Clinicopathologic correlation in
            <i>PGRN</i>
            mutations

Davion, S.; Johnson, Nancy; Weıntraub, Sandra; Mesulam, Marek-Marsel; Engberg, Anna; Mishra, Manjari; Baker, Matt; Adamson, Jennifer; Hutton, Michael; Rademakers, Rosa; Bigio, Eileen H.

doi:10.1212/01.wnl.0000267701.58488.69

Cited by 51 publications

(37 citation statements)

References 64 publications

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“…More recently, HDDD-2 was associated with ubiquitinpositive, tau-negative pathology due to a PGRN mutation 93 . Two familieswithnaPPA have been described, and this was associated with a PGRN mutation 94,95 . Other reports have described families with naPPA and a behavioral disorder due to a PGRN mutation 96,97 .…”

Section: Genetic Associations Of Nonfluent/agrammatic Primary Progresmentioning

confidence: 99%

The non-fluent/agrammatic variant of primary progressive aphasia

Grossman¹

2016

The Behavioral Neurology of Dementia

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In an era of disease-modifying treatments, the non-fluent/agrammatic variant of primary progressive aphasia (naPPA) may help screen for a specific cause of neurodegenerative disease. However, there are controversies surrounding the identification of naPPA. This review describes the characteristic features associated with this discrete, young-onset neurodegenerative condition. Patients with naPPA have a distinct limitation in language emphasizingtheir poor grammatical comprehension and expression, as well as a disorder of speech sound production. Imaging studies associate an impairment of this uniquely human language capacity with disruption of a large-scale neural network centered in left inferior frontal and anterior-superior temporal regions. This corresponds to thepathologic burden of disease anatomically focused in left inferior frontal and anterior-superior temporal regions. A review of the histopathology underlying naPPA relates this condition to frontotemporal lobar degeneration spectrum pathology involving the microtubuleassociated protein tau in a majority of cases. While much work remains to be done, these observations point to unique clinical-pathological correlations that can advance care for an important class of diseases while supplementing our knowledge of human cognitive neuroscience.

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Section: Genetic Associations Of Nonfluent/agrammatic Primary Progresmentioning

confidence: 99%

The non-fluent/agrammatic variant of primary progressive aphasia

Grossman¹

2016

The Behavioral Neurology of Dementia

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“…The loss of functional protein is mainly the result of loss of GRN transcript caused by NMD of transcripts containing PTCs (n 5 52) or by nuclear degradation of transcripts retaining the first intron due to splice-site mutations in intron 1 (n 5 2) Le Ber et al, 2007]. PTCs can be the result from nonsense mutations (n 5 12), splice-site mutations (n 5 10), and small insertions/deletions (n 5 30) Baker et al, 2006;Huey et al, 2006;Pickering-Brown et al, 2006Boeve et al, 2006;Masellis et al, 2006;Gass et al, 2006;Benussi et al, 2008;Bronner et al, 2007;Mesulam et al, 2007;Behrens et al, 2007;Leverenz et al, 2007;Bruni et al, 2007;Van Deerlin et al, 2007;Brouwers et al, 2007;Rademakers et al, 2007;Llado et al, 2007;Le Ber et al, 2007;Davion et al, 2007;Kelley et al, in press;Spina et al, 2007a;Mukherjee et al, 2008;Beck et al, 2008;Le Ber et al, 2008]. Second, loss of translation as a result of mutations affecting the Kozak sequence (n 5 4) Baker et al, 2006;Pickering-Brown et al, 2006;Boeve et al, 2006;Gass et al, 2006;Le Ber et al, 2008] and reduction of secreted protein due to missense mutations affecting the signal sequence (n 5 2) [Mukherjee et al, 2006;Gass et al, 2006;Kelley et al, in press;Mukherjee et al, 2008;Le Ber et al, 2008], results in reduced GRN.…”

Section: Grn Mutation Spectrum Null Mutationsmentioning

confidence: 99%

“…However, because of the clinical heterogeneity of GRN mutations, diagnostic screening should also be considered in other neurodegenerative diseases such as clinically diagnosed AD and PD without mutations in other known genes. Even in patients without obvious family history, genetic testing should be considered, since several GRN mutations were found in apparently sporadic patients Le Ber et al, 2007;Davion et al, 2007]. However, the predictive value of genetic testing is not very high because of several difficulties.…”

