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Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies

See Josephs (doi:10.1093/brain/awx367) for a scientific commentary on this article. In many neurodegenerative disorders, familial forms have provided important insights into the pathogenesis of their corresponding sporadic forms. The first mutations associated with frontotemporal lobar degeneration...

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Autores principales: Forrest, Shelley L, Kril, Jillian J, Stevens, Claire H, Kwok, John B, Hallupp, Marianne, Kim, Woojin S, Huang, Yue, McGinley, Ciara V, Werka, Hellen, Kiernan, Matthew C, Götz, Jürgen, Spillantini, Maria Grazia, Hodges, John R, Ittner, Lars M, Halliday, Glenda M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888940/
https://www.ncbi.nlm.nih.gov/pubmed/29253099
http://dx.doi.org/10.1093/brain/awx328
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author Forrest, Shelley L
Kril, Jillian J
Stevens, Claire H
Kwok, John B
Hallupp, Marianne
Kim, Woojin S
Huang, Yue
McGinley, Ciara V
Werka, Hellen
Kiernan, Matthew C
Götz, Jürgen
Spillantini, Maria Grazia
Hodges, John R
Ittner, Lars M
Halliday, Glenda M
author_facet Forrest, Shelley L
Kril, Jillian J
Stevens, Claire H
Kwok, John B
Hallupp, Marianne
Kim, Woojin S
Huang, Yue
McGinley, Ciara V
Werka, Hellen
Kiernan, Matthew C
Götz, Jürgen
Spillantini, Maria Grazia
Hodges, John R
Ittner, Lars M
Halliday, Glenda M
author_sort Forrest, Shelley L
collection PubMed
description See Josephs (doi:10.1093/brain/awx367) for a scientific commentary on this article. In many neurodegenerative disorders, familial forms have provided important insights into the pathogenesis of their corresponding sporadic forms. The first mutations associated with frontotemporal lobar degeneration (FTLD) were found in the microtubule-associated protein tau (MAPT) gene on chromosome 17 in families with frontotemporal degeneration and parkinsonism (FTDP-17). However, it was soon discovered that 50% of these families had a nearby mutation in progranulin. Regardless, the original FTDP-17 nomenclature has been retained for patients with MAPT mutations, with such patients currently classified independently from the different sporadic forms of FTLD with tau-immunoreactive inclusions (FTLD-tau). The separate classification of familial FTLD with MAPT mutations implies that familial forms cannot inform on the pathogenesis of the different sporadic forms of FTLD-tau. To test this assumption, this study pathologically assessed all FTLD-tau cases with a known MAPT mutation held by the Sydney and Cambridge Brain Banks, and compared them to four cases of four subtypes of sporadic FTLD-tau, in addition to published case reports. Ten FTLD-tau cases with a MAPT mutation (K257T, S305S, P301L, IVS10+16, R406W) were screened for the core differentiating neuropathological features used to diagnose the different sporadic FTLD-tau subtypes to determine whether the categorical separation of MAPT mutations from sporadic FTLD-tau is valid. Compared with sporadic cases, FTLD-tau cases with MAPT mutations had similar mean disease duration but were younger at age of symptom onset (55 ± 4 years versus 70 ± 6 years). Interestingly, FTLD-tau cases with MAPT mutations had similar patterns and severity of neuropathological features to sporadic FTLD-tau subtypes and could be classified into: Pick’s disease (K257T), corticobasal degeneration (S305S, IVS10+16, R406W), progressive supranuclear palsy (S305S) or globular glial tauopathy (P301L, IVS10+16). The finding that the S305S mutation could be classified into two tauopathies suggests additional modifying factors. Assessment of our cases and previous reports suggests that distinct MAPT mutations result in particular FTLD-tau subtypes, supporting the concept that they are likely to inform on the varied cellular mechanisms involved in distinctive forms of sporadic FTLD-tau. As such, FTLD-tau cases with MAPT mutations should be considered familial forms of FTLD-tau subtypes rather than a separate FTDP-17 category, and continued research on the effects of different mutations more focused on modelling their impact to produce the very different sporadic FTLD-tau pathologies in animal and cellular models.
