Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia

Brain. 2016 Dec;139(Pt 12):3202-3216. doi: 10.1093/brain/aww250. Epub 2016 Oct 22.


SEE SCABER AND TALBOT DOI101093/AWW264 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: A GGGGCC repeat expansion in C9orf72 leads to frontotemporal dementia and/or amyotrophic lateral sclerosis. Diverse pathological features have been identified, and their disease relevance remains much debated. Here, we describe two illuminating patients with frontotemporal dementia due to the C9orf72 repeat expansion. Case 1 was a 65-year-old female with behavioural variant frontotemporal dementia accompanied by focal degeneration in subgenual anterior cingulate cortex, amygdala, and medial pulvinar thalamus. At autopsy, widespread RNA foci and dipeptide repeat protein inclusions were observed, but TDP-43 pathology was nearly absent, even in degenerating brain regions. Case 2 was a 74-year-old female with atypical frontotemporal dementia-motor neuron disease who underwent temporal lobe resection for epilepsy 5 years prior to her first frontotemporal dementia symptoms. Archival surgical resection tissue contained RNA foci, dipeptide repeat protein inclusions, and loss of nuclear TDP-43 but no TDP-43 inclusions despite florid TDP-43 inclusions at autopsy 8 years after first symptoms. These findings suggest that C9orf72-specific phenomena may impact brain structure and function and emerge before first symptoms and TDP-43 aggregation.

Keywords: TDP-43; frontotemporal dementia; protein aggregation.

Publication types

  • Case Reports

MeSH terms

  • Aged
  • C9orf72 Protein
  • DNA Repeat Expansion / genetics*
  • DNA-Binding Proteins / metabolism
  • Female
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / pathology
  • Frontotemporal Dementia / physiopathology
  • Humans
  • Proteins / genetics*


  • C9orf72 Protein
  • C9orf72 protein, human
  • DNA-Binding Proteins
  • Proteins
  • TARDBP protein, human