Distinct genetic forms of frontotemporal dementia

Background: Frontotemporal dementia (FTD) is the second most common type of presenile dementia and can be distinguished into various clinical variants. The identification of MAPT and GRN defects and the discovery of the TDP-43 protein in FTD have led to the classification of pathologic and genetic subtypes. In addition to these genetic subtypes, there exist familial forms of FTD with unknown genetic defects. Methods: We investigated the frequency, demographic, and clinical data of patients with FTD with a positive family history in our prospective cohort of 364 patients. Genetic analysis of genes associated with FTD was performed on all patients with a positive family history. Immunohistochemical studies were carried out with a panel of antibodies (tau, ubiquitin, TDP-43) in brains collected at autopsy. Results: In the total cohort of 364 patients, 27% had a positive family history suggestive for an autosomal mode of inheritance, including MAPT (11%) and GRN (6%) mutations. We identified a new Gln300X GRN mutation in a patient with a sporadic FTD. The mean age at onset in GRN patients (61.8 ± 9.9 years) was higher than MAPT patients (52.4 ± 5.9 years). In the remaining 10% of patients with suggestive autosomal dominant inheritance, the genetic defect has yet to be identified. Neuropathologically, this group can be distinguished into familial FTLD+MND and familial FTLD-U with hippocampal sclerosis. Conclusion: Future genetic studies need to identify genetic defects in at least two distinct familial forms of frontotemporal dementia (FTD) with unknown genetic defects: frontotemporal lobe degeneration with ubiquitin-positive inclusions with hippocampal sclerosis and frontotemporal lobe degeneration with motor neuron disease. GLOSSARY: CA1 = cornu ammonis field 1; FTD = frontotemporal dementia; FTD-bv = behavioral variant of FTD; FTD+MND = FTD with motor neuron disease; FTLD = frontotemporal lobe degeneration; FTLD-tau = FTLD with tau-positive pathology; FTLD-U = FTLD with tau-negative, ubiquitin-positive inclusions; HS = hippocampal sclerosis; PNFA = progressive nonfluent aphasia; TDP-43 = TAR-DNA binding protein 43.

[1]  L. Petrucelli,et al.  Progranulin Mediates Caspase-Dependent Cleavage of TAR DNA Binding Protein-43 , 2007, The Journal of Neuroscience.

[2]  B. Dubois,et al.  Progranulin null mutations in both sporadic and familial frontotemporal dementia , 2007, Human mutation.

[3]  J. Morris,et al.  TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. , 2007, The American journal of pathology.

[4]  J. Schneider,et al.  Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration , 2007, Acta Neuropathologica.

[5]  D. Dickson,et al.  TDP‐43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease , 2007, Annals of neurology.

[6]  W. Kamphorst,et al.  TDP-43 pathology in familial frontotemporal dementia and motor neuron disease without Progranulin mutations. , 2007, Brain : a journal of neurology.

[7]  P. Heutink,et al.  Progranulin mutations in Dutch familial frontotemporal lobar degeneration , 2007, European Journal of Human Genetics.

[8]  D. Dickson,et al.  Journal of Neuroinflammation BioMed Central Review , 2006 .

[9]  V. Meininger,et al.  Three families with amyotrophic lateral sclerosis and frontotemporal dementia with evidence of linkage to chromosome 9p. , 2007, Archives of neurology.

[10]  D. Neary,et al.  Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43 , 2007, Acta Neuropathologica.

[11]  M. Spillantini,et al.  Hereditary Frontotemporal Dementia Caused by Tau Gene Mutations , 2007, Brain pathology.

[12]  D. Dickson,et al.  Hippocampal sclerosis dementia differs from hippocampal sclerosis in frontal lobe degeneration , 2006, Acta Neuropathologica.

[13]  S. Melquist,et al.  Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. , 2006, Human molecular genetics.

[14]  Bruce L. Miller,et al.  Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis , 2006, Science.

[15]  Julie S. Snowden,et al.  Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype , 2006, Acta Neuropathologica.

[16]  C. Duijn,et al.  Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21 , 2006, Nature.

[17]  S. Melquist,et al.  Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17 , 2006, Nature.

[18]  F. Baas,et al.  Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. , 2006, Brain : a journal of neurology.

[19]  Ronald C Petersen,et al.  Clinically undetected motor neuron disease in pathologically proven frontotemporal lobar degeneration with motor neuron disease. , 2006, Archives of neurology.

[20]  J. Neuhaus,et al.  Comparison of family histories in FTLD subtypes and related tauopathies , 2005, Neurology.

[21]  W. Kamphorst,et al.  Hereditary Pick's disease with the G272V tau mutation shows predominant three-repeat tau pathology. , 2005, Brain : a journal of neurology.

[22]  Holger Hummerich,et al.  Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia , 2005, Nature Genetics.

[23]  B. Miller,et al.  Frontotemporal lobar degeneration: demographic characteristics of 353 patients. , 2005, Archives of neurology.

[24]  L. Honig,et al.  Most cases of dementia with hippocampal sclerosis may represent frontotemporal dementia , 2005, Neurology.

[25]  P. Rabins,et al.  Dementia in hippocampal sclerosis resembles frontotemporal dementia more than Alzheimer disease , 2004, Neurology.

[26]  D. Dickson,et al.  Hippocampal Sclerosis and Ubiquitin-Positive Inclusions in Dementia Lacking Distinctive Histopathology , 2004, Dementia and Geriatric Cognitive Disorders.

[27]  A. Pestronk,et al.  Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein , 2004, Nature Genetics.

[28]  W. Kamphorst,et al.  Variable phenotypic expression and extensive tau pathology in two families with the novel tau mutation L315R , 2003, Annals of neurology.

[29]  Philip Scheltens,et al.  Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study. , 2003, Brain : a journal of neurology.

[30]  Douglas Walker,et al.  Hippocampal Sclerosis Dementia with Tauopathy , 2003, Brain pathology.

[31]  B. Miller,et al.  Are amyotrophic lateral sclerosis patients cognitively normal? , 2003, Neurology.

[32]  W. Kukull,et al.  Clinical and neuropathological characteristics of hippocampal sclerosis: a community-based study. , 2002, Archives of neurology.

[33]  W. Kamphorst,et al.  A novel tau mutation, S320F, causes a tauopathy with inclusions similar to those in Pick's disease , 2002, Annals of neurology.

[34]  B Miller,et al.  Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick's Disease. , 2001, Archives of neurology.

[35]  W. Kamphorst,et al.  Complex compulsive behaviour in the temporal variant of frontotemporal dementia , 2001, Journal of Neurology.

[36]  K. Jellinger,et al.  Pure hippocampal sclerosis: A rare cause of dementia mimicking Alzheimer’s disease , 2000, Neurology.

[37]  W. Kamphorst,et al.  Phenotypic variation in hereditary frontotemporal dementia with tau mutations , 1999, Annals of neurology.

[38]  D. Geschwind,et al.  Inheritance of frontotemporal dementia. , 1999, Archives of neurology.

[39]  C. Duijn,et al.  High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands. , 1999, American journal of human genetics.

[40]  Ronald C. Petersen,et al.  Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17 , 1998, Nature.

[41]  Shirley A. Miller,et al.  A simple salting out procedure for extracting DNA from human nucleated cells. , 1988, Nucleic acids research.