Acta Neuropathologica

, Volume 114, Issue 1, pp 49–54 | Cite as

The neuropathology and clinical phenotype of FTD with progranulin mutations

Review

Abstract

Mutations in the progranulin gene (PGRN), on chromosome 17q21, have recently been identified as a major cause of familial frontotemporal dementia (FTD). These cases have a characteristic pattern of neuropathology that is a distinct subtype of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), with lentiform neuronal intranuclear inclusions being a consistent feature. There is no abnormal accumulation of PGRN protein in the brain and immunohistochemical and biochemical analysis indicates that the ubiquitinated pathological protein is TDP-43. In these families, FTD is inherited in an autosomal dominant fashion with high penetrance. The clinical phenotype is usually a combination of behavioural abnormality and language disturbance that is most often a form of primary progressive aphasia. Mild parkinsonism is common but motor neuron disease is notably rare. Marked variation in the disease course and clinical features are common, not only between families with different mutations, but also within individual families. This degree of clinical variability makes it difficult to predict which cases of familial FTD will turn out to have a PGRN mutation.

Keywords

Progranulin Frontotemporal dementia TDP-43 

References

  1. 1.
    Ahmed Z, Mackenzie I, Hutton M, Dickson D (2007) Progranulin in frontotemporal lobar degeneration and neuroinflammation. J Neuroinflam 4:7CrossRefGoogle Scholar
  2. 2.
    Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611PubMedCrossRefGoogle Scholar
  3. 3.
    Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Tobinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442:916–919PubMedCrossRefGoogle Scholar
  4. 4.
    Benussi L, Binetti G, Sina E, Gigola L, Bettecken T, Meitinger T, Ghidoni R (2006) A novel deletion in progranulin gene is associated with FTDP-17 and CBS. Neurobiol Aging, Dec5 [Epub ahead of print]Google Scholar
  5. 5.
    Bigio EH, Johnson NA, Rademaker AW, Fung BB, Mesulam MM, Siddique N, Dellefave L, Caliendo J, Freeman S, Siddique T (2004) Neuronal ubiquitinated intranuclear inclusions in familial and non-familial frontotemporal dementia of the motor neuron disease type associated with amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 63:801–811PubMedGoogle Scholar
  6. 6.
    Boeve BF, Baker M, Dickson DW, Parisi JE, Giannini C, Josephs KA, Hutton M, Pickering-Brown SM, Rademakers R, Tang-Wai D, Jack CR, Katarci K, Shiung MM, Golde T, Smith GE, Geda YE, Knopman DS, Petersen RC (2006) Frontotemporal dementia and parkinsonism associated with the IVS1 + 1G→A mutation in progranulin: a clinicopathologic study. Brain 129:3103–3114PubMedCrossRefGoogle Scholar
  7. 7.
    Bronner IF, Rizzu P, Seelaar H, van Mil SE, Anar B, Azmani A, Kaat LD, Roso S, Heutink P, van Swieten JC (2007) Progranulin mutations in Dutch familial frontotemporal lobar degeneration. Eur J Hum Genet, Jan 17 [Epub ahead of print]Google Scholar
  8. 8.
    Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wills H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin JJ, van Duijn C, Peeters K, Sciot R, Santens P, de Pooter T, Mattheijssens M, van den Broeck M, Cuijt I, Vennekens K, de Deyn PP Kumar-Singh S, van Broeckhoven C (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442:920–924PubMedCrossRefGoogle Scholar
  9. 9.
    Daniel R, He Z, Carmichael P, Halper J, Bateman A (2000) Cellular localization of gene expression for progranulin. J Histochem Cytochem 48:999–1009PubMedGoogle Scholar
  10. 10.
    Davidson Y, Kelley T, Mackenzie IRA, Pickering-Brown S, Du Plessis D, Neary D, Snowden JS, Mann DMA (2007) Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol, Jan 12 [Epub ahead of print]Google Scholar
  11. 11.
    Forman MS, Mackenzie IR, Cairns NJ, Swanson E, Boyer PJ, Drachman DA, Jhaveri BS, Karlawish JH, Pestronk A, Smith TW, Tu PH, Watts GDJ, Markesbery WR, Smith CD, Kimonis VE (2006) Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations. J Neuropathol Exp Neurol 65:571–581PubMedGoogle Scholar
  12. 12.
    Gass J, Cannon A, Mackenzie IR, Boeve B, Baker M, Adamson J, Crook R, Melquist S, Kuntz K, Petersen R, Josephs K, Graff-Radford N, Dickson D, Wsolek Z, Gonzales J, Beach T, Bigio E, Mesalum M, White C, Feldman H, Knopman D, Hutton M, Rademakers R (2006) Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 15:2988–3001PubMedCrossRefGoogle Scholar
  13. 13.
    He Z, Bateman A. (2003) Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair, tumorigenesis J Mol Med 81:600–612PubMedCrossRefGoogle Scholar
  14. 14.
