Beck, J. et al. A distinct clinical, neuropsychological and radiological phenotype is associated with progranulin gene mutations in a large UK series. Brain 131, 706-720

MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
Brain (Impact Factor: 9.2). 04/2008; 131(Pt 3):706-20. DOI: 10.1093/brain/awm320
Source: PubMed


Mutations in the progranulin gene (GRN) are a major cause of frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) but the distinguishing clinical and anatomical features of this subgroup remain unclear. In a large UK cohort we found five different frameshift and premature termination mutations likely to be causative of FTLD in 25 affected family members. A previously described 4-bp insertion mutation in GRN exon 2 comprised the majority of cases in our cohort (20/25), with four novel mutations being identified in the other five affected members. Additional novel missense changes were discovered, of uncertain pathogenicity, but deletion of the entire gene was not detected. The patient collection was investigated by a single tertiary referral centre and is enriched for familial early onset FTLD with a high proportion of patients undergoing neuropsychological testing, MRI and eventual neuropathological diagnosis. Age at onset was variable, but four mutation carriers presented in their 40s and when analysed as a group, the mean age at onset of disease in GRN mutation carriers was later than tau gene (MAPT) mutation carriers and duration of disease was shorter when compared with both MAPT and FTLD-U without mutation. The most common clinical presentation seen in GRN mutation carriers was behavioural variant FTLD with apathy as the dominant feature. However, many patients had language output impairment that was either a progressive non-fluent aphasia or decreased speech output consistent with a dynamic aphasia. Neurological and neuropsychological examination also suggests that parietal lobe dysfunction is a characteristic feature of GRN mutation and differentiates this group from other patients with FTLD. MR imaging showed evidence of strikingly asymmetrical atrophy with the frontal, temporal and parietal lobes all affected. Both right- and left-sided predominant atrophy was seen even within the same family. As a group, the GRN carriers showed more asymmetry than in other FTLD groups. All pathologically investigated cases showed extensive type 3 TDP-43-positive pathology, including frequent neuronal cytoplasmic inclusions, dystrophic neurites in both grey and white matter and also neuronal intranuclear inclusions. Finally, we confirmed a modifying effect of APOE-E4 genotype on clinical phenotype with a later onset in the GRN carriers suggesting that this gene has distinct phenotypic effects in different neurodegenerative diseases.

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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.
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    • "On the other hand, cognitive impairment in CBD, once thought to be a rare or late feature, is indeed common and may present early in the course of the disease, sometimes before the onset of motor symptoms (Graham, Bak, & Hodges, 2003; Kelley et al., 2009; Lee et al., 2011; Vidailhet & Cochen, 2006). With respect to episodic memory, an increasing number of studies show altered performances in CBD patients (Beck et al., 2008; Cordato et al., 2001; Graham et al., 2003; Kertesz & McMonagle, 2010; Le Ber et al., 2008; Lee et al., 2011; Mathuranath et al., 2000; Matuszewski et al., 2009; Wenning et al., 1998). Apart from impaired executive test scores, our patient seemed unable to drive. "
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    • "PCA with additional medial temporal lobe (MTL) atrophy supports AD as the most likely cause however the MTL may initially be (relatively) spared in posterior variant AD (PCA), especially in early-onset cases.59 Visual rating of posterior atrophy in combination with MTL atrophy rating has been reported to help discriminate AD from FTD and AD from normal ageing with a sensitivity of 73% and specificity of 87%.60 Gross frontoparietal atrophy (extending into the temporal lobe) confined to a single hemisphere has been described in patients with progranulin mutations and should be considered in the presence of a strong family history.61–63 "
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