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. 2007 Dec;22(6):507–515. doi: 10.1177/1533317507306662

New Genes, New Dilemmas: FTLD Genetics and Its Implications for Families

Jill S Goldman 1, Jennifer Adamson 2, Anna Karydas 3, Bruce L Miller 4, Mike Hutton 5
PMCID: PMC10846215  PMID: 18166610

Abstract

After Alzheimer's disease, frontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in persons less than 65 years of age. Up to 40% of FTLD cases have a positive family history. Research on these families has led to the discovery of four disease-causing genes: microtubule-associated protein tau (MAPT), progranulin (PGRN), valosin-containing protein (VCP), and charged multivesicular body protein 2B (CHMP2B). MAPT and PGRN are responsible for the largest number of familial cases. Each of these genes differs by disease mechanism. Moreover mutations in both genes are associated with significant interfamilial and intrafamilial phenotypic variation. Genetic counseling needs to address the differences between the PGRN and MAPT mutations as well as the variation in clinical symptoms. The aims of this article are to describe the genetics of the FTLD spectrum and aid in the genetic counseling of individuals who may carry genetic mutations.

Keywords: genetics, frontotemporal lobar degeneration, progranulin, tau, genetic counseling

Full Text

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Contributor Information

Jill S. Goldman, Sergievsky Center and Taub Institute, Columbia University, New York, jg2673@columbia.edu .

Jennifer Adamson, Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida.

Anna Karydas, Memory and Aging Center, University of California, San Francisco, California.

Bruce L. Miller, Memory and Aging Center, University of California, San Francisco, California.

Mike Hutton, Sergievsky Center and Taub Institute, Columbia University, New York.