    Huey ED, Grafman J, Wassermann EM, Pietrini P, Tierney MC, Ghetti B, Spina S, Baker M, Hutton M, Elder JW, Berger SL, Heflin KA, Hardy J, Momeni P (2006) Characteristics of frontotemporal dementia patients with progranulin mutation. Ann Neurol 60:374–380PubMedCrossRefGoogle Scholar
  15. 15.
    Josephs KA, Ahmed Z, Katsuse O, Parisi JF, Boeve BF, Knopman DS, Petersen RC, Davies P, Duara R, Graff-Radford NR, Uitti RJ, Rademakers R, Adamson J, Baker M, Hutton ML, Dickson DW (2007) Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions with progranulin gene (PGRN) mutations. J Neuropathol Exp Neurol 66:142–151PubMedGoogle Scholar
  16. 16.
    Katsuse O, Dickson DW (2005) Ubiquitin immunohistochemistry of frontotemporal lobar degeneration differentiates cases with, without motor neuron disease. Alz Dis Assoc Disord 19 (Suppl 1):S37–43CrossRefGoogle Scholar
  17. 17.
    Mackenzie IRA, Baborie A, Pickering-Brown S, du Pleissis D, Jaros E, Perry RH, Neary D, Snowden JS, Mann DMA (2006) Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol 112:539–549PubMedCrossRefGoogle Scholar
  18. 18.
    Mackenzie IRA, Baker M, Pickering-Brown S, Hsiung GYR, Lindholm C, Dwosh E, Gass J, Cannon A, Rademakers R, Hutton M, Feldman HH (2006) The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene. Brain 129:3081–3090PubMedCrossRefGoogle Scholar
  19. 19.
    Mackenzie IR, Baker M, West G, Woulfe J, Qadi N, Gass J, Cannon A, Adamson J, Feldman H, Lindholm C, Melquist S, Pettman R, Sadovnick AD, Dwosh E, Whiteheart SW, Hutton M, Pickering-Brown SM (2006) A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17. Brain 129:853–867PubMedCrossRefGoogle Scholar
  20. 20.
    Mackenzie IRA, Feldman H (2003) Neuronal intranuclear inclusions distinguish familial FTD-MND type from sporadic cases. Acta Neuropathol 105:543–548PubMedGoogle Scholar
  21. 21.
    Mackenzie IRA, Shi J, Shaw CL, DuPlessis D, Neary D, Snowden JS, Mann DMA (2006) Dementia lacking distinctive histology (DLDH) revisited. Acta Neuropathol 112:539–549PubMedCrossRefGoogle Scholar
  22. 22.
    Masellis M, Momeni P, Meschino W, Heffner R, Elder J, Sato C, Liang , St. George-Hyslop P, Hardy J, Bilbao J, Black S, Rogaeva E (2006) Novel splicing mutation in the progranulin gene causing familial corticobasal syndrome. Brain 129:3115–3123PubMedCrossRefGoogle Scholar
  23. 23.
    Mesulam M, Johnson N, Krefft TA, Gass JM, Cannon AD, Adamson JL, Bigio EH, Weintraub S, Dickson DW, Hutton ML, Graff-Radford NR (2007) Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families. Arch Neurol 64:43–47PubMedCrossRefGoogle Scholar
  24. 24.
    Mukherjee O, Pastor P, Cairns NJ, Chakraverty S, Kauwe JSK, Shears S, Behrens MI, Budde J, Hinrichs AL, Norton J, Levitch D, Taylor-Reinwald L, Gitcho M, Tu PH, Grinberg LT, Liscic RM, Armendariz J, Morris JC, Goate AM (2006) HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin. Ann Neurol 60:314–322PubMedCrossRefGoogle Scholar
  25. 25.
    Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VMY (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133PubMedCrossRefGoogle Scholar
  26. 26.
    Pickering-Brown SM, Baker M, Gass J, Boeve BF, Loy CT, Brooks WS, Mackenzie IRA, Martins RN, Kwok JBJ, Halliday GM, Kril J, Schofield PR, Mann DMA, Hutton M (2006) Mutations in progranulin explain atypical phenotypes with variants in MAPT. Brain 129:3124–3126PubMedCrossRefGoogle Scholar
  27. 27.
    Sampathu DM, Neumann M, Kwong LK, Chou TT, Micsenyi M, Truax A, Bruce J, Grossman M, Trojanowski JQ, Lee VMY (2006) Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies. Am J Pathol 169:1343–1352PubMedCrossRefGoogle Scholar
  28. 28.
    Snowden JS, Pickering-Brown SM, Mackenzie IM, Richardson AMT, Varma A, Neary D, Mann DMA (2006) Progranulin gene mutations associated with frontotemporal dementia and progressive non-fluent aphasia. Brain 129:3091–3102PubMedCrossRefGoogle Scholar
  29. 29.
    Spina S, Murrell JR, Huey ED, Wassermann EM, Pietrini P, Baraibar MA, Barbeito AG, Troncoso JC, Vidal R, Ghetti B, Grafman J (2007) Clinicopathologic features of frontotemporal dementia with progranulin sequence variation. Neurology Jan 31:[Epub ahead of print] Google Scholar
  30. 30.
    Trojanowski JQ, Dickson D (2001) Update on the neuropathological diagnosis of frontotemporal dementia. J Neuropathol Exp Neurol 60:1123–1126PubMedGoogle Scholar
  31. 31.
    Woulfe J, Kertesz A, Munoz DG (2001) Frontotemporal dementia with ubiquitinated cytoplasmic and intranuclear inclusions. Acta Neuropathol 102:94–102PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Department of PathologyVancouver General HospitalVancouverCanada

Personalised recommendations