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From the Departments of Neurology (H.S., S.M.R., A.A., R.M., L.D.K., J.C.v.S.), Neuropsychology (I.d.K.), and Clinical Genetics (J.A.M.-K., G.J.B., D.D.), Erasmus Medical Center, Rotterdam; and Department of Human Genetics (B.A., I.F.B., P.R.), Center for Neurogenomics and Cognitive Research (B.A., I.F.B., P.R.), and Neuropathology (W.K., J.M.R.), VU University Medical Center and VU University, Amsterdam.
Address correspondence and reprint requests to Dr. John C. van Swieten, Erasmus University Medical Center Rotterdam, Department of Neurology, Room Hs 611, ’s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
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.
e-Pub ahead of print on August 13, 2008, at www.neurology.org.
Supported by the Hersenstichting (project 13F05[2].14) and Stichting Dioraphte.
Disclosure: The authors report no conflicts of interest.
j.c.vanswieten{at}erasmusmc.nl
Editorial, page 1216
Received December 17, 2007. Accepted in final form April 11, 2008.
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Neurology 2008 71: 1216-1217.
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  M. Grossman Is the glass half empty or half full?: Genetically determined disease in frontotemporal dementia Neurology, October 14, 2008; 71(16): 1216 - 1217. [Full Text] [PDF]
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