Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia

Pietro Fratta, Mark Poulter, Tammaryn Lashley, Jonathan D. Rohrer, James M. Polke, Jon Beck, Natalie Ryan, Davina Hensman, Sarah Mizielinska, Adrian J. Waite, Mang Ching Lai, Tania F. Gendron, Leonard Petrucelli, Elizabeth M.C. Fisher, Tamas Revesz, Jason D. Warren, John Collinge, Adrian M. Isaacs, Simon Mead

Research output: Contribution to journalArticlepeer-review

94 Scopus citations


An expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). We now report the first description of a homozygous patient and compare it to a series of heterozygous cases. The patient developed early-onset frontotemporal dementia without additional features. Neuropathological analysis showed c9FTD/ALS characteristics, with abundant p62-positive inclusions in the frontal and temporal cortices, hippocampus and cerebellum, as well as less abundant TDP-43-positive inclusions. Overall, the clinical and pathological features were severe, but did not fall outside the usual disease spectrum. Quantification of C9orf72 transcript levels in post-mortem brain demonstrated expression of all known C9orf72 transcript variants, but at a reduced level. The pathogenic mechanisms by which the hexanucleotide repeat expansion causes disease are unclear and both gain- and loss-of-function mechanisms may play a role. Our data support a gain-of-function mechanism as pure homozygous loss of function would be expected to lead to a more severe, or completely different clinical phenotype to the one described here, which falls within the usual range. Our findings have implications for genetic counselling, highlighting the need to use genetic tests that distinguish C9orf72 homozygosity.

Original languageEnglish (US)
Pages (from-to)401-409
Number of pages9
JournalActa neuropathologica
Issue number3
StatePublished - Sep 2013


  • ALS
  • C9orf72
  • FTD

ASJC Scopus subject areas

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


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