TY - JOUR
T1 - Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor neuron diseases
AU - Van Rheenen, Wouter
AU - Van Blitterswijk, Marka
AU - Huisman, Mark H.B.
AU - Vlam, Lotte
AU - Van Doormaal, Perry T.C.
AU - Seelen, Meinie
AU - Medic, Jelena
AU - Dooijes, Dennis
AU - De Visser, Marianne
AU - Van Der Kooi, Anneke J.
AU - Raaphorst, Joost
AU - Schelhaas, Helenius J.
AU - Van Der Pol, W. Ludo
AU - Veldink, Jan H.
AU - Van Den Berg, Leonard H.
N1 - Funding Information:
W. van Rheenen, M. van Blitterswijk, M.H.B. Huisman, L. Vlam, P.T.C. van Doormaal, M. Seelen, J. Medic, D. Dooijes, and M. de Visser report no disclosures. A.J. van der Kooi receives support from Prinses Beatrix Fonds. J. Raaphorst and H.J. Schelhaas report no disclosures. W.L. van der Pol received funding for travel from Baxter International Inc. J.H. Veldink receives support from Thierry Latran Foundation. L.H. van den Berg received travel grants and consultancy fees from Baxter; serves on scientific advisory boards for ARISLA (the Italian ALS Association), Prinses Beatrix Fonds, Thierry Latran Foundation, and Biogen Idec; serves as a consultant for and has received funding for travel from Baxter International Inc.; and receives research support from the Prinses Beatrix Fonds, Netherlands ALS Foundation, VSB Fonds, Adessium Foundation, and the European Union. Go to Neurology.org for full disclosures.
Funding Information:
Study funding: The research leading to these results has received funding from the European Community's Health Seventh Framework Programme (FP7/2007–2013) (grant agreement no. 259867).
PY - 2012/8/28
Y1 - 2012/8/28
N2 - 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.
AB - 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.
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U2 - 10.1212/WNL.0b013e3182661d14
DO - 10.1212/WNL.0b013e3182661d14
M3 - Article
C2 - 22843265
AN - SCOPUS:84865068311
SN - 0028-3878
VL - 79
SP - 878
EP - 882
JO - Neurology
JF - Neurology
IS - 9
ER -