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Extended FTLD pedigree segregating a Belgian GRN-null mutation : neuropathological heterogeneity in one family

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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.
Keywords
Frontotemporal lobar degeneration, FTLD, FTD-GRN, FTLD-TDP, Frontotemporal dementia, FTD, Cerebral small vessel disease (SVD), FRONTOTEMPORAL LOBAR DEGENERATION, AMYOTROPHIC-LATERAL-SCLEROSIS, UBIQUITIN-POSITIVE INCLUSIONS, PROGRANULIN GENE-MUTATIONS, PHENOTYPIC VARIABILITY, ALZHEIMERS-DISEASE, CEREBROVASCULAR PATHOLOGY, CLINICAL CHARACTERISTICS, HEXANUCLEOTIDE REPEAT, COGNITIVE IMPAIRMENT

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Chicago
Sieben, Anne, Sara Van Mossevelde, Eline Wauters, Sebastiaan Engelborghs, Julie van der Zee, Tim Van Langenhove, Patrick Santens, et al. 2018. “Extended FTLD Pedigree Segregating a Belgian GRN-null Mutation : Neuropathological Heterogeneity in One Family.” Alzheimers Research & Therapy 10.
APA
Sieben, A., Van Mossevelde, S., Wauters, E., Engelborghs, S., van der Zee, J., Van Langenhove, T., Santens, P., et al. (2018). Extended FTLD pedigree segregating a Belgian GRN-null mutation : neuropathological heterogeneity in one family. ALZHEIMERS RESEARCH & THERAPY, 10.
Vancouver
1.
Sieben A, Van Mossevelde S, Wauters E, Engelborghs S, van der Zee J, Van Langenhove T, et al. Extended FTLD pedigree segregating a Belgian GRN-null mutation : neuropathological heterogeneity in one family. ALZHEIMERS RESEARCH & THERAPY. 2018;10.
MLA
Sieben, Anne, Sara Van Mossevelde, Eline Wauters, et al. “Extended FTLD Pedigree Segregating a Belgian GRN-null Mutation : Neuropathological Heterogeneity in One Family.” ALZHEIMERS RESEARCH & THERAPY 10 (2018): n. pag. Print.
@article{8553836,
  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 {\textrangle} C was identified in 2006. In 2007, a clinical description of the mutation carriers was published that revealed the clinical heterogeneity among IVS1 + 5G {\textrangle} 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 {\textrangle} 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.},
  articleno    = {7},
  author       = {Sieben, Anne and Van Mossevelde, Sara and Wauters, Eline and Engelborghs, Sebastiaan and van der Zee, Julie and Van Langenhove, Tim and Santens, Patrick and Praet, Marleen and Boon, Paul and Miatton, Marijke and Van Hoecke, Sofie and Vandenbulcke, Mathieu and Vandenberghe, Rik and Cras, Patrick and Cruts, Marc and De Deyn, Peter Paul and Van Broeckhoven, Christine and Martin, Jean-Jacques},
  issn         = {1758-9193},
  journal      = {ALZHEIMERS RESEARCH \& THERAPY},
  keyword      = {Frontotemporal lobar degeneration,FTLD,FTD-GRN,FTLD-TDP,Frontotemporal dementia,FTD,Cerebral small vessel disease (SVD),FRONTOTEMPORAL LOBAR DEGENERATION,AMYOTROPHIC-LATERAL-SCLEROSIS,UBIQUITIN-POSITIVE INCLUSIONS,PROGRANULIN GENE-MUTATIONS,PHENOTYPIC VARIABILITY,ALZHEIMERS-DISEASE,CEREBROVASCULAR PATHOLOGY,CLINICAL CHARACTERISTICS,HEXANUCLEOTIDE REPEAT,COGNITIVE IMPAIRMENT},
  pages        = {13},
  title        = {Extended FTLD pedigree segregating a Belgian GRN-null mutation : neuropathological heterogeneity in one family},
  url          = {http://dx.doi.org/10.1186/s13195-017-0334-y},
  volume       = {10},
  year         = {2018},
}

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