Phenotype difference between ALS patients with expanded repeats in C9ORF72 and patients with mutations in other ALS-related genes. Issue 4 (12th April 2012)

• Record Type: Journal Article
• Authors: Millecamps, Stéphanie; Boillée, Séverine; Le Ber, Isabelle; Seilhean, Danielle; Teyssou, Elisa; Giraudeau, Marine; Moigneu, Carine; Vandenberghe, Nadia; Danel-Brunaud, Véronique; Corcia, Philippe; Pradat, Pierre-François; Le Forestier, Nadine; Lacomblez, Lucette; Bruneteau, Gaelle; Camu, William; Brice, Alexis; Cazeneuve, Cécile; LeGuern, Eric; Meininger, Vincent; Salachas, François
• Is Part Of: Journal of medical genetics. Volume 49:Issue 4(2012)
• Page Start: 258
• Page End: 263
• Publication Date: 2012-04-12
• Subjects: Motor neuron disease -- familial ALS -- Genetic analysis -- repeat primed PCR -- GGGGCC repeat -- genetics -- Parkinsons disease -- molecular genetics -- genetic screening/counselling -- epilepsy and seizures; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2011-100699
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : Background: Expanded GGGGCC hexanucleotide repeats in the promoter of the C9ORF72 gene have recently been identified in frontotemporal dementia (FTD), Amyotrophic Lateral Sclerosis (ALS) and ALS-FTD and appear as the most common genetic cause of familial (FALS) and sporadic (SALS) forms of ALS. Methods: We searched for the C9ORF72 repeat expansion in 950 French ALS patients (225 FALS and 725 SALS) and 580 control subjects and performed genotype-phenotype correlations. Results: The repeat expansion was present in 46% of FALS, 8% of SALS and 0% of controls. Phenotype comparisons were made between FALS patients with expanded C9ORF72 repeats and patients carrying another ALS-related gene ( SOD1, TARDBP, FUS ) or a yet unidentified genetic defect. SALS patients with and without C9ORF72 repeat expansions were also compared. The C9ORF72 group presented more frequent bulbar onset both in FALS (p<0.0001 vs SOD1, p=0.002 vs TARDBP, p=0.011 vs FUS, p=0.0153 vs other FALS) and SALS (p=0.047). FALS patients with C9ORF72 expansions had more frequent association with FTD than the other FALS patients (p<0.0001 vs SOD1, p=0.04 vs TARDBP, p=0.004 vs FUS, p=0.03 vs other FALS). C9ORF72 -linked FALS patients presented an older age of onset than SOD1 (p=0.0139) or FUS mutation (p<0.0001) carriers. Disease duration was shorter for C9ORF72 expansion carriers than for SOD1 (p<0.0001) and TARDBP (p=0.0242) carriers, other FALS (p<0.0001) and C9ORF72 -negative SALS (p=0.0006). Conclusions: Our results confirm the major role of expanded repeats in C9ORF72 as causative for ALS and provide evidence for specific phenotypic aspects compared to patients with other ALS-related genes.