Acta Neuropathologica

, Volume 125, Issue 3, pp 425–438 | Cite as

Sequence variants in eukaryotic translation initiation factor 4-gamma (eIF4G1) are associated with Lewy body dementia

  • Shinsuke Fujioka
  • Christina Sundal
  • Audrey J. Strongosky
  • Monica Case Castanedes
  • Rosa Rademakers
  • Owen A. Ross
  • Carles Vilariño-Güell
  • Matthew J. Farrer
  • Zbigniew K. Wszolek
  • Dennis W. DicksonEmail author
Original Paper


We recently reported a missense mutation and four variants in eukaryotic translation initiation factor 4-gamma (EIF4G1) associated with parkinsonism, dementia or both. In those with a positive family history, the mode of inheritance was autosomal dominant. Detailed neuropathologic descriptions of individuals with EIF4G1 genetic variants have not been reported. Herein, we report neuropathologic findings of three individuals from two American families with EIF4G1 variants. The patients had initial clinical presentations of dementia or parkinsonism and all had dementia at the time of autopsy. One family carried an EIF4G1 double variant, c.2056G>T (p.G686C) and c.3589C>T (p.R1197 W), and one family carried variant c.1505C>T (p.A502V). All three patients also carried at least one ε4 allele of apolipoprotein E. One individual presented with cognitive impairment without significant parkinsonism; one presented with memory problems followed by bradykinesia; and the third presented with cardinal signs of Parkinson’s disease, followed more than a year later by cognitive dysfunction. Pathological examination showed diffuse cortical Lewy bodies and Lewy neurites in all patients. A small subset of Lewy bodies and Lewy neurites were immunopositive for eIF4G1. All patients had moderate to frequent non-neuritic, cortical amyloid plaques, mostly medial temporal neurofibrillary pathology (Braak neurofibrillary tangle stages of II to IV), and minimal or no TDP-43 pathology. The results suggest that in some patients variants in EIF4G1 can be associated with pathology that has a high likelihood of association with clinical features of dementia with Lewy bodies.


APOE Dementia with Lewy bodies Diffuse Lewy body disease EIF4G1 Parkinsonism α-Synuclein Tau 



MJF and CVG are grateful to support from the Canada Excellence Research Chairs program. In addition, Leading Edge Endowment Funds provided by the Province of British Columbia, LifeLabs, and Genome BC support the Dr. Donald Rix BC Leadership Chair (MJF). RR was supported by the National Institute of Health (R01 NS065782, R01 AG26251, and P50 AG16574). ZKW was partially supported by the National Institute of Health (RC2 NS070276, R01 NS057567) and Dystonia Medical Research Foundation. ZKW and DWD were supported by National Institute of Health (P50 NS072187.). DWD is supported by the Robert E. Jacoby Professorship. The authors would like to thank Dr. Peter Davies, Albert Einstein College of Medicine for sharing his antibodies for tau, Dr. Leonard Petrucelli, Mayo Clinic Jacksonville for sharing the antibody for TDP-43, and Dr. Pritam Das, Mayo Clinic Jacksonville for sharing antibodies to Aβ.

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Shinsuke Fujioka
    • 1
  • Christina Sundal
    • 1
  • Audrey J. Strongosky
    • 1
  • Monica Case Castanedes
    • 2
  • Rosa Rademakers
    • 2
  • Owen A. Ross
    • 2
  • Carles Vilariño-Güell
    • 3
  • Matthew J. Farrer
    • 3
  • Zbigniew K. Wszolek
    • 1
  • Dennis W. Dickson
    • 2
    • 4
    Email author
  1. 1.Departments of NeurologyMayo ClinicJacksonvilleUSA
  2. 2.Departments of NeuroscienceMayo ClinicJacksonvilleUSA
  3. 3.Department of Medical GeneticsUniversity of British ColumbiaVancouverUSA
  4. 4.Department of NeuropathologyMayo ClinicJacksonvilleUSA

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