Dr E. Jaros, Andrew Brown and Lynne Ramsay have been supported by the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Hospitals NHS Foundation Trust. Quan Hu is supported through 111 Project funding to Professor Jinzhou Tian from People’s Republic of China. We also acknowledge the support of Alzheimer’s Research Trust and Alzheimer’s Society through their funding of the Manchester Brain Bank under the Brains for Dementia Research (BDR) initiative. D.M.A.M. and S.P.B. also receive funding from MRC and Wellcome Trust which supported this study in part.

Supplementary material

401_2011_816_MOESM1_ESM.doc (142 kb)
Supplementary material 1 (DOC 141 kb).

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Julie S. Snowden
    • 1
    • 2
  • Quan Hu
    • 1
    • 3
  • Sara Rollinson
    • 1
  • Nicola Halliwell
    • 1
  • Andrew Robinson
    • 1
  • Yvonne S. Davidson
    • 1
  • Parastoo Momeni
    • 4
  • Atik Baborie
    • 5
  • Timothy D. Griffiths
    • 6
  • Evelyn Jaros
    • 7
    • 8
  • Robert H. Perry
    • 7
  • Anna Richardson
    • 1
    • 2
  • Stuart M. Pickering-Brown
    • 1
  • David Neary
    • 1
    • 2
  • David M. A. Mann
    • 1
    • 2
    Email author
  1. 1.Mental Health and Neurodegeneration Research Group, Faculty of Human and Medical SciencesUniversity of ManchesterManchesterUK
  2. 2.Mental Health and Neurodegeneration Research Group, Cerebral Function UnitGreater Manchester Neuroscience Centre, Salford Royal Foundation NHS TrustSalfordUK
  3. 3.The Neurology Centre, Dongzhimen HospitalBeijing University of Chinese MedicineBeijingPeople’s Republic of China
  4. 4.Department of Internal MedicineTexas Tech University Health Sciences CenterLubbockUSA
  5. 5.Department of NeuropathologyWalton Centre for Neurology and NeurosurgeryLiverpoolUK
  6. 6.Cognitive Neurology ClinicNewcastle General Hospital, Newcastle UniversityNewcastle upon TyneUK
  7. 7.Neuropathology/Cellular PathologyRoyal Victoria InfirmaryNewcastle upon TyneUK
  8. 8.Institute for Ageing and HealthNewcastle UniversityNewcastle upon TyneUK

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