Higher Than Expected Progranulin Mutation Rate in a Case Series of Italian FTLD Patients

Tremolizzo, Lucio; Gelosa, Giorgio; Galbussera, Alessio; Isella, Valeria; Arosio, Cristina; Bertola, Francesca; Casati, Giorgio; Piperno, Alberto; Ferrarese, Carlo; Appollonio, Ildebrando

doi:10.1097/wad.0b013e31819e0cc5

Cited by 12 publications

(3 citation statements)

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“…Our results are placed in between an interval of previous data ranging from 9% (Tremolizzo et al 2009) to 1.6% (Borroni et al 2008) of the genetic contribution of GRN mutations in Italian FTLD cases. Both previously published data referred to a small geographical area in Northern Italy (Monza-Brianza) and one study analyzed 22 FTLD patients (Tremolizzo et al 2009), thus a discrepancy regarding frequency could be expected.…”

Section: Discussionsupporting

confidence: 72%

Progranulin Genetic Screening in Frontotemporal Lobar Degeneration Patients From Central Italy

et al. 2011

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Recently, mutations in the progranulin gene (GRN) were reported to account for the vast majority of Frontotemporal lobar Degeneration (FTLD) and a growing number of reports describe the implication of this gene in the development of the FTLD pathology with a significant variation in clinical features. To better clarify the contribution of GRN mutations to Italian FTLD, we screened 381 subjects: 171 cases and 210 healthy subjects, all from Central Italy, particularly of Tuscan origins. GRN gene was analyzed using High Resolution Melting Analysis and automated Genetic Analyzer. Human Progranulin ELISA Kit was employed to determine the plasma progranulin levels. The screening showed a total of six genetic variants in the GRN gene: 3 pathogenic and 3 non pathogenic in 13 out of 171 patients. The rare intronic variant IVS2 +7 G > A was found in one patient. The pathogenetic mutation, p.T272SfsX10, is confirmed as the most common GRN mutation in Italian FTLD patients with a frequency in our study of 2.32%. Moreover, we identified the first Italian patient with the p.R493X mutation, to date described in 43 families worldwide. Our data report, for the first time, the occurrence of GRN mutations in Tuscany, Central Italy, confirming that genetic variations in this gene could be a considerable genetic cause of FTLD and that genetic screening might be useful both in familial and sporadic FTLD patients.

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Section: Discussionsupporting

confidence: 72%

Progranulin Genetic Screening in Frontotemporal Lobar Degeneration Patients From Central Italy

et al. 2011

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“…In the family 3, the Thr272fs mutation was identified in GRN gene. It was first reported in an Italian family [43] and in other 34 Italian and one French families [44][45][46][47][48][49]. In the family 5, the IVS10+3G>A genetic mutation was identified in the MAPT gene.…”

Section: Discussionmentioning

confidence: 99%

Genetic counselling and testing for inherited dementia: single-centre evaluation of the consensus Italian DIAfN protocol

et al. 2020

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Background A consensus protocol for genetic counselling and testing of familial dementia, the Italian Dominantly Inherited Alzheimer’s and Frontotemporal Network (IT-DIAfN) protocol, has been developed in Italy by a network of expert dementia centres. The aim of this study is to evaluate feasibility and acceptability of the genetic counselling and testing process, as undertaken according to the IT-DIAfN protocol in one of the IT-DIAfN dementia research centres. Methods The protocol was tested by a multidisciplinary team at the IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy, on affected individuals with suspected inherited forms of Alzheimer’s disease (AD) or frontotemporal dementia (FTD), and to healthy at-risk relatives. The genetic counselling and testing process consisted of (i) pre-test consultation and psychological assessment (ii) genetic testing, (iii) genetic test result disclosure and (iv) follow-up consultation and psychological assessment. Results Twenty affected individuals from 17 families fulfilled the family history criteria of the IT-DIAfN protocol for suspected inherited dementia (17 for AD, 2 for FTD, 1 for inclusion body myopathy with Paget disease of bone and frontotemporal dementia) and were included in the protocol. Nineteen out of 20 affected individuals received the genetic test result (one left after the pre-test consultation being not ready to cope with an unfavourable outcome). A pathogenic mutation was found in 6 affected individuals (1 in PSEN1, 2 in PSEN2, 1 in GRN, 1 in MAPT, 1 in VCP). Eleven healthy at-risk relatives asked to undergo predictive testing and were included in the protocol. Three completed the protocol, including follow-up; one did not ask for the genetic test result after genetic testing; and eight withdrew before the genetic testing, mainly due to an increased awareness about the possible consequences of an unfavourable test result. To date, no catastrophic reactions were reported at the follow-up. Conclusions Our case series shows that a structured genetic counselling and testing protocol for inherited dementia can be implemented in both affected individuals and at-risk relatives in a research setting. The procedure was shown to be safe in terms of occurrence of catastrophic events. A formal validation in larger cohorts is needed.

