Exploring dementia and neuronal ceroid lipofuscinosis genes in 100 FTD-like patients from 6 towns and rural villages on the Adriatic Sea cost of Apulia

Abstract Frontotemporal dementia (FTD) refers to a complex spectrum of clinically and genetically heterogeneous disorders. Although fully penetrant mutations in several genes have been identified and can explain the pathogenic mechanisms underlying a great portion of the Mendelian forms of the disea...

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Autores principales:	Celeste Sassi, Rosa Capozzo, Monia Hammer, Chiara Zecca, Monica Federoff, Cornelis Blauwendraat, Nick Bernstein, Jinhui Ding, J. Raphael Gibbs, Timothy Price, Andrew Singleton, Giancarlo Logroscino
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2b986c3faac94510a60bac3aec6cea4f
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spelling	oai:doaj.org-article:2b986c3faac94510a60bac3aec6cea4f2021-12-02T13:18:01ZExploring dementia and neuronal ceroid lipofuscinosis genes in 100 FTD-like patients from 6 towns and rural villages on the Adriatic Sea cost of Apulia10.1038/s41598-021-85494-x2045-2322https://doaj.org/article/2b986c3faac94510a60bac3aec6cea4f2021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85494-xhttps://doaj.org/toc/2045-2322Abstract Frontotemporal dementia (FTD) refers to a complex spectrum of clinically and genetically heterogeneous disorders. Although fully penetrant mutations in several genes have been identified and can explain the pathogenic mechanisms underlying a great portion of the Mendelian forms of the disease, still a significant number of families and sporadic cases remains genetically unsolved. We performed whole exome sequencing in 100 patients with a late-onset and heterogeneous FTD-like clinical phenotype from Apulia and screened mendelian dementia and neuronal ceroid lipofuscinosis genes. We identified a nonsense mutation in SORL1 VPS domain (p.R744X), in 2 siblings displaying AD with severe language problems and primary progressive aphasia and a near splice-site mutation in CLCN6 (p.S116P) segregating with an heterogeneous phenotype, ranging from behavioural FTD to FTD with memory onset and to the logopenic variant of primary progressive aphasia in one family. Moreover 2 sporadic cases with behavioural FTD carried heterozygous mutations in the CSF1R Tyrosin kinase flanking regions (p.E573K and p.R549H). By contrast, only a minority of patients carried pathogenic C9orf72 repeat expansions (1%) and likely moderately pathogenic variants in GRN (p.C105Y, p.C389fs and p.C139R) (3%). In concert with recent studies, our findings support a common pathogenic mechanisms between FTD and neuronal ceroid lipofuscinosis and suggests that neuronal ceroid lipofuscinosis genes should be investigated also in dementia patients with predominant frontal symptoms and language impairments.Celeste SassiRosa CapozzoMonia HammerChiara ZeccaMonica FederoffCornelis BlauwendraatNick BernsteinJinhui DingJ. Raphael GibbsTimothy PriceAndrew SingletonGiancarlo LogroscinoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Celeste Sassi Rosa Capozzo Monia Hammer Chiara Zecca Monica Federoff Cornelis Blauwendraat Nick Bernstein Jinhui Ding J. Raphael Gibbs Timothy Price Andrew Singleton Giancarlo Logroscino Exploring dementia and neuronal ceroid lipofuscinosis genes in 100 FTD-like patients from 6 towns and rural villages on the Adriatic Sea cost of Apulia
description	Abstract Frontotemporal dementia (FTD) refers to a complex spectrum of clinically and genetically heterogeneous disorders. Although fully penetrant mutations in several genes have been identified and can explain the pathogenic mechanisms underlying a great portion of the Mendelian forms of the disease, still a significant number of families and sporadic cases remains genetically unsolved. We performed whole exome sequencing in 100 patients with a late-onset and heterogeneous FTD-like clinical phenotype from Apulia and screened mendelian dementia and neuronal ceroid lipofuscinosis genes. We identified a nonsense mutation in SORL1 VPS domain (p.R744X), in 2 siblings displaying AD with severe language problems and primary progressive aphasia and a near splice-site mutation in CLCN6 (p.S116P) segregating with an heterogeneous phenotype, ranging from behavioural FTD to FTD with memory onset and to the logopenic variant of primary progressive aphasia in one family. Moreover 2 sporadic cases with behavioural FTD carried heterozygous mutations in the CSF1R Tyrosin kinase flanking regions (p.E573K and p.R549H). By contrast, only a minority of patients carried pathogenic C9orf72 repeat expansions (1%) and likely moderately pathogenic variants in GRN (p.C105Y, p.C389fs and p.C139R) (3%). In concert with recent studies, our findings support a common pathogenic mechanisms between FTD and neuronal ceroid lipofuscinosis and suggests that neuronal ceroid lipofuscinosis genes should be investigated also in dementia patients with predominant frontal symptoms and language impairments.
format	article
author	Celeste Sassi Rosa Capozzo Monia Hammer Chiara Zecca Monica Federoff Cornelis Blauwendraat Nick Bernstein Jinhui Ding J. Raphael Gibbs Timothy Price Andrew Singleton Giancarlo Logroscino
author_facet	Celeste Sassi Rosa Capozzo Monia Hammer Chiara Zecca Monica Federoff Cornelis Blauwendraat Nick Bernstein Jinhui Ding J. Raphael Gibbs Timothy Price Andrew Singleton Giancarlo Logroscino
author_sort	Celeste Sassi
title	Exploring dementia and neuronal ceroid lipofuscinosis genes in 100 FTD-like patients from 6 towns and rural villages on the Adriatic Sea cost of Apulia
title_short	Exploring dementia and neuronal ceroid lipofuscinosis genes in 100 FTD-like patients from 6 towns and rural villages on the Adriatic Sea cost of Apulia
title_full	Exploring dementia and neuronal ceroid lipofuscinosis genes in 100 FTD-like patients from 6 towns and rural villages on the Adriatic Sea cost of Apulia
title_fullStr	Exploring dementia and neuronal ceroid lipofuscinosis genes in 100 FTD-like patients from 6 towns and rural villages on the Adriatic Sea cost of Apulia
title_full_unstemmed	Exploring dementia and neuronal ceroid lipofuscinosis genes in 100 FTD-like patients from 6 towns and rural villages on the Adriatic Sea cost of Apulia
title_sort	exploring dementia and neuronal ceroid lipofuscinosis genes in 100 ftd-like patients from 6 towns and rural villages on the adriatic sea cost of apulia
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/2b986c3faac94510a60bac3aec6cea4f
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Exploring dementia and neuronal ceroid lipofuscinosis genes in 100 FTD-like patients from 6 towns and rural villages on the Adriatic Sea cost of Apulia

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