Phenotypic Heterogeneity of the GRN Asp22fs Mutation in a Large Italian Kindred

Pietroboni, Anna M.; Fumagalli, Giorgio; Ghezzi, Laura; Fenoglio, Chiara; Cortini, Francesca; Serpente, María; Cantoni, Claudia; Rotondo, Emanuela; Corti, Priscilla; Carecchio, Miryam; Bassi, Maria Teresa; Bresolin, Nereo; Galbiati, Domenico; Galimberti, Daniela; Scarpini, Elio

doi:10.3233/jad-2011-101704

Cited by 56 publications

(29 citation statements)

References 20 publications

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“…White matter changes such as gliosis and demyelination have long been observed in histological studies of FTD (Englund & Brun, 1987) and several groups have observed significant WMH on MRI brain scans of GRN mutation carriers with FTD who lack vascular risk factors (Caroppo et al, 2014; Ameur et al, 2016; Kelley et al, 2009; Le Ber et al, 2008; Paternicò et al, 2016; Pietroboni et al, 2011; Sudre et al, 2017). However, studies that have characterized in detail the pathological correlates of WMH in GRN mutation associated FTD have until now been lacking.…”

Section: Discussionmentioning

confidence: 99%

“…However, WMH are less commonly seen in frontotemporal dementia (FTD). Several studies have now reported prominent WMH in patients with familial FTD due to progranulin ( GRN ) mutations (Caroppo et al, 2014; Ameur et al, 2016; Kelley et al, 2009; Le Ber et al, 2008; Paternicò et al, 2016; Pietroboni et al, 2011; Sudre et al, 2017) but the pathological changes underlying these have not previously been studied in detail.…”

Section: Introductionmentioning

confidence: 99%

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Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia

et al. 2018

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White matter hyperintensities (WMH) are often seen on MRI brain scans in frontotemporal dementia (FTD) due to progranulin (GRN) mutations, but their pathological correlates are unknown. We examined the histological changes underlying WMH in a patient with GRN mutation associated behavioral variant FTD. In vivo and cadaveric MRI showed progressive, asymmetric frontotemporal and parietal atrophy, and asymmetrical WMH predominantly affecting frontal mid-zones. We first performed segmentation and localization analyses of WMH present on cadaveric MRI FLAIR images, then selected five different brain regions directly matched to differing severities of WMH for histological analysis. We used immunohistochemistry to assess vascular pathology, degree of spongiosis, neuronal and axonal loss, TDP-43, demyelination and astrogliosis, and microglial burden and morphology. Brain regions with significant WMH displayed severe cortical and white matter pathology, and prominent white matter microglial activation and microglial dystrophy, but only mild axonal loss and minimal vascular pathology. Our study suggests that WMH in GRN mutation carriers are not secondary to vascular pathology. Whilst cortical pathology induced axonal degeneration could contribute to white matter damage, individuals with GRN mutations could develop selective white matter vulnerability and myelin loss due to chronic, regional microglial dysfunction arising from GRN haploinsufficiency.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia

et al. 2018

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“…Some individuals with familial FTD caused by GRN mutations had a biomarker profile typical of AD, with decreased Aβ 42 and increased p-tau and t-tau CSF levels [36,37]. However, in other cases, p-tau and t-tau levels were within normal range [38,39]. C9ORF72 repeat expansion carriers were found to have either CSF profiles within a normal range or profiles similar to those of AD patients, with decreased Aβ 42 and increased p-tau and t-tau levels [39,40,41,42,43].…”

Section: Resultsmentioning

confidence: 99%

Cerebrospinal Fluid Biomarkers in Familial Forms of Alzheimer's Disease and Frontotemporal Dementia

Rostgaard

Waldemar

Nielsen

et al. 2015

Dement Geriatr Cogn Disord

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As dementia is a fast-growing health care problem, it is becoming an increasingly urgent need to provide an early diagnosis in order to offer patients the best medical treatment and care. Validated biomarkers which reflect the pathology and disease progression are essential for diagnosis and are important when developing new therapies. Today, the core protein biomarkers amyloid-β₄₂, total tau and phosphorylated tau in the cerebrospinal fluid (CSF) are used to diagnose Alzheimer's disease (AD), because these biomarkers have shown to reflect the underlying amyloid and tau pathology. However, the biomarkers have proved insufficient predictors of dementias with a different pathology, e.g. frontotemporal dementia (FTD); furthermore, the biomarkers are not useful for early AD diagnosis. Familial dementias with a known disease-causing mutation can be extremely valuable to study; yet the biomarker profiles in patients with familial dementias are not clear. This review summarizes CSF biomarker findings from studies on symptomatic and presymptomatic individuals carrying a mutation in one of the genes known to cause early-onset familial AD or FTD. In conclusion, the biomarker profile of inherited AD is quite similar between carriers of different mutations as well as similar to the profile found in sporadic AD, whereas familial FTD does not seem to have a clear biomarker profile. Hence, new biomarkers are needed for FTD.

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“…The serum PGRN levels of the 6 AD patients with an atypical CSF biomarker profile were similar to the ones in the typical-AD CSF profile group. So far, only a few patients clinically diagnosed with MCI or AD have been identified with PGRN mutations [38,39,40,41]. …”

Section: Discussionmentioning

confidence: 99%

“…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]. All pathogenic mutations identified so far are loss of function mutations, most of them leading to premature termination codons, and are predicted to be degraded by nonsense-mediated mRNA decay, producing null alleles [15,16,46].…”

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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Phenotypic Heterogeneity of the GRN Asp22fs Mutation in a Large Italian Kindred

Cited by 56 publications

References 20 publications

Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia

Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia

Cerebrospinal Fluid Biomarkers in Familial Forms of Alzheimer's Disease and Frontotemporal Dementia

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

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