C9ORF72 Repeat Expansions in the Frontotemporal Dementias Spectrum of Diseases: A Flow-chart for Genetic Testing

Article type: Research Article

Authors: Le Ber, Isabelle^{a; b; c; 1} | Camuzat, Agnès^{a; 1} | Guillot-Noel, Lena^{a; 1} | Hannequin, Didier^d | Lacomblez, Lucette^{c; e; f} | Golfier, Véronique^g | Puel, Michèle^h | Martinaud, Olivier^d | Deramecourt, Vincentⁱ | Rivaud-Pechoux, Sophie^a | Millecamps, Stéphanie^a | Vercelletto, Martine^j | Couratier, Philippe^k | Sellal, François^l | Pasquier, Florenceⁱ | Salachas, François^c | Thomas-Antérion, Catherine^m | Didic, Miraⁿ | Pariente, Jérémie^h | Seilhean, Danielle^{a; e; o} | Ruberg, Merle^a | Wargon, Isabelle^{a; b; c} | Blanc, Frédéric^p | Camu, William^q | Michel, Bernard-François^r | Berger, Eric^s | Sauvée, Mathilde^t | Thauvin-Robinet, Christel^u | Mondon, Karl^v | Tournier-Lasserve, Elisabeth^w | Goizet, Cyril^x | Fleury, Marie^p | Viennet, Gabriel^s | Verpillat, Patrice^a | Meininger, Vincent^c | Duyckaerts, Charles^{a; e; o} | Dubois, Bruno^{b; c; e} | Brice, Alexis^{a; b; c; e; y; *} | the French research network on FTLD/FTLD-ALS²

Affiliations: [a] CRicm-UMRS975, Paris, France | [b] AP-HP, Hôpital de la Pitié-Salpêtrière, Centre de Référence des Démences Rares, Paris, France | [c] AP-HP, Hôpital de la Pitié-Salpêtrière, Fédération des maladies du système nerveux, Paris, France | [d] INSERM: Institut National de la Santé et de la Recherche Médicale U614, CNR-MAJ & Département de Neurologie, Rouen University Hospital, France | [e] UPMC Univ Paris06, UMRS975, Paris, France | [f] AP-HP, Hôpital de la Salpêtrière, Service de pharmacologie, Paris, France | [g] Service de Neurologie, CHU, Rennes, France | [h] Inserm; Imagerie Cérébrale et Handicaps Neurologiques UMR 825; Université de Toulouse; UPS; Imagerie Cérébrale et Handicaps Neurologiques UMR 825; Service de Neurologie; Pôle Neurosciences; CHU Purpan, Toulouse, France | [i] Université Lille Nord de France, UDSL EA1046, CHU Lille-Bailleul Memory Center, Lille, France | [j] Service de Neurologie, CHU Guillaume et René Laënnec, Nantes, France | [k] Service de Neurologie, CHU Dupuytren, Limoges, France | [l] Service de Neurologie, CHG, Colmar & Unité INSERM: Institut National de la Santé et de la Recherche Médicale U-692, Université de Strasbourg, France | [m] Service de Neurologie, CHU Bellevue, Saint-Etienne, France | [n] APHM, CHU Timone, Service de Neurologie et Neuropsychologie, Aix-Marseille Univ, INSERM U 1106, Marseille, France | [o] Laboratoire de Neuropathologie R Escourolle, Hôpital de la Pitié-Salpêtrière, Paris, France | [p] Service de Neurologie, Hopitaux Civils, Strasbourg, France | [q] Clinique du motoneurone, CHU Gui de Chauliac, INSERM UMR 1051, Université Montpellier 1, Montpellier, France | [r] Service de Neurogériatrie, Hôpital Sainte Marguerite, Marseille, France | [s] Services de Neurologie & Neuropathologie, CHU, Besançon, France | [t] Service de Neurologie, CHU, Nancy, France | [u] EA GAD, IFR Santé STIC, Université de Bourgogne; Centre de Génétique, CHU, Dijon, France | [v] Service de Neurologie, CHU, Tours, France | [w] Service de génétique moléculaire neuro-vasculaire, APHP-Hôpital Lariboisière, Paris, France | [x] Laboratoire Maladies Rares : Génétique et Métabolisme (MRGM), EA4576, Université Bordeaux et Service de Génétique Médicale, CHU Bordeaux, France | [y] AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique et Cytogénétique, Paris, France

Correspondence: [*] Correspondence to: Pr. Alexis Brice, CR-ICM-UMRS_975, ICM, Hôpital de la Salpêtrière, 47, Boulevard de l'hôpital, 75 651 Paris Cedex 13, France. E-mail: alexis.brice@upmc.fr.

Note: [1] These authors contributed equally to this work.

Note: [2] The French research network on FTLD/FTLD-ALS includes: Alexis Brice (Hôpital de la Salpêtrière, Paris), Frédéric Blanc (Hôpitaux Civils, Strasbourg) Franc¸oise Clerget-Darpoux (Hôpital Paul Brousse, Villejuif), Philippe Couratier (CHU Limoges), Phillipe Corcia (CHU Tours), Mira Didic (CHU La Timone, Marseille), Bruno Dubois (Hôpital de la Salpêtrière, Paris), Charles Duyckaerts (Hôpital de la Salpêtrière, Paris), Véronique Golfier (CHU, Rennes), Didier Hannequin (Rouen University Hospital), Lucette Lacomblez (Hôpital de la Salpêtrière, Paris), Isabelle Le Ber (Hôpital de la Salpêtrière, Paris), Richard Levy (CHU Saint Antoine, Paris), Bernard-Franc¸ois Michel (CH Sainte-Marguerite, Marseille), Vincent Meininger (Hôpital de la Salpêtrière, Paris), Florence Pasquier (CHU, Lille), Catherine Thomas-Anterion (CHU Bellevue, Saint-Etienne), Michèle Puel (CHU Purpan, Toulouse), François Salachas (Hôpital de la Salpêtrière, Paris), François Sellal (CH Colmar), Martine Vercelletto (CHU Laennec, Nantes), Patrice Verpillat (Hôpital de la Salpêtrière, Paris), William Camu (CHU G. de Chauliac, Montpellier).

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.

Keywords: Amyotrophic lateral sclerosis, C9ORF72, frontotemporal dementia, frontotemporal lobar degeneration, protein TDP43

DOI: 10.3233/JAD-121456

Journal: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 485-499, 2013