Dataset Information

Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration.

ABSTRACT:

Objective

To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD).

Participants and design

A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)-positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathogenic GRN mutations (GRN+ FTLD-TDP), assessed their genetic and clinical characteristics, and compared them with 453 patients with FTLD-TDP in which GRN mutations were excluded (GRN- FTLD-TDP). No patients were known to be related. Neuropathologic characteristics were confirmed as FTLD-TDP in 79 of the 97 GRN+ FTLD-TDP cases and all of the GRN- FTLD-TDP cases.

Results

Age at onset of FTLD was younger in patients with GRN+ FTLD-TDP vs GRN- FTLD-TDP (median, 58.0 vs 61.0 years; P < .001), as was age at death (median, 65.5 vs 69.0 years; P < .001). Concomitant motor neuron disease was much less common in GRN+ FTLD-TDP vs GRN- FTLD-TDP (5.4% vs 26.3%; P < .001). Fifty different GRN mutations were observed, including 2 novel mutations: c.139delG (p.D47TfsX7) and c.378C>A (p.C126X). The 2 most common GRN mutations were c.1477C>T (p.R493X, found in 18 patients, representing 18.6% of GRN cases) and c.26C>A (p.A9D, found in 6 patients, representing 6.2% of cases). Patients with the c.1477C>T mutation shared a haplotype on chromosome 17; clinically, they resembled patients with other GRN mutations. Patients with the c.26C>A mutation appeared to have a younger age at onset of FTLD and at death and more parkinsonian features than those with other GRN mutations.

Conclusion

GRN+ FTLD-TDP differs in key features from GRN- FTLD-TDP.

SUBMITTER: Chen-Plotkin AS

PROVIDER: S-EPMC3160280 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Publications

Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration.

Chen-Plotkin Alice S AS Martinez-Lage Maria M Sleiman Patrick M A PM Hu William W Greene Robert R Wood Elisabeth McCarty EM Bing Shaoxu S Grossman Murray M Schellenberg Gerard D GD Hatanpaa Kimmo J KJ Weiner Myron F MF White Charles L CL Brooks William S WS Halliday Glenda M GM Kril Jillian J JJ Gearing Marla M Beach Thomas G TG Graff-Radford Neill R NR Dickson Dennis W DW Rademakers Rosa R Boeve Bradley F BF Pickering-Brown Stuart M SM Snowden Julie J van Swieten John C JC Heutink Peter P Seelaar Harro H Murrell Jill R JR Ghetti Bernardino B Spina Salvatore S Grafman Jordan J Kaye Jeffrey A JA Woltjer Randall L RL Mesulam Marsel M Bigio Eileen E Lladó Albert A Miller Bruce L BL Alzualde Ainhoa A Moreno Fermin F Rohrer Jonathan D JD Mackenzie Ian R A IR Feldman Howard H HH Hamilton Ronald L RL Cruts Marc M Engelborghs Sebastiaan S De Deyn Peter P PP Van Broeckhoven Christine C Bird Thomas D TD Cairns Nigel J NJ Goate Allison A Frosch Matthew P MP Riederer Peter F PF Bogdanovic Nenad N Lee Virginia M Y VM Trojanowski John Q JQ Van Deerlin Vivianna M VM

Archives of neurology 20110401 4

<h4>Objective</h4>To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD).<h4>Participants and design</h4>A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)-positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathog ...[more]

PMID: 21482928

Similar Datasets

Project description:ObjectiveTo identify clinicopathological differences between frontotemporal lobar degeneration (FTLD) due to mutations in progranulin (FTLD-GRN) and chromosome 9 open reading frame 72 (FTLD-C9ORF72).MethodsWe performed quantitative neuropathologic comparison of 17 FTLD-C9ORF72 and 15 FTLD-GRN with a focus on microglia. For clinical comparisons, only cases with high quality medical documentation and concurring diagnoses by at least two neurologists were included (14 FTLD-GRN and 13 FTLD-C9ORF72). Neuropathological analyses were limited to TDP-43 Type A to assure consistent assessment between the groups, acknowledging that Type A is a minority of C9ORF72 patients. Furthermore, only cases with sufficient tissue from all regions were studied (11 FTLD-GRN and 11 FTLD-C9ORF72). FTLD cases were also compared to age- and sex-matched normal controls. Immunohistochemistry was performed for pTDP-43, IBA-1, CD68, and GFAP. Morphological characterization of microglia was performed in sections of cortex blinded to clinical and genetic information.ResultsFTLD-GRN patients had frequent asymmetric clinical features, including aphasia and apraxia, as well as more asymmetric cortical atrophy. Neuropathologically, FTLD-C9ORF72 had greater hippocampal tau pathology and more TDP-43 neuronal cytoplasmic inclusions. FTLD-GRN had more neocortical microvacuolation, as well as more IBA-1-positive ameboid microglia in superficial cortical layers and in subcortical white matter. FTLD-GRN also had more microglia with nuclear condensation, possibly indicating apoptosis. Microglial morphology with CD68 immunohistochemistry in FTLD-GRN and FTLD-C9ORF72 differed from controls.InterpretationOur findings underscore differences in microglial response in FTLD-C9ORF72 and FTLD-GRN as shown by significant differences in ameboid microglia in gray and white matter. These results suggest the differential contribution of microglial dysfunction in FTLD-GRN and FTLD-C9ORF72 and suggest that clinical, neuroimaging and pathologic differences could in part be related to differences in microglia response.

Dataset Information

Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration.

Objective

Participants and design

Results

Conclusion

Publications

Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration.

Similar Datasets

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