Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration

Chen‐Plotkin, Alice S.; Martinez‐Lage, Maria; Sleiman, Patrick; Hu, William T.; Greene, Robert A.; Wood, Elisabeth McCarty; Bing, Shaoxu; Grossman, Murray; Schellenberg, Gerard D.; Hatanpaa, Kimmo J.; Weiner, Myron; White, Charles L.; Brooks, William S.; Halliday, Glenda M.; Kril, Jillian J.; Gearing, Marla; Beach, Thomas G.; Graff‐Radford, Neill R.; Dickson, Dennis W.; Rademakers, Rosa; Boeve, Bradley F.; Pickering‐Brown, Stuart; Snowden, Julie S.; Swieten, John C. van; Heutink, Peter; Seelaar, Harro; Murrell, Jill R.; Ghetti, Bernardino; Spina, Salvatore; Grafman, Jordan; Kaye, Jeffrey; Woltjer, Randall L.; Mesulam, Marsel; Bigio, Eileen H.; Lladó, Albert; Miller, Bruce L.; Alzualde, Ainhoa; Moreno, Fermín; Rohrer, Jonathan D.; Mackenzie, Ian R.; Feldman, Howard; Hamilton, Ronald L.; Cruts, Marc; Engelborghs, Sebastiaan; Deyn, Peter Paul De; Broeckhoven, Christine Van; Bird, Thomas D.; Cairns, Nigel J.; Goate, Alison M.; Frosch, Matthew P.; Riederer, Peter; Bogdanović, Nenad; Lee, Virginia M.‐Y.; Trojanowski, John Q.; Deerlin, Vivianna M. Van

doi:10.1001/archneurol.2011.53

Cited by 107 publications

(72 citation statements)

References 44 publications

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“…Mutations of the progranulin (GRN) gene on chromosome 17 represents another common cause of autosomal dominant FTD, accounting for approximately 5-11 % of all FTD cases and 6.8-23 % of familial FTD [19,[21][22][23]. Hallucinations are reported in 25 % of FTD patients with progranulin mutations and delusions in ∼6 % [9].…”

Section: Grn and Psychosismentioning

confidence: 99%

Psychotic Symptoms in Frontotemporal Dementia

Hall

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2015

Curr Neurol Neurosci Rep

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Although psychotic features have long been recognized in association with frontotemporal dementia (FTD), recent genetic discoveries enabling further subtyping of FTD have revealed that psychotic symptoms are frequent in some forms of FTD. Hallucinations and delusions can even precede onset of other cognitive or behavioural symptoms in patients with FTD. In this review, we explore the frequency and types of psychotic symptoms reported in patients with FTD, as well as in other neuropsychiatric disorders, to aid practitioners' consideration of these features in the diagnosis of FTD and related disorders.

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Section: Grn and Psychosismentioning

confidence: 99%

Psychotic Symptoms in Frontotemporal Dementia

Hall

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2015

Curr Neurol Neurosci Rep

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“…In subpopulations of patients with familial FTLD, the GRN mutation frequency can be up to 26% [8,9] . The spectrum of clinical presentations associated with mutations in GRN is highly heterogeneous and may also include progressive supranuclear palsy, CBD, AD, dementia with Lewy bodies (DBL), Parkinson disease and amyotrophic lateral sclerosis [5,10,11] . All GRN mutations identified thus far cause disease through a uniform disease mechanism, i.e.…”

Section: Optimal Plasma Progranulin Cutoff Value For Predicting Null mentioning

confidence: 99%

Optimal Plasma Progranulin Cutoff Value for Predicting Null Progranulin Mutations in Neurodegenerative Diseases: A Multicenter Italian Study

