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

Isabelle Le Ber; Agnès Camuzat; Lena Guillot-Noel; Didier Hannequin; Lucette Lacomblez; Véronique Golfier; Michèle Puel; Olivier Martinaud; Vincent Deramecourt; Sophie Rivaud-Pechoux; Stéphanie Millecamps; Martine Vercelletto; Philippe Couratier; François Sellal; Florence Pasquier; François Salachas; Catherine Thomas-Antérion; Mira Didic; Jérémie Pariente; Danielle Seilhean; Merle Ruberg; Isabelle Wargon; Frédéric Blanc; William Camu; Bernard-François Michel; Eric Berger; Mathilde Sauvée; Christel Thauvin-Robinet; Karl Mondon; Elisabeth Tournier-Lasserve; Cyril Goizet; Marie Fleury; Gabriel Viennet; Patrice Verpillat; Vincent Meininger; Charles Duyckaerts; Bruno Dubois; Alexis Brice

doi:10.3233/JAD-121456

Article dans une revue

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, *}

* Auteur correspondant

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 Service 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

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.

Type de document :

Article dans une revue

Domaine :

Sciences du Vivant [q-bio] / Santé publique et épidémiologie

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https://hal-unilim.archives-ouvertes.fr/hal-00924796
Contributeur : Elisabeth Grelier Connectez-vous pour contacter le contributeur
Soumis le : mardi 7 janvier 2014 - 10:53:59
Dernière modification le : jeudi 20 janvier 2022 - 11:42:01

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

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