Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration

Alice S. Chen-Plotkin, Maria Martinez-Lage, Patrick M.A. Sleiman, William Hu, Robert Greene, Elisabeth Mc Carty Wood, Shaoxu Bing, Murray Grossman, Gerard D. Schellenberg, Kimmo J. Hatanpaa, Myron F. Weiner, Charles L. White, William S. Brooks, Glenda M. Halliday, Jillian J. Kril, Marla Gearing, Thomas G. Beach, Neill R. Graff-Radford, Dennis W. Dickson, Rosa RademakersBradley F. Boeve, Stuart M. Pickering-Brown, Julie Snowden, John C. Van Swieten, Peter Heutink, Harro Seelaar, Jill R. Murrell, Bernardino Ghetti, Salvatore Spina, Jordan Grafman, Jeffrey A. Kaye, Randall L. Woltjer, Marsel Mesulam, Eileen Bigio, Albert Lladó, Bruce L. Miller, Ainhoa Alzualde, Fermin Moreno, Jonathan D. Rohrer, Ian R.A. Mackenzie, Howard H. Feldman, Ronald L. Hamilton, Marc Cruts, Sebastiaan Engelborghs, Peter P. De Deyn, Christine Van Broeckhoven, Thomas D. Bird, Nigel J. Cairns, Allison Goate, Matthew P. Frosch, Peter F. Riederer, Nenad Bogdanovic, Virginia M.Y. Lee, John Q. Trojanowski, Vivianna M. Van Deerlin

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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+ FTLDTDP 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+ FTLDTDP 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.

Original languageEnglish (US)
Pages (from-to)488-497
Number of pages10
JournalArchives of Neurology
Volume68
Issue number4
DOIs
StatePublished - Apr 2011

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Clinical Neurology

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    Chen-Plotkin, A. S., Martinez-Lage, M., Sleiman, P. M. A., Hu, W., Greene, R., Wood, E. M. C., Bing, S., Grossman, M., Schellenberg, G. D., Hatanpaa, K. J., Weiner, M. F., White, C. L., Brooks, W. S., Halliday, G. M., Kril, J. J., Gearing, M., Beach, T. G., Graff-Radford, N. R., Dickson, D. W., ... Van Deerlin, V. M. (2011). Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration. Archives of Neurology, 68(4), 488-497. https://doi.org/10.1001/archneurol.2011.53