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, 13) , Isabelle Wargon (17) , Frédéric Blanc (18) , William Camu (19) , Bernard-François Michel , Eric Berger , Mathilde Sauvée , Christel Thauvin-Robinet (20, 21) , Karl Mondon (22) , Elisabeth Tournier-Lasserve , Cyril Goizet (23) , Marie Fleury (18) , Gabriel Viennet (24) , Patrice Verpillat (7) , Vincent Meininger (13) , Charles Duyckaerts , Bruno Dubois (1) , Alexis Brice (13, 1)

1 CRICM - Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière
2 GMFC - Génétique du cancer et des maladies neuropsychiatriques
3 LIF - Laboratoire d'Imagerie Fonctionnelle
4 Neurologie générale et maladies inflammatoires du système nerveux [Toulouse]
5 ICHN - Imagerie cérébrale et handicaps neurologiques
6 TCDV - Troubles cognitifs vasculaires et dégénératifs - EA 2691
7 Neurologie et thérapeutique expérimentale
8 Service de neurologie [Nantes]
9 NET - Neuroépidémiologie Tropicale
10 Service de Neurologie [CHU Limoges]
11 Service de neurologie
12 Département de neurologie [Lille]
13 CHU Pitié-Salpêtrière [AP-HP]
14 CMRR - Centre de Mémoire de Ressource et Recherche
15 Service de neurologie et de neuropsychologie
16 The Mediterranean Institute of Neurobiology
17 Physiologie et physiopathologie de la motricité chez l'homme
18 Service de Neurologie [Strasbourg]
19 SLA CHRU Montpellier - Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier]
20 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
21 Department of Experimental Cardiology
22 iBraiN - Imaging, Brain & Neuropsychiatry
23 Service de génétique médicale
24 E2SNC / ESTROGENES - Estrogènes, Expression génique et pathologies du Système Nerveux Central - UFC

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.

Domaines: Santé publique et épidémiologie

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, 2013, 34 (2), pp.485-99. ⟨10.3233/JAD-121456⟩. ⟨hal-00924796⟩