Relations between C9orf72 expansion size in blood, age at onset, age at collection and transmission across generations in patients and presymptomatic carriers

Clémence Fournier (1) , Mathieu Barbier (1) , Agnès Camuzat (1, 2) , Vincent Anquetil (3, 1) , Serena Lattante (4) , Fabienne Clot (3) , Cécile Cazeneuve (5) , Daisy Rinaldi (1) , Philippe Couratier (6, 7) , Vincent Deramecourt (8) , Mario Sabatelli (4) , Serge Belliard (9) , Martine Vercelletto (10) , Sylvie Forlani (1) , Ludmila Jornea (1) , Eric E. Leguern (3, 1) , Alexis Brice (1) , Sophie Auriacombe (11) , Frédéric Blanc (12) , Claire Bouteleau-Bretonnière (13) , Mathieu Ceccaldi (14) , Mira Didic (14, 15) , Charles Duyckaerts (1) , Frédérique Etcharry-Bouix (16) , Véronique Golfier (9) , Lucette Lacomblez (1) , Bernard-François Michel (17) , Catherine Thomas-Antérion (12) , Jérémie Pariente (18) , François Sellal (19) , Eve Benchetrit (20) , Hugo Bertin (21) , Anne Bertrand (3) , Anne Bissery (3) , Stéphanie Bombois (8) , Marie-Paule Boncoeur (6, 22) , Pascaline Cassagnaud (8) , Mathieu Chastan (23) , Yaohua Chen (8) , Marie Chupin (21) , Olivier Colliot (24) , Xavier Delbeucq (8) , Christine Delmaire (25) , Emmanuel Gérardin (26) , Claude Hossein-Foucher (27) , Bruno Dubois (1) , Marie Habert (1) , Didier Hannequin (28) , Géraldine Lautrette (7) , Thibaud Lebouvier (29) , Isabelle Le Ber (1) , Stéphane Lehéricy (1) , Benjamin Le Toullec (30) , Richard Lévy (3) , Martine Martineau (1) , Anne Mackowiak (8) , Jacques Monteil (31) , Florence Pasquier (8) , Grégory Petyt (8) , François Pradat (3) , Assi-Hervé Oya (3) , Adeline Rollin-Sillaire (32) , François Salachas (3) , Sabrina Sayah (1) , David Wallon (28)

1 ICM - Institut du Cerveau = Paris Brain Institute
2 EPHE - École pratique des hautes études
3 CHU Pitié-Salpêtrière [AP-HP]
4 Unicatt - Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma]
5 Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière]
6 NET - Neuroépidémiologie Tropicale
7 Service de Neurologie [CHU Limoges]
8 CHRU Lille - Centre Hospitalier Régional Universitaire [Lille]
9 CHU Pontchaillou [Rennes]
10 Service de neurologie [Nantes]
11 Service de neurologie [Bordeaux]
12 CMRR Strasbourg - Centre Mémoire Ressources et Recherche [Strasbourg]
13 CHU Nantes - Centre hospitalier universitaire de Nantes
14 APHM - Assistance Publique - Hôpitaux de Marseille
15 INS - Institut de Neurosciences des Systèmes
16 CHU Angers - Centre Hospitalier Universitaire d'Angers
17 Hôpitaux Sud - Hôpital Sainte-Marguerite [CHU - APHM]
18 ToNIC - Toulouse Neuro Imaging Center
19 Service de Neurologie [Strasbourg]
20 Service de Neurologie [CHU Pitié-Salpêtrière]
21 Centre d'Acquisition et de Traitement des Images [Paris]
22 Service de Radiologie et Imagerie Médicale [CHU Limoges]
23 Service de médecine nucléaire [Rouen]
24 ARAMIS - Algorithms, models and methods for images and signals of the human brain
25 Services de neuroradiologie [Lille]
26 CHU Rouen
27 Troubles cognitifs vasculaires et dégénératifs
28 Centre Normandie de Génomique et de Médecine Personnalisée - Département de génétique [CHU Rouen]
29 Neuropathies du système nerveux entérique et pathologies digestives; implication des cellules gliales entériques
30 CIC Neurosciences - Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière]
31 CHU Limoges
32 Département de neurologie [Lille]

A (GGGGCC)n repeat expansion in C9orf72 gene is the major cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The relations between the repeats size and the age at disease onset (AO) or the clinical phenotype (FTD vs. ALS) were investigated in 125 FTD, ALS, and presymptomatic carriers. Positive correlations were found between repeats number and the AO (p < 10e-4) but our results suggested that the association was mainly driven by age at collection (p < 10e-4). A weaker association was observed with clinical presentation (p = 0.02), which became nonsignificant after adjustment for the age at collection in each group. Importantly, repeats number variably expanded or contracted over time in carriers with multiple blood samples, as well as through generations in parent-offspring pairs, conversely to what occurs in several expansion diseases with anticipation at the molecular level. Finally, this study establishes that measure of repeats number in lymphocytes is not a reliable biomarker predictive of the AO or disease outcome in C9orf72 long expansion carriers.

Mots clés: Amyotrophic Lateral sclerosis; Anticipation; TDP-43; Frontotemporal lobar degeneration; Frontotemporal dementia; C9orf72

Domaines: Sciences du Vivant [q-bio]; Santé publique et épidémiologie

Clémence Fournier, Mathieu Barbier, Agnès Camuzat, Vincent Anquetil, Serena Lattante, et al.. Relations between C9orf72 expansion size in blood, age at onset, age at collection and transmission across generations in patients and presymptomatic carriers. Neurobiology of Aging, 2019, 74, pp.234.e1-234.e8. ⟨10.1016/j.neurobiolaging.2018.09.010⟩. ⟨hal-02025976⟩