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.

• Authors: 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 3rd, William S Brooks, Glenda M Halliday, Jillian J Kril, Marla Gearing, Thomas G Beach, Neill R Graff-Radford, Dennis W Dickson, Rosa Rademakers, 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
• Journal: Archives of neurology (Arch Neurol) Vol. 68 Issue 4 Pg. 488-97 (Apr 2011) ISSN: 1538-3687 [Electronic] United States
• PMID: 21482928 (Publication Type: Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• GRN protein, human
• Genetic Markers
• Intercellular Signaling Peptides and Proteins
• Progranulins
• Protein Precursors

Topics

• Aged
• Female
• Frontotemporal Lobar Degeneration (diagnosis, genetics)
• Genetic Markers (genetics)
• Humans
• Intercellular Signaling Peptides and Proteins (genetics)
• Male
• Middle Aged
• Mutation (genetics)
• Parkinsonian Disorders (genetics)
• Progranulins
• Protein Precursors (genetics)