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“…A frequência de mutações de GRN em casos famíliais de DFT foi mais alta do que a observada na França, Portugal, EUA e Reino Unido, mas similar à relatada na casuística italiana. Mutações de GRN são particularmente frequentes em casuísticas italianas, e foram encontradas em 24-71% dos casos familiais de DFT [351][352][353]. No norte da Itália, a mutação GRN p.T272Sfs*10 é a mais frequente, e os resultados de um estudo que realizou análise de haplótipos indicaram que a maior parte dos casos daquela região descendem de um único fundador 138,354.…”

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Pesquisa de mutações do gene GRN e dosagem plasmática de progranulina em casuística brasileira de degeneração lobar frontotemporal

Takada¹

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Introdução: A demência frontotemporal (DFT) inclui a variante comportamental da demência frontotemporal (vcDFT), a variante semântica da afasia progressiva primária (vsAPP), e a variante não fluente da APP (vnfAPP). Os genes em que são encontradas mutações causadoras de DFT mais frequentemente são: GRN (que codifica a progranulina), MAPT (que codifica a proteína tau) e C9orf72. Métodos: Foram incluídos probandos diagnosticados com vcDFT, vsAPP ou vnfAPP, com base com os critérios diagnósticos mais recentes, e um grupo de indivíduos cognitivamente normais. Os éxons 2-12 de GRN e os éxons 1, 9-13 de MAPT foram sequenciados pelo método de Sanger, e foi realizada dosagem de progranulina no plasma. Resultados: foram incluídos 62 probandos, sendo 44 com vcDFT, 9 com vsAPP, e 9 com vnfAPP. Antecedente familiar de demência foi positivo em 45,1% dos probandos, e de DFT, em 24,1%. Os 60 indivíduos do grupo controle tinham idade média de 60,8±8,5 anos. Foram identificadas seis mutações nulas em GRN (p.Q130X, p.V200Gfs*18, p.Q257Pfs*26, p.Q300X, p.S301Cfs*60 e p.D317Afs*11) e uma mutação patogênica em MAPT (p.N279K). A dosagem média de progranulina plasmática nos pacientes com mutações de GRN foi de 29,8±11,9ng/ml Conclusões: A frequência de mutações patogênicas em GRN nesta casuística foi de 9,6%, e a de mutações em MAPT foi de 1,6%. Entre casos familiais de DFT, a frequência de mutações em GRN foi de 33,3%, e em MAPT foi de 6,7%. Duas das mutações encontradas em GRN (p.Q130X e p.D317Afs*11) ainda não foram descritas em casos de DFT. O valor de corte de 70ng/ml identificou as mutações nulas de GRN com sensibilidade e especificidade de 100%. Descritores: degeneração lobar frontotemporal; demência frontotemporal; afasia primária progressiva não fluente; genética; tauopatias; proteinopatias TDP-43; mutação.

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Higher Than Expected Progranulin Mutation Rate in a Case Series of Italian FTLD Patients

Cited by 12 publications

References 6 publications

Progranulin Genetic Screening in Frontotemporal Lobar Degeneration Patients From Central Italy

Progranulin Genetic Screening in Frontotemporal Lobar Degeneration Patients From Central Italy

Genetic counselling and testing for inherited dementia: single-centre evaluation of the consensus Italian DIAfN protocol

Pesquisa de mutações do gene GRN e dosagem plasmática de progranulina em casuística brasileira de degeneração lobar frontotemporal

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