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Brain Advance Access originally published online on August 6, 2007
Brain 2007 130(9):2277-2291; doi:10.1093/brain/awm167
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

A novel locus for dementia with Lewy bodies: a clinically and genetically heterogeneous disorder

Veerle Bogaerts1,3,6, Sebastiaan Engelborghs4,6,7, Samir Kumar-Singh1,3,6, Dirk Goossens2,6, Barbara Pickut7, Julie van der Zee1,3,6, Kristel Sleegers1,3,6, Karin Peeters1,3,6, Jean-Jacques Martin5,6, Jurgen Del-Favero2,6, Thomas Gasser8, Dennis W. Dickson9, Zbigniew K. Wszolek10, Peter P. De Deyn4,6,7, Jessie Theuns1,3,6 and Christine Van Broeckhoven1,3,6

1Neurodegenerative Brain Diseases Group and 2Applied Molecular Genomics Group, Department of Molecular Genetics, VIB, 3Laboratory of Neurogenetics, 4Laboratory of Neurochemistry and Behavior, 5Laboratory of Neuropathology, Institute Born-Bunge, and 6University of Antwerp, Antwerpen, Belgium, 7Department of Neurology, Memory Clinic, Middelheim General Hospital, Antwerpen, Belgium, 8Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany, 9Department of Pathology and Neuroscience, and 10Department of Neurology, Mayo Clinic College of Medicine, Jacksonville, FL, USA

Correspondence to: Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB – Department of Molecular Genetics, University of Antwerp – CDE, Building V Universiteitsplein 1, BE-2610 Antwerpen, Belgium E-mail: christine.vanbroeckhoven{at}ua.ac.be

Dementia with Lewy bodies (DLB) represents the second most frequent type of neurodegenerative dementia in the elderly. Although most patients have sporadic DLB, a limited number of DLB families have been described, suggesting that genetic factors may contribute to DLB pathogenesis. Here, we describe a three-generation Belgian family with prominent dementia and parkinsonism, consistent with a diagnosis of DLB, that was autopsy confirmed for the index patient. In a genome-wide scan and subsequent finemapping of candidate loci we obtained significant linkage to 2q35-q36 (Z = 3.01 at D2S1242). Segregation analysis defined a candidate region of 9.2 Mb between D2S433 and chr2q36.3-8, adjacent to the previously reported PARK11 locus. In addition, haplotype sharing studies in another DLB family of close geographical origin with similar clinical and neuropathological features highlighted the specificity of a 2q35-q36 haplotype harbouring a pathogenic mutation that causes DLB in the Belgian family. So far, extensive sequence analysis of five candidate genes within the 2q35-q36 region has not revealed a disease-causing mutation. Together, our data re-emphasize the genetic heterogeneity of DLB, and strongly support the existence of a gene for familial DLB on 2q35-q36. Once identified this will be the first novel causal gene for DLB and can be expected to open new avenues for biological studies of the disease process.

Key Words: dementia with Lewy bodies; autosomal dominant inheritance; linkage analysis; genetic heterogeneity; 2q35-q36

Abbreviations: AAO, age at onset; AD, Alzheimer's disease; DLB, dementia with Lewy bodies; DLBD, diffuse Lewy body disease; LB, Lewy body; LBD, Lewy body disease; LOD, logarithm of odds; MAQ, multiplex amplicon quantification; MMSE, mini-mental state examination; mPCR, multiplex PCR; NFT, neurofibrillary tangles; PD, Parkinson's disease; PDD, Parkinson's disease with dementia; STR, short tandem repeat

Received May 11, 2007. Revised June 20, 2007. Accepted June 28, 2007.


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