C9ORF72 repeat expansions in the frontotemporal dementias spectrum of diseases: a flow-chart for genetic testing.

Isabelle Le Ber 1 Agnès Camuzat 1 Lena Guillot-Noel 1 Didier Hannequin 2 Lucette Lacomblez 3 Véronique Golfier Michèle Puel 4, 5 Olivier Martinaud 2 Vincent Deramecourt 6 Sophie Rivaud-Pechoux 7 Stéphanie Millecamps 1 Martine Vercelletto 8 Philippe Couratier 9, 10 François Sellal 11 Florence Pasquier 12 François Salachas 13 Catherine Thomas-Antérion 14 Mira Didic 15 Jérémie Pariente 5, 4 Danielle Seilhean 16 Merle Ruberg 7, 17 Isabelle Wargon 18 Frédéric Blanc 19 William Camu 20 Bernard-François Michel Eric Berger Mathilde Sauvée Christel Thauvin-Robinet 21, 22 Karl Mondon 23 Elisabeth Tournier-Lasserve Cyril Goizet 24 Marie Fleury 19 Gabriel Viennet 25 Patrice Verpillat 7 Vincent Meininger 13 Charles Duyckaerts Bruno Dubois 1 Alexis Brice 17, 1, *
Abstract : Frontotemporal dementia (FTD) refers to a disease spectrum including the behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy/corticobasal degeneration syndrome (PSP/CBDS), and FTD with amyotrophic lateral sclerosis (FTD-ALS). A GGGGCC expansion in C9ORF72 is a major cause of FTD and ALS. C9ORF72 was analyzed in 833 bvFTD, FTD-ALS, PPA, and PSP/CBDS probands; 202 patients from 151 families carried an expansion. C9ORF72 expansions were much more frequent in the large subgroup of patients with familial FTD-ALS (65.9%) than in those with pure FTD (12.8%); they were even more frequent than in familial pure ALS, according to estimated frequencies in the literature (23-50%). The frequency of carriers in non-familial FTD-ALS (12.7%) indicates that C9ORF72 should be analyzed even when family history is negative. Mutations were detected in 6.8% of PPA patients, and in 3.2% of patients with a clinical phenotype of PSP, thus enlarging the phenotype spectrum of C9ORF72. Onset was later in C9ORF72 (57.4 years, 95%CI: 55.9-56.1) than in MAPT patients (46.8, 95%CI: 43.0-50.6; p = 0.00001) and the same as in PGRN patients (59.6 years; 95%CI: 57.6-61.7; p = 0.4). ALS was more frequent in C9ORF72 than in MAPT and PGRN patients; onset before age 50 and parkinsonism were indicative of MAPT mutations, whereas hallucinations were indicative of PGRN mutations; prioritization of genetic testing is thus possible. Penetrance was age- and gender-dependent: by age 50, 78% of male carriers were symptomatic, but only 52% of females. This can also guide genetic testing and counseling. A flowchart for genetic testing is thus proposed.
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Contributeur : Elisabeth Grelier <>
Soumis le : mardi 7 janvier 2014 - 10:53:59
Dernière modification le : mercredi 24 juillet 2019 - 09:02:03

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Isabelle Le Ber, Agnès Camuzat, Lena Guillot-Noel, Didier Hannequin, Lucette Lacomblez, et al.. C9ORF72 repeat expansions in the frontotemporal dementias spectrum of diseases: a flow-chart for genetic testing.. Journal of Alzheimer's Disease, IOS Press, 2013, 34 (2), pp.485-99. ⟨10.3233/JAD-121456⟩. ⟨hal-00924796⟩

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