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 McCarty 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 Rademakers & 35 others Bradley 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

Research output: Contribution to journalArticle

72 Citations (Scopus)

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

Fingerprint

Frontotemporal Lobar Degeneration
Mutation
Degeneration
Age of Onset
Chromosomes, Human, Pair 17

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Chen-Plotkin, A. S., Martinez-Lage, M., Sleiman, P. M. A., Hu, W., Greene, R., Wood, E. M., ... 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

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

In: Archives of Neurology, Vol. 68, No. 4, 04.2011, p. 488-497.

Research output: Contribution to journalArticle

Chen-Plotkin, AS, Martinez-Lage, M, Sleiman, PMA, Hu, W, Greene, R, Wood, EM, Bing, S, Grossman, M, Schellenberg, GD, Hatanpaa, KJ, Weiner, MF, White, CL, Brooks, WS, Halliday, GM, Kril, JJ, Gearing, M, Beach, TG, Graff-Radford, NR, Dickson, DW, Rademakers, R, Boeve, BF, Pickering-Brown, SM, Snowden, J, Van Swieten, JC, Heutink, P, Seelaar, H, Murrell, JR, Ghetti, B, Spina, S, Grafman, J, Kaye, JA, Woltjer, RL, Mesulam, M, Bigio, E, Lladó, A, Miller, BL, Alzualde, A, Moreno, F, Rohrer, JD, Mackenzie, IRA, Feldman, HH, Hamilton, RL, Cruts, M, Engelborghs, S, De Deyn, PP, Van Broeckhoven, C, Bird, TD, Cairns, NJ, Goate, A, Frosch, MP, Riederer, PF, Bogdanovic, N, Lee, VMY, Trojanowski, JQ & Van Deerlin, VM 2011, 'Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration', Archives of Neurology, vol. 68, no. 4, pp. 488-497. https://doi.org/10.1001/archneurol.2011.53
Chen-Plotkin AS, Martinez-Lage M, Sleiman PMA, Hu W, Greene R, Wood EM et al. Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration. Archives of Neurology. 2011 Apr;68(4):488-497. https://doi.org/10.1001/archneurol.2011.53
Chen-Plotkin, Alice S. ; Martinez-Lage, Maria ; Sleiman, Patrick M A ; Hu, William ; Greene, Robert ; Wood, Elisabeth McCarty ; Bing, Shaoxu ; Grossman, Murray ; Schellenberg, Gerard D. ; Hatanpaa, Kimmo J. ; Weiner, Myron F. ; White, Charles L. ; Brooks, William S. ; Halliday, Glenda M. ; Kril, Jillian J. ; Gearing, Marla ; Beach, Thomas G. ; Graff-Radford, Neill R. ; Dickson, Dennis W. ; Rademakers, Rosa ; Boeve, Bradley F. ; Pickering-Brown, Stuart M. ; Snowden, Julie ; Van Swieten, John C. ; Heutink, Peter ; Seelaar, Harro ; Murrell, Jill R. ; Ghetti, Bernardino ; Spina, Salvatore ; Grafman, Jordan ; Kaye, Jeffrey A. ; Woltjer, Randall L. ; Mesulam, Marsel ; Bigio, Eileen ; Lladó, Albert ; Miller, Bruce L. ; Alzualde, Ainhoa ; Moreno, Fermin ; Rohrer, Jonathan D. ; Mackenzie, Ian R A ; Feldman, Howard H. ; Hamilton, Ronald L. ; Cruts, Marc ; Engelborghs, Sebastiaan ; De Deyn, Peter P. ; Van Broeckhoven, Christine ; Bird, Thomas D. ; Cairns, Nigel J. ; Goate, Allison ; Frosch, Matthew P. ; Riederer, Peter F. ; Bogdanovic, Nenad ; Lee, Virginia M Y ; Trojanowski, John Q. ; Van Deerlin, Vivianna M. / Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration. In: Archives of Neurology. 2011 ; Vol. 68, No. 4. pp. 488-497.
@article{9f8a02bb8e804e1ba41fa298f46171b0,
title = "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+ 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.",
author = "Chen-Plotkin, {Alice S.} and Maria Martinez-Lage and Sleiman, {Patrick M A} and William Hu and Robert Greene and Wood, {Elisabeth McCarty} and Shaoxu Bing and Murray Grossman and Schellenberg, {Gerard D.} and Hatanpaa, {Kimmo J.} and Weiner, {Myron F.} and White, {Charles L.} and Brooks, {William S.} and Halliday, {Glenda M.} and Kril, {Jillian J.} and Marla Gearing and Beach, {Thomas G.} and Graff-Radford, {Neill R.} and Dickson, {Dennis W.} and Rosa Rademakers and Boeve, {Bradley F.} and Pickering-Brown, {Stuart M.} and Julie Snowden and {Van Swieten}, {John C.} and Peter Heutink and Harro Seelaar and Murrell, {Jill R.} and Bernardino Ghetti and Salvatore Spina and Jordan Grafman and Kaye, {Jeffrey A.} and Woltjer, {Randall L.} and Marsel Mesulam and Eileen Bigio and Albert Llad{\'o} and Miller, {Bruce L.} and Ainhoa Alzualde and Fermin Moreno and Rohrer, {Jonathan D.} and Mackenzie, {Ian R A} and Feldman, {Howard H.} and Hamilton, {Ronald L.} and Marc Cruts and Sebastiaan Engelborghs and {De Deyn}, {Peter P.} and {Van Broeckhoven}, Christine and Bird, {Thomas D.} and Cairns, {Nigel J.} and Allison Goate and Frosch, {Matthew P.} and Riederer, {Peter F.} and Nenad Bogdanovic and Lee, {Virginia M Y} and Trojanowski, {John Q.} and {Van Deerlin}, {Vivianna M.}",
year = "2011",
month = "4",
doi = "10.1001/archneurol.2011.53",
language = "English (US)",
volume = "68",
pages = "488--497",
journal = "Archives of Neurology",
issn = "0003-9942",
publisher = "American Medical Association",
number = "4",