Section: Diagnostic Relevancementioning

confidence: 99%

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

2008

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Communicated by Mark H. PaalmanMutations in the gene encoding granulin (HUGO gene symbol GRN, also referred to as progranulin, PGRN), located at chromosome 17q21, were recently linked to tau-negative ubiquitin-positive frontotemporal lobar degeneration (FTLDU). Since then, 63 heterozygous mutations were identified in 163 families worldwide, all leading to loss of functional GRN, implicating a haploinsufficiency mechanism. Together, these mutations explained 5 to 10% of FTLD. The high mutation frequency, however, might still be an underestimation because not all patient samples were examined for all types of loss-of-function mutations and because several variants, including missense mutations, have a yet uncertain pathogenic significance. Although the complete phenotypic spectrum associated with GRN mutations is not yet fully characterized, it was shown that it is highly heterogeneous, suggesting the influence of modifying factors. A role of GRN in neuronal survival was suggested but the exact mechanism by which neurodegeneration and deposition of pathologic brain inclusions occur still has to be clarified. Hum Mutat 29(12), [1373][1374][1375][1376][1377][1378][1379][1380][1381][1382][1383][1384][1385][1386] 2008.

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“…This concept, defined as molecular nexopathies, hypothesized that GRN mutations cause a specific and preferential involvement of long intrahemispheric tracts between target networks and off-target pathways (i.e., temporoparietal regions). More research is needed to bridge the gap between molecular aspects of FTLD and the neuropathologic alterations driving the clinical and radiologic presentation (39,40). Large international initiatives with multimodal imaging techniques with high-level statistical tools are required to confirm and extend the field of the molecular nexopathies.…”

Section: Discussionmentioning

confidence: 99%

The Neuroimaging Signature of Frontotemporal Lobar Degeneration Associated with Granulin Mutations: An Effective Connectivity Study

et al. 2013

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It has been suggested that monogenic frontotemporal lobar degeneration (FTLD) due to Granulin (GRN) mutations might present a specific pattern of atrophy, as compared with FTLD GRN-negative disease. Recent literature has suggested that the study of functional neural networks, rather than regional structural damage, might better elucidate the pathogenic mechanisms, showing complex relationships among structural alterations observed with conventional neuroimaging. The aim of this study was to evaluate effective brain connectivity in FTLD patients carrying GRN mutations (GRN1), compared with FTLD patients without pathogenetic GRN mutations (GRN2) and healthy controls (HCs). Methods: Twenty-six FTLD patients (13 GRN1 and 13 GRN2 matched for age, sex, and phenotype) and 13 age-and sex-matched HCs underwent brain perfusion SPECT. Brain regions involved in FTLD (dorsolateral, anterior cingulate, orbitofrontal, posterior temporal, temporal pole, and parietal) were used as regions of interest to identify functionally interconnected areas. An effective connectivity (path) analysis was defined with a PC algorithm (named after its inventors Peter Spirtes and Clark Glymour) search procedure and structural equation fitting. Statistically significant differences among the 3 groups were determined. Results: The best-fitting model was obtained by the data-driven approach, and brain connectivity pathways resembling state-of-the-art anatomic knowledge were obtained. When GRN1 and GRN2 groups were considered, the former presented a selective bilateral parietotemporal disconnection, compared with GRN2 patients. Furthermore, in FTLD GRN1 patients an increased compensative connectivity of the temporal regions (temporal pole and posterior temporal cortices) was observed. Conclusion: The present work suggests that impairment of effective functional connectivity of the parietotemporal regions is the hallmark of GRNrelated FTLD. However, compensative mechanisms-which should be further investigated-may occur.Key Words: frontotemporal dementia; frontotemporal lobar degeneration; granulin; mutation; SPECT; path analysis Fr ontotemporal lobar degeneration (FTLD) is a common cause of young onset neurodegenerative dementia (1,2). FTLD is clinically and pathologically heterogeneous (3), and genetic factors play a significant role, with a genetic basis implicated in up to 40% of cases (4).Discovery of disease-causing mutations in the Granulin (GRN) and microtubule-associated protein t-(MAPT) genes and the expanded hexanucleotide repeat insertion within C9orf72 have allowed a giant step forward in the knowledge of causative mechanisms of FTLD. Accordingly, recent literature has carefully detailed the peculiar features of these genetic forms, with the attempt to facilitate early and accurate diagnosis.Autosomal-dominant inherited GRN disease has been associated with a varied clinical spectrum, ranging from behavioral variant frontotemporal dementia (bvFTD) to nonfluent/aggramatic subtypes of primary progressive aphasia (nfvPPA), and with a widespre...

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Clinicopathologic correlation in PGRN mutations

Cited by 51 publications

References 64 publications

The non-fluent/agrammatic variant of primary progressive aphasia

The non-fluent/agrammatic variant of primary progressive aphasia

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

The Neuroimaging Signature of Frontotemporal Lobar Degeneration Associated with Granulin Mutations: An Effective Connectivity Study

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