References

  1. Neary D., Snowden JS, Gustafson L., et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998;51:1546-1554. [DOI] [PubMed] [Google Scholar]
  2. Ratnavalli E. , Brayne C., Dawson K., Hodges JR The prevalence of frontotemporal dementia . Neurology. 2002. ;58: 1615-1621. [DOI] [PubMed] [Google Scholar]
  3. Rosso SM, Donker Kaat L., Baks T., et al. Frontotemporal dementia in the Netherlands: patient characteristics and prevalence estimates from a population-based study. Brain . 2003;126(Pt 9):2016-2022. [DOI] [PubMed] [Google Scholar]
  4. Bird T., Knopman D., VanSwieten J., et al. Epidemiology and genetics of frontotemporal dementia/Pick's disease. Ann Neurol. 2003;54(suppl 5):S29-S31. [DOI] [PubMed] [Google Scholar]
  5. Chow TW, Miller BL, Hayashi VN, Geschwind DH Inheritance of frontotemporal dementia. Arch Neurol. 1999;56:817-822. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Amador-Ortiz C., Lin WL, Ahmed Z., et al. TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease. Ann Neurol. 2007;61:435-445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. McKhann GM, Albert MS, Grossman M., Miller B., Dickson D., Trojanowski JQ Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick's Disease. Arch Neurol. 2001;58:1803-1809. [DOI] [PubMed] [Google Scholar]
  8. Boxer AL, Miller BL Clinical features of frontotemporal dementia. Alzheimer Dis Assoc Disord. 2005;19(suppl 1): S3-S6. [DOI] [PubMed] [Google Scholar]
  9. Lomen-Hoerth C., Murphy J., Langmore S., Kramer JH, Olney RK, Miller B. Are amyotrophic lateral sclerosis patients cognitively normal? Neurology. 2003;60:1094-1097. [DOI] [PubMed] [Google Scholar]
  10. Neary D., Snowden J., Mann D. Frontotemporal dementia. Lancet Neurol. 2005. ;4:771-780. [DOI] [PubMed] [Google Scholar]
  11. Boeve BF, Lang AE, Litvan I. Corticobasal degeneration and its relationship to progressive supranuclear palsy and frontotemporal dementia. Ann Neurol. 2003;54 (suppl 5):S15-S19. [DOI] [PubMed] [Google Scholar]
  12. Graff-Radford NR, Woodruff BK Frontotemporal dementia. Semin Neurol. 2007;27:48-57. [DOI] [PubMed] [Google Scholar]
  13. Tuite PJ, Clark HB, Bergeron C., et al. Clinical and pathologic evidence of corticobasal degeneration and progressive supranuclear palsy in familial tauopathy. Arch Neurol. 2005;62:1453-1457. [DOI] [PubMed] [Google Scholar]
  14. Shi J., Shaw CL, Du Plessis D, et al. Histopathological changes underlying frontotemporal lobar degeneration with clinicopathological correlation. Acta Neuropathol (Berl). 2005;110:501-512. [DOI] [PubMed] [Google Scholar]
  15. Mackenzie IR , Baker M., Pickering-Brown S., et al. The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene. Brain. 2006;129(Pt 11):3081-3090. [DOI] [PubMed] [Google Scholar]
  16. Poorkaj P., Grossman M., Steinbart E., et al. Frequency of tau gene mutations in familial and sporadic cases of non-Alzheimer dementia. Arch Neurol. 2001. ;58: 383-387. [DOI] [PubMed] [Google Scholar]
  17. Goldman JS, Farmer JM, Van Deerlin VM, Wilhelmsen KC, Miller BL, Grossman M. Frontotemporal dementia: genetics and genetic counseling dilemmas . Neurologist. 2004;10:227-234. [DOI] [PubMed] [Google Scholar]
  18. Gass J., Cannon A., Mackenzie IR, et al. Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet. 2006;15:2988-3001. [DOI] [PubMed] [Google Scholar]
  19. Wilhelmsen KC, Lynch T., Pavlou E., Higgins M., Nygaard TG Localization of disinhibition-dementia-parkinsonismamyotrophy complex to 17q21-22. Am J Hum Genet. 1994;55:1159-1165. [PMC free article] [PubMed] [Google Scholar]
  20. Foster NL, Wilhelmsen K., Sima AA, Jones MZ, D'Amato CJ, Gilman S. Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Conference Participants. Ann Neurol. 1997;41:706-715. [DOI] [PubMed] [Google Scholar]
  21. Hutton M., Lendon CL, Rizzu P., et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998;393:702-705. [DOI] [PubMed] [Google Scholar]
  22. Poorkaj P., Bird TD, Wijsman E., et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia . Ann Neurol. 1998;43:815-825. [DOI] [PubMed] [Google Scholar]
  23. Spillantini MG, Murrell JR, Goedert M., Farlow MR, Klug A., Ghetti B. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci USA. 1998;95:7737-7741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Fabre SF, Forsell C., Viitanen M., et al. Clinic-based cases with frontotemporal dementia show increased cerebrospinal fluid tau and high apolipoprotein E epsilon4 frequency, but no tau gene mutations. Exp Neurol. 2001;168:413-418. [DOI] [PubMed] [Google Scholar]
  25. Houlden H., Baker M., Adamson J., et al. Frequency of tau mutations in three series of non-Alzheimer's degenerative dementia. Ann Neurol. 1999;46:243-248. [DOI] [PubMed] [Google Scholar]
  26. Rizzu P., Van Swieten JC, Joosse M., et al. High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands. Am J Hum Genet. 1999;64:414-421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Binetti G., Nicosia F., Benussi L., et al. Prevalence of TAU mutations in an Italian clinical series of familial frontotemporal patients. Neurosci Lett. 2003;338:85-87. [DOI] [PubMed] [Google Scholar]
  28. Le Ber I., van der Zee J., Hannequin D., et al. Progranulin null mutations in both sporadic and familial frontotemporal dementia [published online ahead of print April 13, 2007]. Hum Mutat. [DOI] [PubMed] [Google Scholar]
  29. Rademakers R. , Cruts M., van Broeckhoven C. The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum Mutat. 2004;24:277-295. [DOI] [PubMed] [Google Scholar]
  30. Goedert M., Jakes R. Mutations causing neurodegenerative tauopathies. Biochim Biophys Acta. 2005;1739: 240-250. [DOI] [PubMed] [Google Scholar]