}

TY - JOUR

T1 - Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration

AU - Chen-Plotkin, Alice S.

AU - Martinez-Lage, Maria

AU - Sleiman, Patrick M A

AU - Hu, William

AU - Greene, Robert

AU - Wood, Elisabeth McCarty

AU - Bing, Shaoxu

AU - Grossman, Murray

AU - Schellenberg, Gerard D.

AU - Hatanpaa, Kimmo J.

AU - Weiner, Myron F.

AU - White, Charles L.

AU - Brooks, William S.

AU - Halliday, Glenda M.

AU - Kril, Jillian J.

AU - Gearing, Marla

AU - Beach, Thomas G.

AU - Graff-Radford, Neill R.

AU - Dickson, Dennis W.

AU - Rademakers, Rosa

AU - Boeve, Bradley F.

AU - Pickering-Brown, Stuart M.

AU - Snowden, Julie

AU - Van Swieten, John C.

AU - Heutink, Peter

AU - Seelaar, Harro

AU - Murrell, Jill R.

AU - Ghetti, Bernardino

AU - Spina, Salvatore

AU - Grafman, Jordan

AU - Kaye, Jeffrey A.

AU - Woltjer, Randall L.

AU - Mesulam, Marsel

AU - Bigio, Eileen

AU - Lladó, Albert

AU - Miller, Bruce L.

AU - Alzualde, Ainhoa

AU - Moreno, Fermin

AU - Rohrer, Jonathan D.

AU - Mackenzie, Ian R A

AU - Feldman, Howard H.

AU - Hamilton, Ronald L.

AU - Cruts, Marc

AU - Engelborghs, Sebastiaan

AU - De Deyn, Peter P.

AU - Van Broeckhoven, Christine

AU - Bird, Thomas D.

AU - Cairns, Nigel J.

AU - Goate, Allison

AU - Frosch, Matthew P.

AU - Riederer, Peter F.

AU - Bogdanovic, Nenad

AU - Lee, Virginia M Y

AU - Trojanowski, John Q.

AU - Van Deerlin, Vivianna M.

PY - 2011/4

Y1 - 2011/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=79953879390&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79953879390&partnerID=8YFLogxK

U2 - 10.1001/archneurol.2011.53

DO - 10.1001/archneurol.2011.53

M3 - Article

VL - 68

SP - 488

EP - 497

JO - Archives of Neurology

JF - Archives of Neurology

SN - 0003-9942

IS - 4

ER -