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APP locus duplication in a Finnish family with dementia and intracerebral haemorrhage
  1. A Rovelet-Lecrux1,
  2. T Frebourg1,
  3. H Tuominen2,
  4. K Majamaa3,
  5. D Campion4,
  6. A M Remes5
  1. 1
    The INSERM U614, IFRMP, Faculty of Medicine, Rouen, France
  2. 2
    Department of Pathology, University of Oulu, Oulu, Finland
  3. 3
    Department of Neurology, University of Turku, Turku, Finland
  4. 4
    The INSERM U614, IFRMP, Faculty of Medicine, Rouen, France
  5. 5
    Department of Neurology, University of Oulu and Clinical Research Centre, Oulu University Hospital, Oulu, Finland
  1. Dr A M Remes, Department of Neurology, University of Oulu, Box 5000, FIN-90014 Oulu, Finland; anne.remes{at}oulu.fi

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Missense mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) have been found to cause some forms of autosomal dominant early onset Alzheimer disease (AD). Autosomal dominant point mutations in the APP gene are associated with β-amyloid peptide related cerebral amyloid angiopathy (CAA) and AD.1 Duplications of the APP locus on chromosome 21 have recently been reported to be associated with a phenotype similar to that caused by point mutations in the APP gene, including progressive AD and strokes and intracerebral haemorrhage (ICH) of variable frequency.24 The neuropathological findings have been consistent with a diagnosis of definite AD according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). The most prominent feature in all cases has been severe CAA in the leptomeningeal vessels together with superficial and deep intraparenchymatous small arteries, capillaries and venules.

Figure 1 Detection of amyloid precursor protein (APP) duplication by quantitative multiplex PCR of short fluorescent fragments (QMPSF). The electropherogram of the affected subject (in red) was superimposed on that of a normal individual (in blue) by adjusting the peaks obtained from the control amplicon PCBD2 located on chromosome 5 to the same level. The vertical axis shows fluorescence in arbitrary units and the horizontal axis indicates the size of the amplicons in base pairs. Arrows indicate heterozygous duplication of the amplicons, as detected by a 1.5 fold heightening of the corresponding peaks. This QMPSF covers four genes located at 21q21: MRPL39, GABPA, APP and CYYR1.

We have previously described detailed clinical features of a four generation Finnish family, including 14 …

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