Extended FTLD pedigree segregating a Belgian GRN-null mutation: neuropathological heterogeneity in one family
Abstract Background In this paper, we describe the clinical and neuropathological findings of nine members of the Belgian progranulin gene (GRN) founder family. In this family, the loss-of-function mutation IVS1 + 5G > C was identified in 2006. In 2007, a clinical description of the mutation carr...
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doaj-62394803736045fe8e421489ba4a07da2020-11-24T21:43:29ZengBMCAlzheimer’s Research & Therapy1758-91932018-01-0110111310.1186/s13195-017-0334-yExtended FTLD pedigree segregating a Belgian GRN-null mutation: neuropathological heterogeneity in one familyAnne Sieben0Sara Van Mossevelde1Eline Wauters2Sebastiaan Engelborghs3Julie van der Zee4Tim Van Langenhove5Patrick Santens6Marleen Praet7Paul Boon8Marijke Miatton9Sofie Van Hoecke10Mathieu Vandenbulcke11Rik Vandenberghe12Patrick Cras13Marc Cruts14Peter Paul De Deyn15Christine Van Broeckhoven16Jean-Jacques Martin17Institute Born-Bunge, Neuropathology and Laboratory of Neurochemistry and Behavior, University of AntwerpNeurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIBNeurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIBInstitute Born-Bunge, Neuropathology and Laboratory of Neurochemistry and Behavior, University of AntwerpNeurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIBDepartment of Neurology, Ghent University HospitalDepartment of Neurology, Ghent University HospitalDepartment of Pathology, Ghent University HospitalDepartment of Neurology, Ghent University HospitalDepartment of Neurology, Ghent University HospitalDepartment of Electronics and Information Systems, Ghent UniversityDepartment of Neurosciences, Faculty of Medicine, KU LeuvenDepartment of Neurosciences, Faculty of Medicine, KU LeuvenInstitute Born-Bunge, Neuropathology and Laboratory of Neurochemistry and Behavior, University of AntwerpNeurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIBInstitute Born-Bunge, Neuropathology and Laboratory of Neurochemistry and Behavior, University of AntwerpNeurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIBInstitute Born-Bunge, Neuropathology and Laboratory of Neurochemistry and Behavior, University of AntwerpAbstract Background In this paper, we describe the clinical and neuropathological findings of nine members of the Belgian progranulin gene (GRN) founder family. In this family, the loss-of-function mutation IVS1 + 5G > C was identified in 2006. In 2007, a clinical description of the mutation carriers was published that revealed the clinical heterogeneity among IVS1 + 5G > C carriers. We report our comparison of our data with the published clinical and neuropathological characteristics of other GRN mutations as well as other frontotemporal lobar degeneration (FTLD) syndromes, and we present a review of the literature. Methods For each case, standardized sampling and staining were performed to identify proteinopathies, cerebrovascular disease, and hippocampal sclerosis. Results The neuropathological substrate in the studied family was compatible in all cases with transactive response DNA-binding protein (TDP) proteinopathy type A, as expected. Additionally, most of the cases presented also with primary age-related tauopathy (PART) or mild Alzheimer’s disease (AD) neuropathological changes, and one case had extensive Lewy body pathology. An additional finding was the presence of cerebral small vessel changes in every patient in this family. Conclusions Our data show not only that the IVS1 + 5G > C mutation has an exclusive association with FTLD-TDP type A proteinopathy but also that other proteinopathies can occur and should be looked for. Because the penetrance rate of the clinical phenotype of carriers of GRN mutations is age-dependent, further research is required to investigate the role of co-occurring age-related pathologies such as AD, PART, and cerebral small vessel disease.http://link.springer.com/article/10.1186/s13195-017-0334-yFrontotemporal lobar degenerationFTLDFTD-GRNFTLD-TDPFrontotemporal dementiaFTD |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Anne Sieben Sara Van Mossevelde Eline Wauters Sebastiaan Engelborghs Julie van der Zee Tim Van Langenhove Patrick Santens Marleen Praet Paul Boon Marijke Miatton Sofie Van Hoecke Mathieu Vandenbulcke Rik Vandenberghe Patrick Cras Marc Cruts Peter Paul De Deyn Christine Van Broeckhoven Jean-Jacques Martin |
