Clinicopathologic correlation in PGRN mutations

Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
Neurology (Impact Factor: 8.29). 10/2007; 69(11):1113-21. DOI: 10.1212/01.wnl.0000267701.58488.69
Source: PubMed


Frontotemporal dementia (FTD) has been linked to the microtubule associated protein tau (MAPT) gene region of chromosome 17. However, many chromosome-17 linked FTLDs do not have MAPT mutations or tau protein deposits, but have ubiquitin positive, tau and alpha-synuclein negative inclusions. Mutations in the progranulin (PGRN) gene, located 1.7 Mb from MAPT at 17q21.31, were recently discovered in some of these individuals. The pathologic phenotype in all cases has thus far included ubiquitinated neuronal intranuclear inclusions (NIIs) and neuronal cytoplasmic inclusions (NCIs).
PGRN mutation analysis was performed in 12 individuals. Informed consent was obtained from next of kin under an IRB-approved protocol. We compared clinical and pathologic findings in those cases with and without PGRN mutations.
PGRN mutations were found in four patients, two with clinical FTD and a positive family history, and two with clinical primary progressive aphasia (PPA), one with and one without a family history. All four cases with, and five of eight cases without, PGRN mutations had ubiquitinated NCIs and NIIs. Brains of individuals with PGRN mutations are associated with more frequent frontal NCIs and dystrophic neurites, less frequent dentate gyrus NCIs, and more frequent striatal NIIs than FTLD-U cases without PGRN mutations.
PGRN mutations at 17q21 may occur in apparently sporadic frontotemporal lobar dementia with ubiquitinated inclusions cases and in cases presenting with either primary progressive aphasia or the behavioral variant of frontotemporal dementia. Some cases without PGRN mutations also have ubiquitinated neuronal intranuclear inclusions. Clinicopathologic differences are observed among individuals with and without PGRN mutations.

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    • "About 70–90% patients with PGRN mutations show a positive family history for dementia or parkinsonism and they account for only a few incidences of sporadic FTD.[30–33] PGRN mutation carriers display clinical heterogeneity, FTD being the most frequent followed by PNFA. It is evidenced that noncoding genetic variability in PGRN can affect the disease onset and progression in FTLD-U and amyotrophic lateral sclerosis (ALS). "
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    ABSTRACT: Frontotemporal lobar degeneration (FTLD) is a highly heterogenous group of progressive neurodegenerative disorders characterized by atrophy of prefrontal and anterior temporal cortices. Recently, the research in the field of FTLD has gained increased attention due to the clinical, neuropathological, and genetic heterogeneity and has increased our understanding of the disease pathogenesis. FTLD is a genetically complex disorder. It has a strong genetic basis and 50% of patients show a positive family history for FTLD. Linkage studies have revealed seven chromosomal loci and a number of genes including MAPT, PGRN, VCP, and CHMB-2B are associated with the disease. Neuropathologically, FTLD is classified into tauopathies and ubiquitinopathies. The vast majority of FTLD cases are characterized by pathological accumulation of tau or TDP-43 positive inclusions, each as an outcome of mutations in MAPT or PGRN, respectively. Identification of novel proteins involved in the pathophysiology of the disease, such as progranulin and TDP-43, may prove to be excellent biomarkers of disease progression and thereby lead to the development of better therapeutic options through pharmacogenomics. However, much more dissections into the causative pathways are needed to get a full picture of the etiology. Over the past decade, advances in research on the genetics of FTLD have revealed many pathogenic mutations leading to different clinical manifestations of the disease. This review discusses the current concepts and recent advances in our understanding of the genetics of FTLD.
    Annals of Indian Academy of Neurology 12/2010; 13(Suppl 2):S55-62. DOI:10.4103/0972-2327.74246 · 0.60 Impact Factor
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    • "Cases with and without GRN mutations have similar demographics but GRN cases often have greater language deficits (Van Deerlin et al. 2007). Pathologically, NCI and DN may be more frequent in the frontal cortex but less frequent in the DG in GRN cases (Hatanpaa et al. 2008; Davion et al. 2007). Moreover cases lacking GRN mutations may have a less severe pathology affecting the neocortex and striatum while NII are usually absent or infrequent (Mackenzie et al. 2006b). "
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    ABSTRACT: Studies suggest that frontotemporal lobar degeneration with transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP) is heterogeneous with division into four or five subtypes. To determine the degree of heterogeneity and the validity of the subtypes, we studied neuropathological variation within the frontal and temporal lobes of 94 cases of FTLD-TDP using quantitative estimates of density and principal components analysis (PCA). A PCA based on the density of TDP-43 immunoreactive neuronal cytoplasmic inclusions, oligodendroglial inclusions, neuronal intranuclear inclusions, and dystrophic neurites, surviving neurons, enlarged neurons, and vacuolation suggested that cases were not segregated into distinct subtypes. Variation in the density of the vacuoles was the greatest source of variation between cases. A PCA based on TDP-43 pathology alone suggested that cases of FTLD-TDP with progranulin (GRN) mutation segregated to some degree. The pathological phenotype of all four subtypes overlapped but subtypes 1 and 4 were the most distinctive. Cases with coexisting motor neuron disease (MND) or hippocampal sclerosis (HS) also appeared to segregate to some extent. We suggest: (1) pathological variation in FTLD-TDP is best described as a 'continuum' without clearly distinct subtypes, (2) vacuolation was the single greatest source of variation and reflects the 'stage' of the disease, and (3) within the FTLD-TDP 'continuum' cases with GRN mutation and with coexisting MND or HS may have a more distinctive pathology.
    Journal of Neural Transmission 12/2009; 117(2):227-39. DOI:10.1007/s00702-009-0350-6 · 2.40 Impact Factor
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    • "Previous studies on large series evaluated the genetic contribution of GRN mutations in FTD (Gass et al., 2006), or the neuropathological aspects of this disease (Mackenzie, 2007). Two series, based on pathological examination of FTLD-U cases, included basic clinical data collected retrospectively in smaller numbers of patients (Josephs et al., 2007; Davion et al., 2007). In a study that screened only for the GRN p.Arg493X mutation in patients with FTLD from North-America, 30 families had this mutation (20% of the cohort) due to a founder effect in 27 of the 30 families (Rademakers et al., 2007). "
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