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spelling pubmed-58889402018-04-11 Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies Forrest, Shelley L Kril, Jillian J Stevens, Claire H Kwok, John B Hallupp, Marianne Kim, Woojin S Huang, Yue McGinley, Ciara V Werka, Hellen Kiernan, Matthew C Götz, Jürgen Spillantini, Maria Grazia Hodges, John R Ittner, Lars M Halliday, Glenda M Brain Original Articles See Josephs (doi:10.1093/brain/awx367) for a scientific commentary on this article. In many neurodegenerative disorders, familial forms have provided important insights into the pathogenesis of their corresponding sporadic forms. The first mutations associated with frontotemporal lobar degeneration (FTLD) were found in the microtubule-associated protein tau (MAPT) gene on chromosome 17 in families with frontotemporal degeneration and parkinsonism (FTDP-17). However, it was soon discovered that 50% of these families had a nearby mutation in progranulin. Regardless, the original FTDP-17 nomenclature has been retained for patients with MAPT mutations, with such patients currently classified independently from the different sporadic forms of FTLD with tau-immunoreactive inclusions (FTLD-tau). The separate classification of familial FTLD with MAPT mutations implies that familial forms cannot inform on the pathogenesis of the different sporadic forms of FTLD-tau. To test this assumption, this study pathologically assessed all FTLD-tau cases with a known MAPT mutation held by the Sydney and Cambridge Brain Banks, and compared them to four cases of four subtypes of sporadic FTLD-tau, in addition to published case reports. Ten FTLD-tau cases with a MAPT mutation (K257T, S305S, P301L, IVS10+16, R406W) were screened for the core differentiating neuropathological features used to diagnose the different sporadic FTLD-tau subtypes to determine whether the categorical separation of MAPT mutations from sporadic FTLD-tau is valid. Compared with sporadic cases, FTLD-tau cases with MAPT mutations had similar mean disease duration but were younger at age of symptom onset (55 ± 4 years versus 70 ± 6 years). Interestingly, FTLD-tau cases with MAPT mutations had similar patterns and severity of neuropathological features to sporadic FTLD-tau subtypes and could be classified into: Pick’s disease (K257T), corticobasal degeneration (S305S, IVS10+16, R406W), progressive supranuclear palsy (S305S) or globular glial tauopathy (P301L, IVS10+16). The finding that the S305S mutation could be classified into two tauopathies suggests additional modifying factors. Assessment of our cases and previous reports suggests that distinct MAPT mutations result in particular FTLD-tau subtypes, supporting the concept that they are likely to inform on the varied cellular mechanisms involved in distinctive forms of sporadic FTLD-tau. As such, FTLD-tau cases with MAPT mutations should be considered familial forms of FTLD-tau subtypes rather than a separate FTDP-17 category, and continued research on the effects of different mutations more focused on modelling their impact to produce the very different sporadic FTLD-tau pathologies in animal and cellular models. Oxford University Press 2018-02 2017-12-14 /pmc/articles/PMC5888940/ /pubmed/29253099 http://dx.doi.org/10.1093/brain/awx328 Text en © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Articles
Forrest, Shelley L
Kril, Jillian J
Stevens, Claire H
Kwok, John B
Hallupp, Marianne
Kim, Woojin S
Huang, Yue
McGinley, Ciara V
Werka, Hellen
Kiernan, Matthew C
Götz, Jürgen
Spillantini, Maria Grazia
Hodges, John R
Ittner, Lars M
Halliday, Glenda M
Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies
title Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies
title_full Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies
title_fullStr Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies
title_full_unstemmed Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies
title_short Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies
title_sort retiring the term ftdp-17 as mapt mutations are genetic forms of sporadic frontotemporal tauopathies
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888940/
https://www.ncbi.nlm.nih.gov/pubmed/29253099
http://dx.doi.org/10.1093/brain/awx328
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