Le Ber, I. et al. Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study. Brain 131, 732-746

1INSERM, UMR_S679 Neurologie & Thérapeutique Expérimentale, F-75013, Paris, France.
Brain (Impact Factor: 9.2). 04/2008; 131(Pt 3):732-46. DOI: 10.1093/brain/awn012
Source: PubMed


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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    • "The left middle temporal gyrus, which is early and consistently involved in this study, is implicated in language and semantic processing as well as in the recognition and retrieval of semantic information [22]. The involvement of this region fits well with clinical presentation of language disorders, especially agrammatic/nonfluent variant of FTD, characterizing a subset of GRN patients [1] [3]. The lateral temporal lobe also plays a role in theory of mind [23] that is one of the first detectable cognitive deficits in the early stage of FTD, and that significantly decreases in GRN carriers approaching the age of onset of the disease [16]. "
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    ABSTRACT: The preclinical stage of frontotemporal lobar degeneration (FTLD) is not well characterized. We conducted a brain metabolism (FDG-PET) and structural (cortical thickness) study to detect early changes in asymptomatic GRN mutation carriers (aGRN+) that were evaluated longitudinally over a 20-month period. At baseline, a left lateral temporal lobe hypometabolism was present in aGRN+ without any structural changes. Importantly, this is the first longitudinal study and, across time, the metabolism more rapidly decreased in aGRN+ in lateral temporal and frontal regions. The main structural change observed in the longitudinal study was a reduction of cortical thickness in the left lateral temporal lobe in carriers. A limit of this study is the relatively small sample (n = 16); nevertheless, it provides important results. First, it evidences that the pathological processes develop a long time before clinical onset, and that early neuroimaging changes might be detected approximately 20 years before the clinical onset of disease. Second, it suggests that metabolic changes are detectable before structural modifications and cognitive deficits. Third, both the baseline and longitudinal studies provide converging results implicating lateral temporal lobe as early involved in GRN disease. Finally, our study demonstrates that structural and metabolic changes could represent possible biomarkers to monitor the progression of disease in the presymptomatic stage toward clinical onset.
    Full-text · Article · Sep 2015 · Journal of Alzheimer's disease: JAD
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    • "Among FTD with a known genetic background, psychotic symptoms have been found to be especially common in both progranulin and C9ORF72 carriers, sometimes even presenting years before dementia onset (Shinagawa et al., 2014). One study reported a prevalence of psychotic symptoms in 25% of progranulin mutation carriers (Le Ber et al., 2008), and in C9ORF72 carriers, various studies found a prevalence of around 50% or even more (Sha et al., 2012; Snowden et al., 2012). "
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    ABSTRACT: Background: Frontotemporal dementia (FTD) constitutes a spectrum of neurodegenerative disorders associated with degeneration of, predominantly, the frontal and temporal lobes. The clinical heterogeneity is evident, and early diagnosis is a challenge. The primary objectives were to characterize psychotic symptoms, initial clinical diagnoses and family history in neuropathologically verified FTD-patients and to analyze possible correlations with different neuropathological findings. Methods: The medical records of 97 consecutive patients with a neuropathological diagnosis of frontotemporal lobar degeneration (FTLD) were reevaluated. Psychotic symptoms (hallucinations, delusions, paranoid ideas), initial diagnosis and family history for psychiatric disorders were analyzed. Results: Psychotic symptoms were present in 31 patients (32%). There were no significant differences in age at onset, disease duration or gender between patients with and without psychotic symptoms. Paranoid ideas were seen in 20.6%, and hallucinations and delusions in 17.5% in equal measure. Apart from a strong correlation between psychotic symptoms and predominantly right-sided brain degeneration, the majority of patients (77.4%) were tau-negative. Only 14.4% of the patients were initially diagnosed as FTD, while other types of dementia were seen in 34%, other psychiatric disorders in 42%, and 9.2% with other cognitive/neurological disorders. The patients who were initially diagnosed with a psychiatric disorder were significantly younger than the patients with other initial clinical diagnoses. A positive heredity for dementia or other psychiatric disorder was seen in 42% and 26% of the patients respectively. Conclusions: Psychotic symptoms, not covered by current diagnostic criteria, are common and may lead to clinical misdiagnosis in FTD.
    Full-text · Article · Dec 2014 · International Psychogeriatrics
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    • "Granulin (GRN) gene has been identified as a major cause of autosomal dominant FTLD, leading to TDP-43 inclusions by a haploinsufficiency mechanism (Cruts et al., 2006; Toh et al., 2011). FTLD patients carrying GRN mutations clinically present unpredictable phenotypic variability even within families carrying the same mutation (Beck et al., 2008; Bruni et al., 2007; Chen-Plotkin et al., 2011; Kelley et al., 2009; Larner, 2012; Le Ber 2008; Li et al., 2008; Moreno et al., 2009; Pickering-Brown et al., 2008; Rademakers et al., 2007; van Swieten and Heutink, 2008; Yu et al., 2010), and bvFTD and avPPA represent the most frequent pictures. Aim of the present study was to dissect clinical heterogeneity in patients carrying the same GRN mutation. "
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    ABSTRACT: Phenotype in patients with granulin (GRN) mutations is unpredictable, ranging from behavioral variant frontotemporal dementia (bvFTD) to agrammatic variant of primary progressive aphasia (avPPA). To date the wide clinical variability of FTLD-GRN remains unexplained. The aim of the study was to identify genetic pathways differentiating phenotypic expression in patients carrying GRN mutations. Patients carrying the same GRNT272SfsX10 mutation were enrolled, a careful clinical assessment was carried out, and the diagnosis of either bvFTD (n = 10, age = 63.9 ± 9.4) or avPPA (n = 6, age = 58.8 ± 4.7) was done. Microarray gene expression analysis on leukocytes was performed. Genes differentially expressed between the groups were validated by real time polymerase chain reaction considering an age-matched healthy controls group (n = 16, age = 58.4 ± 10.7). We further considered a group of FTD with no GRN mutations (GRN-) (n = 21, 13 bvFTD, and 8 avPPA) for comparisons. Real-time polymerase chain reaction (PCR) confirmed a significant decrease in leukocytes mRNA messenger RNA (mRNA) levels of RAP1GAP in bvFTD patients as compared with avPPA (p = 0.049). This finding was specific for patients with GRN mutations, as we did not observe this pattern in FTD GRN-patients (p = 0.99). The alteration of RAP1GAP mRNA levels may explain the clinical variability of GRN-FTLD patients. This is the first report linking a molecular pathway to specific phenotype expression in FTLD-GRN. To understand the clinical relevance of our early results it will be mandatory to extend the observation to other clinical and neuropathological series.
    Full-text · Article · Nov 2013 · Neurobiology of aging
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