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Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study
- Source :
- Brain-A Journal of Neurology, Brain-A Journal of Neurology, Oxford University Press (OUP), 2008, 131 (Pt 3), pp.732-46. ⟨10.1093/brain/awn012⟩, Brain-A Journal of Neurology, 2008, 131 (Pt 3), pp.732-46. ⟨10.1093/brain/awn012⟩, Brain
- Publication Year :
- 2008
- Publisher :
- Oxford University Press (OUP), 2008.
-
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.
- Subjects :
- Male
Pathology
Neuropsychological Tests
MESH: Epidemiologic Methods
MESH: Aphasia, Primary Progressive
Apraxia
MESH: Magnetic Resonance Imaging
Primary progressive aphasia
Progranulins
MESH: Aged, 80 and over
0302 clinical medicine
MESH: Motor Neuron Disease
Corticobasal degeneration
Age of Onset
MESH: Brain Mapping
MESH: Heterozygote
Aged, 80 and over
MESH: Aged
Brain Mapping
0303 health sciences
MESH: Middle Aged
Parkinsonism
Brain
MESH: Neuropsychological Tests
Middle Aged
Magnetic Resonance Imaging
MESH: Dementia
3. Good health
Phenotype
Disease Progression
Intercellular Signaling Peptides and Proteins
Female
MESH: Disease Progression
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Psychology
Haploinsufficiency
Frontotemporal dementia
Adult
Heterozygote
medicine.medical_specialty
MESH: Mutation
MESH: Age of Onset
MESH: Phenotype
MESH: Brain
03 medical and health sciences
medicine
Humans
Dementia
Motor Neuron Disease
MESH: Intercellular Signaling Peptides and Proteins
Aged
030304 developmental biology
MESH: Humans
Lewy body
MESH: Adult
medicine.disease
MESH: Male
MESH: Cognition Disorders
Aphasia, Primary Progressive
Mutation
Neurology (clinical)
Cognition Disorders
Epidemiologic Methods
MESH: Female
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 14602156 and 00068950
- Volume :
- 131
- Database :
- OpenAIRE
- Journal :
- Brain
- Accession number :
- edsair.doi.dedup.....e07accc721ca43c87e20b564df45d077