Phenotype Variability in Progranulin Mutation Carriers: A Clinical, ‎Neuropsychological, Imaging and Genetic Study

3515's picture
Journal Title, Volume, Page: 
Brain. , 131(Pt 3):732-46
Year of Publication: 
2008
Authors: 
Mustapha Ghanim
INSERM, UMR_S679 Neurologie & The¤rapeutique Expe¤rimentale, F-75013
Current Affiliation: 
Faculty of Medicine & Health Sciences, Department of Biomedical Sciences, An-Najah National University, Nablus, Palestine
Isabelle Le Ber
INSERM, UMR_S679 Neurologie & The¤rapeutique Expe¤rimentale, F-75013
Didier Hannequin
INSERM U614 and Department of Neurology, Rouen University Hospita
Agnes Camuzat
INSERM, UMR_S679 Neurologie & The¤rapeutique Expe¤rimentale, F-75013
Florence Pasquier
Department of Neurology and EA2691, University Hospital, Lille
Eric Guedj
Service Central de Biophysique et Medecine Nucle¤aire, Hopital de la Timone, APHM
Anne Rovelet-Lecrux
INSERM U614 and Department of Neurology, Rouen University Hospita
Valerie Hahn-Barma
AP-HP, Pitie -Salpetriere Hospital, Centre des Maladies Cognitives et Comportementales, Paris
Julie van der Zee
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium
Fabienne Clot
INSERM, UMR_S679 Neurologie & The¤rapeutique Expe¤rimentale, F-75013
Serge Bakchine
Service de Neurologie, CHU Maison Blanche, Reims
Michele Pue
Service de Neurologie, CHU Purpan, Toulouse
Lucette Lacomblez
AP-HP, Hopital de la Salpetriere, F-75013
Jacqueline Mikol
Service d’ Anatomie et Cytologie Pathologiques, Hopital Lariboisiere, Paris
Vincent Deramecourt
Department of Neurology and EA2691, University Hospital, Lille
Pascal Lejeune
Service de Neurologie, Centre Hospitalier Departemental, La Roche sur Yon
Vincent de la Sayette
Service de Neurologie, CHU Cote de nacre, Caen
Serge Belliard
Service de Neurologie, CHU, Rennes
Martine Vercelletto
Service de Neurologie, CHU Guillaume et Rene Laennec, Nantes
Christian Meyrignac
Service de Neurologie, Centre Hospitalier Intercommunal, Creteil
Christine Van Broeckhoven
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium
Jean-Charles Lambert
INSERM U744, Institut Pasteur, Lille
Patrice Verpillat
INSERM, UMR_S679 Neurologie & The¤rapeutique Expe¤rimentale, F-75013
Dominique Campion
INSERM U614 and Department of Neurology, Rouen University Hospital
Marie-Odile Habert
Department of Nuclear Medicine, CHU Pitie -Salpetriere, AP-HP, Universite Pierre et Marie Curie-Paris6, INSERM U678, Paris, F-75013
Bruno Dubois
AP-HP, Hopital de la Salpetriere, F-75013
Alexis Brice
AP-HP, Hopital de la Salpetriere, F-75013
French research network on FTD/FTD-MND
Preferred Abstract (Original): 
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.
AttachmentSize
Phenotype Variability in Progranulin Mutation Carriers: A Clinical, ‎Neuropsychological, Imaging and Genetic Study486.16 KB