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. Mackenzie

Research output: Contribution to journalArticlepeer-review

121 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)409-417
Number of pages9
JournalActa neuropathologica
Volume123
Issue number3
DOIs
StatePublished - Mar 2012

Keywords

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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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