Clinicopathologic features of frontotemporal dementia with Progranulin sequence variation

S. Spina, J. R. Murrell, E. D. Huey, E. M. Wassermann, P. Pietrini, M. A. Baraibar, A. G. Barbeito, J. C. Troncoso, Ruben Vidal, Bernardino Ghetti, J. Grafman

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Abstract

BACKGROUND: Frontotemporal lobar degeneration with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) has been associated with frontotemporal dementia (FTD) and ALS. Recently, mutations in Progranulin (PGRN), predicted to cause premature truncation of the PGRN coding sequence, were found in patients with inherited FTLD-U and ub-ir neuronal intranuclear inclusions (NII). OBJECTIVE: To describe clinical, pathologic, and genetic features of three FTD patients having either a family history of FTD (A.III.1 and B.II.1) or of ALS (C.III.1). METHODS: Patients underwent a single clinical assessment, MRI, and [F]fluorodeoxyglucose PET brain scan. Neuropathologic examination and genetic analyses were carried out. RESULTS: Patients presented clinically with the behavioral variant of FTD. Language dysfunctions were marked with comprehension being particularly affected. Neuroimaging revealed frontotemporal atrophy and glucose hypometabolism, with predominant left-side involvement, in Patients A.III.1 and B.II.1. Subject C.III.1 displayed mild atrophy and symmetric anterior hypometabolism. All patients were neuropathologically diagnosed with FTLD-U. Ub-ir NII were noted in Patients A.III.1 and B.II.1 but were absent in Patient C.III.1. The following PGRN sequence variations were found: IVS6-2A→G (A.III.1), R493X (B.II.1), and R433W (C.III.1). IVS6-2A→G may lead to skipping of exon 7 with consequent frameshift of the coding sequence and premature termination of PGRN translation. CONCLUSIONS: We have found two PGRN mutations associated with FTD, in affected individuals who are members of families with possible autosomal dominant FTD. A third PGRN sequence variation (R433W) was found in an FTD patient with family history of ALS.

Original languageEnglish
Pages (from-to)820-827
Number of pages8
JournalNeurology
Volume68
Issue number11
DOIs
StatePublished - Mar 2007

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Frontotemporal Dementia
Frontotemporal Lobar Degeneration
Intranuclear Inclusion Bodies
Ubiquitin
Atrophy
Mutation
Neuroimaging
Positron-Emission Tomography
Exons
Language
Glucose

ASJC Scopus subject areas

  • Neuroscience(all)

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Spina, S., Murrell, J. R., Huey, E. D., Wassermann, E. M., Pietrini, P., Baraibar, M. A., ... Grafman, J. (2007). Clinicopathologic features of frontotemporal dementia with Progranulin sequence variation. Neurology, 68(11), 820-827. https://doi.org/10.1212/01.wnl.0000254460.31273.2d

Clinicopathologic features of frontotemporal dementia with Progranulin sequence variation. / Spina, S.; Murrell, J. R.; Huey, E. D.; Wassermann, E. M.; Pietrini, P.; Baraibar, M. A.; Barbeito, A. G.; Troncoso, J. C.; Vidal, Ruben; Ghetti, Bernardino; Grafman, J.

In: Neurology, Vol. 68, No. 11, 03.2007, p. 820-827.

Research output: Contribution to journalArticle

Spina, S, Murrell, JR, Huey, ED, Wassermann, EM, Pietrini, P, Baraibar, MA, Barbeito, AG, Troncoso, JC, Vidal, R, Ghetti, B & Grafman, J 2007, 'Clinicopathologic features of frontotemporal dementia with Progranulin sequence variation', Neurology, vol. 68, no. 11, pp. 820-827. https://doi.org/10.1212/01.wnl.0000254460.31273.2d
Spina S, Murrell JR, Huey ED, Wassermann EM, Pietrini P, Baraibar MA et al. Clinicopathologic features of frontotemporal dementia with Progranulin sequence variation. Neurology. 2007 Mar;68(11):820-827. https://doi.org/10.1212/01.wnl.0000254460.31273.2d
Spina, S. ; Murrell, J. R. ; Huey, E. D. ; Wassermann, E. M. ; Pietrini, P. ; Baraibar, M. A. ; Barbeito, A. G. ; Troncoso, J. C. ; Vidal, Ruben ; Ghetti, Bernardino ; Grafman, J. / Clinicopathologic features of frontotemporal dementia with Progranulin sequence variation. In: Neurology. 2007 ; Vol. 68, No. 11. pp. 820-827.
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abstract = "BACKGROUND: Frontotemporal lobar degeneration with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) has been associated with frontotemporal dementia (FTD) and ALS. Recently, mutations in Progranulin (PGRN), predicted to cause premature truncation of the PGRN coding sequence, were found in patients with inherited FTLD-U and ub-ir neuronal intranuclear inclusions (NII). OBJECTIVE: To describe clinical, pathologic, and genetic features of three FTD patients having either a family history of FTD (A.III.1 and B.II.1) or of ALS (C.III.1). METHODS: Patients underwent a single clinical assessment, MRI, and [F]fluorodeoxyglucose PET brain scan. Neuropathologic examination and genetic analyses were carried out. RESULTS: Patients presented clinically with the behavioral variant of FTD. Language dysfunctions were marked with comprehension being particularly affected. Neuroimaging revealed frontotemporal atrophy and glucose hypometabolism, with predominant left-side involvement, in Patients A.III.1 and B.II.1. Subject C.III.1 displayed mild atrophy and symmetric anterior hypometabolism. All patients were neuropathologically diagnosed with FTLD-U. Ub-ir NII were noted in Patients A.III.1 and B.II.1 but were absent in Patient C.III.1. The following PGRN sequence variations were found: IVS6-2A→G (A.III.1), R493X (B.II.1), and R433W (C.III.1). IVS6-2A→G may lead to skipping of exon 7 with consequent frameshift of the coding sequence and premature termination of PGRN translation. CONCLUSIONS: We have found two PGRN mutations associated with FTD, in affected individuals who are members of families with possible autosomal dominant FTD. A third PGRN sequence variation (R433W) was found in an FTD patient with family history of ALS.",
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AU - Spina, S.

