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Abstract

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.

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Published In

Neurology®
Volume 71Number 16October 14, 2008
Pages: 1220-1226
PubMed: 18703462

Publication History

Published online: August 13, 2008
Published in print: October 14, 2008

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Authors

Affiliations & Disclosures

H. Seelaar
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.
W. Kamphorst, MD, PhD
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.
S. M. Rosso, MD, PhD
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.
A. Azmani
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.
R. Masdjedi
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.
I. de Koning, PhD
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.
J. A. Maat-Kievit, MD, PhD
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.
B. Anar
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.
L. Donker Kaat, MD
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.
G. J. Breedveld
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.
D. Dooijes, MD, PhD
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.
J. M. Rozemuller, MD, PhD
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.
I. F. Bronner, MSc
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.
P. Rizzu, PhD
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.
J. C. van Swieten, MD, PhD
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.

Notes

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

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