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J Med Genet. 2012 Apr;49(4):258-63. doi: 10.1136/jmedgenet-2011-100699.

Phenotype difference between ALS patients with expanded repeats in C9ORF72 and patients with mutations in other ALS-related genes.

Author information

1
Centre de Recherche de l’Institut du Cerveau et de la Moelle Epinière, INSERMUMR_S975, CNRS UMR7225, Université Pierre et Marie Curie-Paris 6, Hôpital Pitié-Salpêtrière, Paris, France. stephanie.millecamps@upmc.fr

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.

PMID:
22499346
DOI:
10.1136/jmedgenet-2011-100699
[Indexed for MEDLINE]

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