  31. van Swieten JC , Rosso SM, van Herpen E., Kamphorst W., Ravid R., Heutink P. Phenotypic variation in frontotemporal dementia and parkinsonism linked to chromosome 17. Dement Geriatr Cogn Disord. 2004;17:261-264. [DOI] [PubMed] [Google Scholar]
  32. Bugiani O., Murrell JR, Giaccone G., et al. Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau. J Neuropathol Exp Neurol. 1999;58:667-677. [DOI] [PubMed] [Google Scholar]
  33. Casseron W. , Azulay JP, Guedj E., Gastaut JL, Pouget J. Familial autosomal dominant cortico-basal degeneration with the P301S mutation in the tau gene: an example of phenotype variability. J Neurol. 2005;252:1546-1548. [DOI] [PubMed] [Google Scholar]
  34. Bird TD, Nochlin D., Poorkaj P., et al. A clinical pathological comparison of three families with frontotemporal dementia and identical mutations in the tau gene (P301L). Brain. 1999;122(Pt 4):741-756. [DOI] [PubMed] [Google Scholar]
  35. Stanford PM , Shepherd CE, Halliday GM, et al. Mutations in the tau gene that cause an increase in three repeat tau and frontotemporal dementia. Brain. 2003;126(Pt 4):814-826. [DOI] [PubMed] [Google Scholar]
  36. Soliveri P. , Rossi G., Monza D., et al. A case of dementia parkinsonism resembling progressive supranuclear palsy due to mutation in the tau protein gene. Arch Neurol. 2003;60:1454-1456. [DOI] [PubMed] [Google Scholar]
  37. Stanford PM , Brooks WS, Teber ET, et al. Frequency of tau mutations in familial and sporadic frontotemporal dementia and other tauopathies . J Neurol. 2004;251: 1098-1104. [DOI] [PubMed] [Google Scholar]
  38. Houlden H., Baker M., Morris HR, et al. Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype. Neurology. 2001. ;56:1702-1706. [DOI] [PubMed] [Google Scholar]
  39. Baba Y., Baker MC, Le Ber I., et al. Clinical and genetic features of families with frontotemporal dementia and parkinsonism linked to chromosome 17 with a P301S tau mutation . J Neural Transm. 2007;114:947-950. [DOI] [PubMed] [Google Scholar]
  40. Baker M., Mackenzie IR, Pickering-Brown SM, et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006;442:916-919. [DOI] [PubMed] [Google Scholar]
  41. Skibinski G. , Parkinson NJ, Brown JM, et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat Genet. 2005;37:806-808. [DOI] [PubMed] [Google Scholar]
  42. Brown J., Ashworth A., Gydesen S., et al. Familial nonspecific dementia maps to chromosome 3. Hum Mol Genet. 1995;4:1625-1628. [DOI] [PubMed] [Google Scholar]
  43. Cannon A., Baker M., Boeve B., et al. CHMP2B mutations are not a common cause of frontotemporal lobar degeneration. Neurosci Lett. 2006;398:83-84. [DOI] [PubMed] [Google Scholar]
  44. Momeni P., Rogaeva E., Van Deerlin V., et al. Genetic variability in CHMP2B and frontotemporal dementia. Neurodegener Dis. 2006;3:129-133. [DOI] [PubMed] [Google Scholar]
  45. Watts GD, Wymer J., Kovach MJ, et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein . Nat Genet. 2004;36:377-381. [DOI] [PubMed] [Google Scholar]
  46. Morita M., Al-Chalabi A., Andersen PM, et al. A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology. 2006;66:839-844. [DOI] [PubMed] [Google Scholar]
  47. Vance C., Al-Chalabi A., Ruddy D., et al. Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. Brain. 2006;129(Pt 4):868-876. [DOI] [PubMed] [Google Scholar]
  48. Cruts M., Gijselinck I., van der Zee J., et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature. 2006;442:920-924. [DOI] [PubMed] [Google Scholar]
  49. He Z., Bateman A. Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis. J Mol Med. 2003;81:600-612. [DOI] [PubMed] [Google Scholar]
  50. He Z., Ong CH, Halper J., Bateman A. Progranulin is a mediator of the wound response. Nat Med. 2003;9:225-229. [DOI] [PubMed] [Google Scholar]
  51. Daniel R., Daniels E., He Z., Bateman A. Progranulin (acrogranin/PC cell-derived growth factor/granulin-epithelin precursor) is expressed in the placenta, epidermis, microvasculature, and brain during murine development. Dev Dyn. 2003;227:593-599. [DOI] [PubMed] [Google Scholar]
  52. Masellis M. , Momeni P., Meschino W., et al. Novel splicing mutation in the progranulin gene causing familial corticobasal syndrome. Brain. 2006;129(Pt 11):3115-3123. [DOI] [PubMed] [Google Scholar]
  53. Mesulam M., Johnson N., Krefft TA, et al. Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families. Arch Neurol. 2007;64:43-47. [DOI] [PubMed] [Google Scholar]
  54. Snowden JS, Pickering-Brown SM, Mackenzie IR, et al. Progranulin gene mutations associated with frontotemporal dementia and progressive non-fluent aphasia. Brain. 2006;129(Pt 11):3091-3102. [DOI] [PubMed] [Google Scholar]
  55. Davidson Y. , Kelley T., Mackenzie IR, et al. Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol (Berl). 2007;113:521-533. [DOI] [PubMed] [Google Scholar]
  56. Boeve BF, Baker M., Dickson DW, et al. Frontotemporal dementia and parkinsonism associated with the IVS1+ 1G→A mutation in progranulin: a clinicopathologic study. Brain. 2006;129(Pt 11):3103-3114. [DOI] [PubMed] [Google Scholar]
  57. Pickering-Brown SM, Baker M., Gass J., et al. Mutations in progranulin explain atypical phenotypes with variants in MAPT. Brain. 2006. ;129(Pt 11):3124-3126. [DOI] [PubMed] [Google Scholar]
  58. International Huntington Association and the World Federation of Neurology Research Group on Huntington's Chorea. Guidelines for the molecular genetics predictive test in Huntington's disease . J Med Genet. 1994;31:555-559. [DOI] [PMC free article] [PubMed] [Google Scholar]

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