Brain Advance Access originally published online on September 7, 2006
Brain 2006 129(11):2966-2976; doi:10.1093/brain/awl237
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Phenotype associated with APP duplication in five families
1 Department of Neurology, University Hospital IFRMP 2 Inserm U614, Faculty of Medicine IFRMP 3 Department of Genetics, University Hospital Rouen 4 Department of Neuropathology, University Hospital Rouen 5 Department of Neurology, University Hospital Nantes 6 Department of Geriatry CHG Pau 7 Department of Neurology, University Hospital Saint-Etienne 8 Department of Neurology, University Hospital Angers 9 Laboratoire de Biologie Cellulaire, University Hospital Angers 10 Department of Neurology and EA2691, University Hospital Lille 11 Department of Pathology, University Hospital Bordeaux 12 Institut de Pharmacologie Moleculaire et Cellulaire, UMR6097 CNRS/UNSA, Equipe labellisée Fondation pour la Recherche Médicale Valbonne, France
Correspondence to: Didier Hannequin, Department of Neurology, 1 rue de Germont, 76031 Rouen, Cedex, France E-mail: Didier.hannequin{at}chu-rouen.fr
Different duplications of the APP locus have been identified in five families with autosomal dominant early onset Alzheimer's disease (ADEOAD) and Aß-related cerebral amyloid angiopathy (CAA). This study describes the phenotype of this new entity. Clinical, neuropsychological, imagery and neuropathological data were reviewed. The phenotype was not dependent on the size of the duplication and there was no clinical feature of Down's syndrome. Dementia was observed in all cases; intracerebral haemorrhage (ICH) was reported in 6 (26%) and seizures occurred in 12 (57%) of 21 patients. Age of onset of dementia ranged from 42 to 59 years, ICH from 53 to 64 years and age at death from 46 to 75 years. The neuropathological findings in five cases demonstrated Alzheimer's disease and severe CAA lesions that were reminiscent from those reported in brains of Down's syndrome patients. A striking feature consisted in intraneuronal Aßx-40 accumulation located in the granular cell layer of the dentate gyrus and in the pyramidal cell layer of the Ammon's horn.
Key Words: amyloid angiopathy; Alzheimer's disease; APP duplication; Down's syndrome; intracerebral haemorrhage
Abbreviations: Aß, amyloid ß peptides; ADEOAD, autosomal dominant early onset Alzheimer's disease; BG, basal ganglia; CAA, cerebral amyloid angiopathy; HE, haematoxylin–eosin; ICH, intracerebral haemorrhage; WMC, white matter changes
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Received July 10, 2006. Revised August 4, 2006. Accepted August 8, 2006.
*These authors have contributed equally to this work.
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