Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study.

Isabelle Le Ber (1) , Agnès Camuzat (1) , Didier Hannequin (2, 3, 4) , Florence Pasquier (5) , Eric Guedj (6) , Anne Rovelet-Lecrux (3) , Valérie Hahn-Barma (7) , Julie van Der Zee (8) , Fabienne Clot (1) , Serge Bakchine (9) , Michèle Puel (10) , Mustapha Ghanim (1) , Lucette Lacomblez (11, 11) , Jacqueline Mikol (12) , Vincent Deramecourt (13) , Pascal Lejeune (14) , Vincent de La Sayette (15, 16) , Serge Belliard (17) , Martine Vercelletto (18) , Christian Meyrignac (19) , Christine van Broeckhoven (8) , Jean-Charles Lambert (20) , Patrice Verpillat (1) , Dominique Campion (2) , Marie-Odile Habert (21, 11) , Bruno Dubois (22, 23) , Alexis Brice (1, 11, 11)

1 Neurologie et thérapeutique expérimentale
2 Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques
3 Service de neurologie [Rouen]
4 Department of Genetics
5 Département de neurologie [Lille]
6 Service Central de Biophysique et de Médecine Nucléaire
7 Centre des Maladies Cognitives et Comportementales [Paris]
8 Neurodegenerative Brain Diseases Group, Department of Molecular Genetics
9 URCA - Université de Reims Champagne-Ardenne
10 Neurologie générale et maladies inflammatoires du système nerveux [Toulouse]
11 CHU Pitié-Salpêtrière [AP-HP]
12 Service d′Anatomie et de Cytologie Pathologiques [Lariboisiere]
13 Neuroendocrinologie et physiopathologie neuronale
14 Centre Hospitalier Intercommunal
15 Laboratoire de Neuropsychologie
16 Service de Neurologie [CHU Caen]
17 Service de neurologie [Rennes]
18 Clinique neurologique
19 Service de neurologie
20 Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations
21 LIF - Laboratoire d'Imagerie Fonctionnelle
22 Neuro-anatomie fonctionnelle du comportement et de ses troubles
23 Centre du Langage et de Neuropsychologie

Frontotemporal dementia (FTD), characterized by behavioural and language disorders, is a clinically, genetically and pathologically heterogeneous group of diseases. The most recently identified of the four known genes is GRN, associated with 17q-linked FTD with ubiquitin-immunoreactive inclusions. GRN was analysed in 502 probands with frontal variant FTD (fvFTD), FTD with motoneuron disease (FTD-MND), primary progressive aphasia (PPA) and corticobasal degeneration syndrome (CBDS). We studied the clinical, neuropsychological and brain perfusion characteristics of mutation carriers. Eighteen mutations, seven novel were found in 24 families including 32 symptomatic mutation carriers. No copy number variation was found. The phenotypes associated with GRN mutations vary greatly: 20/32 (63%) carriers had fvFTD, the other (12/32, 37%) had clinical diagnoses of PPA, CBDS, Lewy body dementia or Alzheimer's disease. Parkinsonism developed in 13/32 (41%), visual hallucinations in 8/32 (25%) and motor apraxia in 5/21 (24%). Constructional disorders were present in 10/21 (48%). Episodic memory disorders were frequent (16/18, 89%), consistent with hippocampal amnestic syndrome in 5/18 (28%). Hypoperfusion was observed in the hippocampus, parietal lobe and posterior cingulate gyrus, as well as the frontotemporal cortices. The frequency of mutations according to phenotype was 5.7% (20/352) in fvFTD, 17.9% (19/106) in familial forms, 4.4% in PPA (3/68), 3.3% in CBDS (1/30). Hallucinations, apraxia and amnestic syndrome may help differentiate GRN mutation carriers from others FTD patients. Variable phenotypes and neuropsychological profiles, as well as brain perfusion profiles associated with GRN mutations may reflect different patterns of neurodegeneration. Since all the mutations cause a progranulin haploinsufficiency, additional factors probably explain the variable clinical presentation of the disease.

Domaines: Neurosciences [q-bio.NC]

Isabelle Le Ber, Agnès Camuzat, Didier Hannequin, Florence Pasquier, Eric Guedj, et al.. Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study.. Brain - A Journal of Neurology , 2008, 131 (Pt 3), pp.732-46. ⟨10.1093/brain/awn012⟩. ⟨hal-00280762⟩