Document Detail

Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor neuron diseases.
MedLine Citation:
PMID:  22843265     Owner:  NLM     Status:  Publisher    
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.
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
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-7-25
Journal Detail:
Title:  Neurology     Volume:  -     ISSN:  1526-632X     ISO Abbreviation:  -     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-7-30     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0401060     Medline TA:  Neurology     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
From the Department of Neurology (W.v.R., M.B., M.H.B.H., L.V., P.T.C.v.D., M.S., J.M., W.L.v.d.P., J.H.V., L.H.v.d.B.), Rudolph Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht; Department of Medical Genetics (D.D.), University Medical Center Utrecht, Utrecht; Department of Neurology (M.d.V., A.J.v.d.K., J.R.), Academic Medical Center, University of Amsterdam, Amsterdam; and Department of Neurology (H.J.S.), Donders Institute for Brain, Cognition and Behavior, Center for Neurosciences, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
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