Acta Neuropathologica

, Volume 123, Issue 3, pp 409–417

Clinical and pathological features of amyotrophic lateral sclerosis caused by mutation in the C9ORF72 gene on chromosome 9p


  • Heather Stewart
    • Division of NeurologyUniversity of British Columbia
  • Nicola J. Rutherford
    • Department of NeuroscienceMayo Clinic
  • Hannah Briemberg
    • Division of NeurologyUniversity of British Columbia
  • Charles Krieger
    • Division of NeurologyUniversity of British Columbia
  • Neil Cashman
    • Division of NeurologyUniversity of British Columbia
  • Marife Fabros
    • Division of NeurologyUniversity of British Columbia
  • Matt Baker
    • Department of NeuroscienceMayo Clinic
  • Alice Fok
    • Division of NeurologyUniversity of British Columbia
  • Mariely DeJesus-Hernandez
    • Department of NeuroscienceMayo Clinic
  • Andrew Eisen
    • Division of NeurologyUniversity of British Columbia
  • Rosa Rademakers
    • Department of NeuroscienceMayo Clinic
    • Department of PathologyUniversity of British Columbia and Vancouver General Hospital
Original Paper

DOI: 10.1007/s00401-011-0937-5

Cite this article as:
Stewart, H., Rutherford, N.J., Briemberg, H. et al. Acta Neuropathol (2012) 123: 409. doi:10.1007/s00401-011-0937-5


Two studies recently identified a GGGGCC hexanucleotide repeat expansion in a non-coding region of the chromosome 9 open-reading frame 72 gene (C9ORF72) as the cause of chromosome 9p-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In a cohort of 231 probands with ALS, we identified the C9ORF72 mutation in 17 familial (27.4%) and six sporadic (3.6%) cases. Patients with the mutation presented with typical motor features of ALS, although subjects with the C9ORF72 mutation had more frequent bulbar onset, compared to those without this mutation. Dementia was significantly more common in ALS patients and families with the C9ORF72 mutation and was usually early-onset FTD. There was striking clinical heterogeneity among the members of individual families with the mutation. The associated neuropathology was a combination of ALS with TDP-ir inclusions and FTLD-TDP. In addition to TDP-43-immunoreactive pathology, a consistent and specific feature of cases with the C9ORF72 mutation was the presence of ubiquitin-positive, TDP-43-negative inclusions in a variety of neuroanatomical regions, such as the cerebellar cortex. These findings support the C9ORF72 mutation as an important newly recognized cause of ALS, provide a more detailed characterization of the associated clinical and pathological features and further demonstrate the clinical and molecular overlap between ALS and FTD.


Amyotrophic lateral sclerosisFrontotemporal dementiaFrontotemporal lobar degenerationC9ORF72TDP-43Chromosome 9p

Copyright information

© Springer-Verlag 2012