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)

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 Fédération des Maladies du Système Nerveux
14 CMRR - Centre de Mémoire de Ressource et Recherche
15 Service de neurologie et de neuropsychologie
16 The Mediterranean Institute of Neurobiology
17 Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière]
18 Physiologie et physiopathologie de la motricité chez l'homme
19 Service de Neurologie [Strasbourg]
20 SLA CHRU Montpellier - Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier]
21 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
22 Department of Experimental Cardiology
23 iBrain - Inserm U1253 - UNIV Tours - Imagerie et cerveau
24 Service de génétique médicale
25 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⟩