Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor neuron diseases

Wouter Van Rheenen, Marka Van Blitterswijk, Mark H.B. Huisman, Lotte Vlam, Perry T.C. Van Doormaal, Meinie Seelen, Jelena Medic, Dennis Dooijes, Marianne De Visser, Anneke J. Van Der Kooi, Joost Raaphorst, Helenius J. Schelhaas, W. Ludo Van Der Pol, Jan H. Veldink, Leonard H. Van Den Berg

Research output: Contribution to journalArticlepeer-review

74 Scopus citations


Objective: To assess the frequency and phenotype of hexanucleotide repeat expansions in C9ORF72 in a large cohort of patients of Dutch descent with familial (fALS) and sporadic (sALS) amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS). Methods: Included were 78 patients with fALS, 1,422 with sALS, 246 with PMA, and 110 with PLS, and 768 control subjects. Repeat expansions were determined by a repeat primed PCR. Familial aggregation of dementia and Parkinson disease (PD) was examined among patients with ALS who carried the repeat expansion. Results: The expanded repeat was found in 33 (37%) of all patients with fALS, in 87 (6.1%) patients with sALS, in 4 (1.6%) patients with PMA, and in 1 (0.9%) patient with PLS. None of the controls carried the mutation. Patients with ALS with the repeat expansion had an earlier age at onset (median 59.3 vs 61.9 years, hazard ratio 1.55, p = 5 × 10-5) and shorter survival (median 2.5 vs 2.7 years, hazard ratio 1.46, p=8 × 10-4). Dementia, but not PD, occurred nearly twice as often in relatives of patients with the expansion compared to all patients with ALS or controls (p=9 × 10-4). Conclusions: The hexanucleotide repeat expansion in C9ORF72 is a major cause of fALS and apparently sporadic ALS in the Netherlands. Patients who carry the repeat expansion have an earlier onset, shorter survival, and familial aggregation of dementia. These results challenge the classic definition of fALS and may justify genetic testing in patients with sALS.

Original languageEnglish (US)
Pages (from-to)878-882
Number of pages5
Issue number9
StatePublished - Aug 28 2012

ASJC Scopus subject areas

  • Clinical Neurology


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