AU - Murrell, J. R.

AU - Huey, E. D.

AU - Wassermann, E. M.

AU - Pietrini, P.

AU - Baraibar, M. A.

AU - Barbeito, A. G.

AU - Troncoso, J. C.

AU - Vidal, Ruben

AU - Ghetti, Bernardino

AU - Grafman, J.

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N2 - BACKGROUND: Frontotemporal lobar degeneration with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) has been associated with frontotemporal dementia (FTD) and ALS. Recently, mutations in Progranulin (PGRN), predicted to cause premature truncation of the PGRN coding sequence, were found in patients with inherited FTLD-U and ub-ir neuronal intranuclear inclusions (NII). OBJECTIVE: To describe clinical, pathologic, and genetic features of three FTD patients having either a family history of FTD (A.III.1 and B.II.1) or of ALS (C.III.1). METHODS: Patients underwent a single clinical assessment, MRI, and [F]fluorodeoxyglucose PET brain scan. Neuropathologic examination and genetic analyses were carried out. RESULTS: Patients presented clinically with the behavioral variant of FTD. Language dysfunctions were marked with comprehension being particularly affected. Neuroimaging revealed frontotemporal atrophy and glucose hypometabolism, with predominant left-side involvement, in Patients A.III.1 and B.II.1. Subject C.III.1 displayed mild atrophy and symmetric anterior hypometabolism. All patients were neuropathologically diagnosed with FTLD-U. Ub-ir NII were noted in Patients A.III.1 and B.II.1 but were absent in Patient C.III.1. The following PGRN sequence variations were found: IVS6-2A→G (A.III.1), R493X (B.II.1), and R433W (C.III.1). IVS6-2A→G may lead to skipping of exon 7 with consequent frameshift of the coding sequence and premature termination of PGRN translation. CONCLUSIONS: We have found two PGRN mutations associated with FTD, in affected individuals who are members of families with possible autosomal dominant FTD. A third PGRN sequence variation (R433W) was found in an FTD patient with family history of ALS.

AB - BACKGROUND: Frontotemporal lobar degeneration with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) has been associated with frontotemporal dementia (FTD) and ALS. Recently, mutations in Progranulin (PGRN), predicted to cause premature truncation of the PGRN coding sequence, were found in patients with inherited FTLD-U and ub-ir neuronal intranuclear inclusions (NII). OBJECTIVE: To describe clinical, pathologic, and genetic features of three FTD patients having either a family history of FTD (A.III.1 and B.II.1) or of ALS (C.III.1). METHODS: Patients underwent a single clinical assessment, MRI, and [F]fluorodeoxyglucose PET brain scan. Neuropathologic examination and genetic analyses were carried out. RESULTS: Patients presented clinically with the behavioral variant of FTD. Language dysfunctions were marked with comprehension being particularly affected. Neuroimaging revealed frontotemporal atrophy and glucose hypometabolism, with predominant left-side involvement, in Patients A.III.1 and B.II.1. Subject C.III.1 displayed mild atrophy and symmetric anterior hypometabolism. All patients were neuropathologically diagnosed with FTLD-U. Ub-ir NII were noted in Patients A.III.1 and B.II.1 but were absent in Patient C.III.1. The following PGRN sequence variations were found: IVS6-2A→G (A.III.1), R493X (B.II.1), and R433W (C.III.1). IVS6-2A→G may lead to skipping of exon 7 with consequent frameshift of the coding sequence and premature termination of PGRN translation. CONCLUSIONS: We have found two PGRN mutations associated with FTD, in affected individuals who are members of families with possible autosomal dominant FTD. A third PGRN sequence variation (R433W) was found in an FTD patient with family history of ALS.

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