Acta Neuropathologica

, Volume 127, Issue 3, pp 451–458

Early dipeptide repeat pathology in a frontotemporal dementia kindred with C9ORF72 mutation and intellectual disability

  • Malcolm Proudfoot
  • Nick J. Gutowski
  • Dieter Edbauer
  • David A. Hilton
  • Mark Stephens
  • Julia Rankin
  • Ian R. A. Mackenzie
Case Report

DOI: 10.1007/s00401-014-1245-7

Cite this article as:
Proudfoot, M., Gutowski, N.J., Edbauer, D. et al. Acta Neuropathol (2014) 127: 451. doi:10.1007/s00401-014-1245-7

Abstract

Familial cases of frontotemporal dementia (FTD) provide an opportunity to study the pathophysiology of this clinically diverse condition. The C9ORF72 mutation is the most common cause of familial FTD, recent pathological descriptions challenge existing TDP-43 based hypotheses of sporadic FTD pathogenesis. Non-ATG dependent translation of the hexanucleotide expansion into aggregating dipeptide repeat (DPR) proteins may represent a novel pathomechanism. We report detection of the DPR aggregates very early in C9ORF72 FTD development and also describe childhood intellectual disability as a clinical feature preceding dementia. The index case presented with psychiatric symptoms, progressing into typical FTD. Autopsy revealed extensive neuronal DPR aggregates but only minimal TDP-43 pathology. Her intellectually disabled elder son, also carrying the C9ORF72 mutation, died aged 26 years and at autopsy only DPR aggregates without TDP-43 were found. A second son also has intellectual disability, his C9ORF72 status is unknown, but chromosomal microarray revealed no other cause of disability. These cases both extend the existing phenotype of C9ORF72 mutation and highlight the potential significance of DPR translation early in disease development.

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Malcolm Proudfoot
    • 1
  • Nick J. Gutowski
    • 1
    • 2
  • Dieter Edbauer
    • 3
    • 4
    • 5
  • David A. Hilton
    • 6
  • Mark Stephens
    • 7
  • Julia Rankin
    • 8
  • Ian R. A. Mackenzie
    • 9
  1. 1.Department of NeurologyRoyal Devon and Exeter NHS Foundation TrustExeterUK
  2. 2.University of Exeter Medical SchoolExeterUK
  3. 3.German Center for Neurodegenerative Diseases (DZNE)MunichGermany
  4. 4.Adolf Butenandt Institute, BiochemistryLudwig-Maximilians UniversityMunichGermany
  5. 5.Munich Cluster of Systems Neurology (SyNergy)MunichGermany
  6. 6.Department of Cellular and Anatomical PathologyDerriford HospitalPlymouthUK
  7. 7.Institute of Medical GeneticsUniversity Hospital of WalesCardiffUK
  8. 8.Department of Clinical GeneticsRoyal Devon and Exeter NHS Foundation TrustExeterUK
  9. 9.Department of PathologyUniversity of British Columbia and Vancouver General HospitalVancouverCanada

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