Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study.
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.
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Isabelle
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1INSERM, UMR_S679 Neurologie & Thérapeutique Expérimentale, F-75013, Paris, France.
Camuzat
Agnès
A
Hannequin
Didier
D
Pasquier
Florence
F
Guedj
Eric
E
Rovelet-Lecrux
Anne
A
Hahn-Barma
Valérie
V
van der Zee
Julie
J
Clot
Fabienne
F
Bakchine
Serge
S
Puel
Michèle
M
Ghanim
Mustapha
M
Lacomblez
Lucette
L
Mikol
Jacqueline
J
Deramecourt
Vincent
V
Lejeune
Pascal
P
de la Sayette
Vincent
V
Belliard
Serge
S
Vercelletto
Martine
M
Meyrignac
Christian
C
Van Broeckhoven
Christine
C
Lambert
Jean-Charles
JC
Verpillat
Patrice
P
Campion
Dominique
D
Habert
Marie-Odile
MO
Dubois
Bruno
B
Brice
Alexis
A
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
C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins