title: Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study.
abstract: 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.
authors.affiliation: 1INSERM, UMR_S679 Neurologie & Thérapeutique Expérimentale, F-75013, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Le Ber
authors.forename: Agnès
authors.initials: A
authors.lastname: Camuzat
authors.forename: Didier
authors.initials: D
authors.lastname: Hannequin
authors.forename: Florence
authors.initials: F
authors.lastname: Pasquier
authors.forename: Eric
authors.initials: E
authors.lastname: Guedj
authors.forename: Anne
authors.initials: A
authors.lastname: Rovelet-Lecrux
authors.forename: Valérie
authors.initials: V
authors.lastname: Hahn-Barma
authors.forename: Julie
authors.initials: J
authors.lastname: van der Zee
authors.forename: Fabienne
authors.initials: F
authors.lastname: Clot
authors.forename: Serge
authors.initials: S
authors.lastname: Bakchine
authors.forename: Michèle
authors.initials: M
authors.lastname: Puel
authors.forename: Mustapha
authors.initials: M
authors.lastname: Ghanim
authors.forename: Lucette
authors.initials: L
authors.lastname: Lacomblez
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Mikol
authors.forename: Vincent
authors.initials: V
authors.lastname: Deramecourt
authors.forename: Pascal
authors.initials: P
authors.lastname: Lejeune
authors.forename: Vincent
authors.initials: V
authors.lastname: de la Sayette
authors.forename: Serge
authors.initials: S
authors.lastname: Belliard
authors.forename: Martine
authors.initials: M
authors.lastname: Vercelletto
authors.forename: Christian
authors.initials: C
authors.lastname: Meyrignac
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Lambert
authors.forename: Patrice
authors.initials: P
authors.lastname: Verpillat
authors.forename: Dominique
authors.initials: D
authors.lastname: Campion
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Habert
authors.forename: Bruno
authors.initials: B
authors.lastname: Dubois
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D018888:Aphasia, Primary Progressive / Q000235:genetics; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D001931:Brain Mapping / Q000379:methods; D003072:Cognition Disorders / Q000209:etiology; D003704:Dementia / Q000235:genetics* / Q000473:pathology / Q000523:psychology; D018450:Disease Progression; D004812:Epidemiologic Methods; D005260:Female; D006579:Heterozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000235:genetics; D009154:Mutation; D009483:Neuropsychological Tests; D010641:Phenotype; D000077153:Progranulins
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins