Corticobasal and ataxia syndromes widen the spectrum of C9ORF72 hexanucleotide expansion disease

Clin Genet. 2013 Mar;83(3):279-83. doi: 10.1111/j.1399-0004.2012.01903.x. Epub 2012 Jul 4.


Recently, a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 was reported as the cause of chromosome 9p21-linked frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS). We here report the prevalence of the expansion in a hospital-based cohort and associated clinical features indicating a wider clinical spectrum of C9ORF72 disease than previously described. We studied 280 patients previously screened for mutations in genes involved in early onset autosomal dominant inherited dementia disorders. A repeat-primed polymerase chain reaction amplification assay was used to identify pathogenic GGGGCC expansions. As a potential modifier, confirmed cases were further investigated for abnormal CAG expansions in ATXN2. A pathogenic GGGGCC expansion was identified in a total of 14 probands. Three of these presented with atypical clinical features and were previously diagnosed with clinical olivopontocerebellar degeneration (OPCD), atypical Parkinsonian syndrome (APS) and a corticobasal syndrome (CBS). Further, the pathogenic expansion was identified in six FTD patients, four patients with FTD-ALS and one ALS patient. All confirmed cases had normal ATXN2 repeat sizes. Our study widens the clinical spectrum of C9ORF72 related disease and confirms the hexanucleotide expansion as a prevalent cause of FTD-ALS disorders. There was no indication of a modifying effect of the ATXN2 gene.

MeSH terms

  • Adult
  • Aged
  • Amyotrophic Lateral Sclerosis / diagnosis
  • Amyotrophic Lateral Sclerosis / genetics*
  • Ataxia / diagnosis
  • Ataxia / genetics*
  • Base Sequence
  • C9orf72 Protein
  • Cohort Studies
  • DNA Repeat Expansion / genetics*
  • Family Health
  • Female
  • Frontotemporal Dementia / diagnosis
  • Frontotemporal Dementia / genetics*
  • Genetic Predisposition to Disease / genetics
  • Genetic Testing
  • Humans
  • Male
  • Middle Aged
  • Proteins / genetics*
  • Syndrome


  • C9orf72 Protein
  • C9orf72 protein, human
  • Proteins