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Multicenter Study
. 2008 Mar;131(Pt 3):732-46.
doi: 10.1093/brain/awn012. Epub 2008 Feb 1.

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

Isabelle Le Ber  1 , Agnès Camuzat, Didier Hannequin, Florence Pasquier, Eric Guedj, Anne Rovelet-Lecrux, Valérie Hahn-Barma, Julie van der Zee, Fabienne Clot, Serge Bakchine, Michèle Puel, Mustapha Ghanim, Lucette Lacomblez, Jacqueline Mikol, Vincent Deramecourt, Pascal Lejeune, Vincent de la Sayette, Serge Belliard, Martine Vercelletto, Christian Meyrignac, Christine Van Broeckhoven, Jean-Charles Lambert, Patrice Verpillat, Dominique Campion, Marie-Odile Habert, Bruno Dubois, Alexis Brice; French research network on FTD/FTD-MND
Affiliations
Multicenter Study

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

Isabelle Le Ber et al. Brain. 2008 Mar.

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.

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