Acta Neuropathologica

, Volume 123, Issue 3, pp 409–417 | Cite as

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

  • Heather Stewart
  • Nicola J. Rutherford
  • Hannah Briemberg
  • Charles Krieger
  • Neil Cashman
  • Marife Fabros
  • Matt Baker
  • Alice Fok
  • Mariely DeJesus-Hernandez
  • Andrew Eisen
  • Rosa Rademakers
  • Ian R. A. MackenzieEmail author
Original Paper


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 sclerosis Frontotemporal dementia Frontotemporal lobar degeneration C9ORF72 TDP-43 Chromosome 9p 



We are grateful to the patients and family members who participated in this research. We thank Margaret Luk (research technologist, Vancouver General Hospital) for her excellent technical assistance. This work was supported by grants from the Canadian Institutes of Health Research [operating grants #179009, #74580 to IM], the Pacific Alzheimer’s Research Foundation [center grant C06-01 to IM], the ALS Association [to RR] and the National Institutes of Health [grants # R01 NS065782, R01 AG026251 to RR].


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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Heather Stewart
    • 1
  • Nicola J. Rutherford
    • 2
  • Hannah Briemberg
    • 1
  • Charles Krieger
    • 1
  • Neil Cashman
    • 1
  • Marife Fabros
    • 1
  • Matt Baker
    • 2
  • Alice Fok
    • 1
  • Mariely DeJesus-Hernandez
    • 2
  • Andrew Eisen
    • 1
  • Rosa Rademakers
    • 2
  • Ian R. A. Mackenzie
    • 3
    Email author
  1. 1.Division of NeurologyUniversity of British ColumbiaVancouverCanada
  2. 2.Department of NeuroscienceMayo ClinicJacksonvilleUSA
  3. 3.Department of PathologyUniversity of British Columbia and Vancouver General HospitalVancouverCanada

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