spellingShingle |
Anne Sieben Sara Van Mossevelde Eline Wauters Sebastiaan Engelborghs Julie van der Zee Tim Van Langenhove Patrick Santens Marleen Praet Paul Boon Marijke Miatton Sofie Van Hoecke Mathieu Vandenbulcke Rik Vandenberghe Patrick Cras Marc Cruts Peter Paul De Deyn Christine Van Broeckhoven Jean-Jacques Martin Extended FTLD pedigree segregating a Belgian GRN-null mutation: neuropathological heterogeneity in one family Alzheimer’s Research & Therapy Frontotemporal lobar degeneration FTLD FTD-GRN FTLD-TDP Frontotemporal dementia FTD |
author_facet |
Anne Sieben Sara Van Mossevelde Eline Wauters Sebastiaan Engelborghs Julie van der Zee Tim Van Langenhove Patrick Santens Marleen Praet Paul Boon Marijke Miatton Sofie Van Hoecke Mathieu Vandenbulcke Rik Vandenberghe Patrick Cras Marc Cruts Peter Paul De Deyn Christine Van Broeckhoven Jean-Jacques Martin |
author_sort |
Anne Sieben |
title |
Extended FTLD pedigree segregating a Belgian GRN-null mutation: neuropathological heterogeneity in one family |
title_short |
Extended FTLD pedigree segregating a Belgian GRN-null mutation: neuropathological heterogeneity in one family |
title_full |
Extended FTLD pedigree segregating a Belgian GRN-null mutation: neuropathological heterogeneity in one family |
title_fullStr |
Extended FTLD pedigree segregating a Belgian GRN-null mutation: neuropathological heterogeneity in one family |
title_full_unstemmed |
Extended FTLD pedigree segregating a Belgian GRN-null mutation: neuropathological heterogeneity in one family |
title_sort |
extended ftld pedigree segregating a belgian grn-null mutation: neuropathological heterogeneity in one family |
publisher |
BMC |
series |
Alzheimer’s Research & Therapy |
issn |
1758-9193 |
publishDate |
2018-01-01 |
description |
Abstract Background In this paper, we describe the clinical and neuropathological findings of nine members of the Belgian progranulin gene (GRN) founder family. In this family, the loss-of-function mutation IVS1 + 5G > C was identified in 2006. In 2007, a clinical description of the mutation carriers was published that revealed the clinical heterogeneity among IVS1 + 5G > C carriers. We report our comparison of our data with the published clinical and neuropathological characteristics of other GRN mutations as well as other frontotemporal lobar degeneration (FTLD) syndromes, and we present a review of the literature. Methods For each case, standardized sampling and staining were performed to identify proteinopathies, cerebrovascular disease, and hippocampal sclerosis. Results The neuropathological substrate in the studied family was compatible in all cases with transactive response DNA-binding protein (TDP) proteinopathy type A, as expected. Additionally, most of the cases presented also with primary age-related tauopathy (PART) or mild Alzheimer’s disease (AD) neuropathological changes, and one case had extensive Lewy body pathology. An additional finding was the presence of cerebral small vessel changes in every patient in this family. Conclusions Our data show not only that the IVS1 + 5G > C mutation has an exclusive association with FTLD-TDP type A proteinopathy but also that other proteinopathies can occur and should be looked for. Because the penetrance rate of the clinical phenotype of carriers of GRN mutations is age-dependent, further research is required to investigate the role of co-occurring age-related pathologies such as AD, PART, and cerebral small vessel disease. |
topic |
Frontotemporal lobar degeneration FTLD FTD-GRN FTLD-TDP Frontotemporal dementia FTD |
url |
http://link.springer.com/article/10.1186/s13195-017-0334-y |
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