et al. 2011

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Background: Recently, attention was drawn to a role for progranulin in the central nervous system with the identification of mutations in the progranulin gene (GRN) as an important cause of frontotemporal lobar degeneration. GRN mutations are associated with a strong reduction of circulating progranulin and widely variable clinical phenotypes: thus, the dosage of plasma progranulin is a useful tool for a quick and inexpensive large-scale screening of carriers of GRN mutations. Objective: To establish the best cutoff threshold for normal versus abnormal levels of plasma progranulin. Methods: 309 cognitively healthy controls (25–87 years of age), 72 affected and unaffected GRN+ null mutation carriers (24–86 years of age), 3 affected GRN missense mutation carriers, 342 patients with neurodegenerative diseases and 293 subjects with mild cognitive impairment were enrolled at the Memory Clinic, IRCCS S. Giovanni di Dio-Fatebenefratelli, Brescia, Italy, and at the Alzheimer Unit, Ospedale Maggiore Policlinico and IRCCS Istituto Neurologico C. Besta, Milan, Italy. Plasma progranulin levels were measured using an ELISA kit (AdipoGen Inc., Seoul, Korea). Results: Plasma progranulin did not correlate with age, gender or body mass index. We established a new plasma progranulin protein cutoff level of 61.55 ng/ml that identifies, with a specificity of 99.6% and a sensitivity of 95.8%, null mutation carriers among subjects attending to a memory clinic. Affected and unaffected GRN null mutation carriers did not differ in terms of circulating progranulin protein (p = 0.686). A significant disease anticipation was observed in GRN+ subjects with the lowest progranulin levels. Conclusion: We propose a new plasma progranulin protein cutoff level useful for clinical practice.

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“…In FTLD populations, PGRN mutation frequency ranged from 5 to 26% (http://www.molgen.ua.ac.be/FTDmutations and Cruts et al [35]) and the spectrum of clinical presentation of the mutation carriers is considerably heterogeneous, even in family members carrying the same mutation [36,37]. Besides the classical FTLD presentations, PGRN mutation carriers have been associated with other clinical diagnosis such as mild cognitive impairment (MCI) [38], AD [39,40,41], Parkinson's disease [40], CBS [41,42,43] and progressive supranuclear palsy (PSP) [44,45].…”

Section: Introductionmentioning

confidence: 99%

Progranulin Peripheral Levels as a Screening Tool for the Identification of Subjects with Progranulin Mutations in a Portuguese Cohort

et al. 2013

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Background: Progranulin (PGRN) mutations are associated with different clinical phenotypes, including frontotemporal lobar degeneration (FTLD), corticobasal syndrome (CBS) and Alzheimer's disease (AD). As all pathogenic PGRN mutations identified so far cause disease through haploinsufficiency, determination of PGRN levels has been proposed as a reliable method to identify mutation carriers. Objective: To evaluate the accuracy of peripheral PGRN levels in the identification of the PGRN mutation carriers detected thus far in our Portuguese cohort. Methods: Serum PGRN levels were measured in 244 subjects (124 patients in the spectrum of FTLD, 2 asymptomatic descendants of a FTLD patient, 56 AD patients and 64 controls) by a novel commercial ELISA kit. Results: Low PGRN levels were detected in 7 individuals (5 behavioral variant frontotemporal dementia, 1 CBS, and 1 still clinically unaffected) that constituted the group of the null PGRN mutation carriers previously identified in our molecular diagnostic laboratory. The pathogenic mutations found consisted of 4 insertion-deletions, causing frameshifts resulting in premature stop codons, 3 of which were novel. In addition, a normal PGRN level was found in a patient harboring a novel missense variant. For this novel ELISA kit, we established a PGRN cut-off level that identified with 100% accuracy the pathogenic mutation carriers. Conclusion: This study supports the use of a novel assay for the determination of PGRN levels as a screening procedure to identify patients harboring null PGRN mutations. This approach would significantly decrease the required PGRN mutation analysis workload and should be extended to other clinical phenotypes than behavioral variant frontotemporal dementia and to apparently sporadic cases.

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Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration

Cited by 107 publications

References 44 publications

Psychotic Symptoms in Frontotemporal Dementia

Psychotic Symptoms in Frontotemporal Dementia

Optimal Plasma Progranulin Cutoff Value for Predicting Null Progranulin Mutations in Neurodegenerative Diseases: A Multicenter Italian Study

Progranulin Peripheral Levels as a Screening Tool for the Identification of Subjects with Progranulin Mutations in a Portuguese Cohort

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