• 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, and Leonard H van den Berg.
• Department of Neurology, Rudolph Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht.
• Neurology. 2012 Aug 28;79(9):878-82.

ObjectiveTo 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).MethodsIncluded 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.ResultsThe 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)).ConclusionsThe 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.

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