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Frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is the name for a group of clinically, pathologically and genetically heterogeneous disorders associated with atrophy in the frontal lobe and temporal lobe of the brain, with sparing of the parietal and occipital lobes.

In the over 65 age group, FTLD is probably the fourth most common cause of dementia after Alzheimer's disease, Dementia with Lewy bodies and vascular dementia. In the below 65 age group, it is the second most common cause after Alzheimer's disease.

There are three clinical subtypes described:

Histology

There are 3 main histological subtypes found at post-mortem:

  • tau inclusions (Pick's disease, MAPT mutations, corticobasal degeneration, progressive supranuclear palsy)
  • ubiquitin positive (tau-negative) inclusions - in the majority of cases that have this type of pathology the ubiquitinated inclusions contain a protein called TDP-43. There are three subtypes of this type of pathology described in the recent consensus criteria by Cairns et al: type 1 with neurites predominantly, type 2 with cytoplasmic inclusions predominantly; and type 3 with intranuclear inclusions. It should be noted that not all ubiquitin-positive, tau negative cases stain for TDP-43 e.g. the CHMP2B cases but also other cases.
  • Dementia lacking distinctive histology (DLDH) - a rare and controversial entity - new analyses have allowed many cases to be reclassified into one of the positively-defined subgroups.

Genetics

Many cases (possibly up to 50%) of FTLD are genetic rather than sporadic. There are 2 major genes in which mutations cause FTLD:

  • Mutations in the Tau gene (on chromosome 17q21 - known as MAPT or Microtubule Associated Protein Tau) can cause FTLD and there are over 40 known mutations at present.
  • A series of new mutations associated with FTLD has been recently described in the progranulin gene which is remarkably also on chromosome 17q21. Patients with progranulin mutations have type 3 ubiquitin-positive, TDP-43 positive, tau-negative pathology at post-mortem. Progranulin is associated with tumorgenesis when overproduced, whereas the mutations seen in the progranulin gene associated with FTLD suggests a deficit in progranulin may be the problem.

There are currently 2 other known genes that can cause FTLD:

  • CHMP2B (on chromosome 3) which is associated with a behavioural syndrome (mainly in a large Jutland cohort)
  • VCP (valosin-containing protein, on chromosome 9) which is associated with the IBMPFD syndrome (inclusion body myopathy, Paget's disease and frontotemporal dementia).

These 2 genes only account for a tiny proportion of cases.

A locus on chromosome 9 is associated with FTD-MND (or FTD-ALS) i.e. frontotemporal dementia associated with motor neurone disease (or amyotrophic lateral sclerosis) - the hunt for this gene is currently the focus of a number of research labs around the world.

Examples

United States Senator Pete Domenici (R-NM) is a known sufferer of FTLD, and the illness is the main reason behind his October 4, 2007 announcement of retirement at the end of his term.

External links

References

  • Mackenzie IR, Baborie A, Pickering-Brown S, Plessis DD, Jaros E, Perry RH, Neary D, Snowden JS, Mann DM. Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol (Berl). 2006 Nov;112(5):539-49. Epub 2006 Sep 26.
  • Davidson Y, Kelley T, Mackenzie IR, Pickering-Brown S, Du Plessis D, Neary D, Snowden JS, Mann DM. Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol (Berl). 2007 Jan 12; [Epub ahead of print]
  • Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF. "Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria." 'Neurology' (1998) 51(6):1546-54. Available:
  • Pickering-Brown SM. The complex aetiology of frontotemporal lobar degeneration. Exp Neurol. 2007 Jul;206(1):1-10. Epub 2007 Mar 24.

Further reading Hodges, John R. The Frontotemporal Dementia Syndromes. Cambridge University Press. 2007 ISBN 978-0-521-85477-1

See also

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