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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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

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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.

Publications

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

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