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Early-Onset Cerebral Amyloid Angiopathy and Alzheimer Disease Related to an APP Locus Triplication
Lou Grangeon1, Kévin Cassinari1, Stéphane Rousseau1
1Department of Neurology and CNR-MAJ (L.G., D.W.), Normandie University, UNIROUEN, Inserm U1245, CHU Rouen, CIC-CRB1404, F 76000; Department of Genetics and CNR-MAJ (K.C., S.R., N.L.M., A.R.-L., D.C., G.N.), Normandie University, UNIROUEN, Inserm U1245 and CHU Rouen, F 76000; Department of Neurology (B.C., M.F.), Lyon University Hospital; Department of Neurology (O.M.), Grenoble University Hospital; Department of Histology (J.B.), Grenoble University Hospital; AP-HP (M.M., T.C., E.T.-L.), Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Service de Génétique Moléculaire Neurovasculaire, INSERM UMR 1141, NeuroDiderot,Université de Paris; Department of Histology Embryology and Cytogenetics (E.P.), Jean Verdier Hospital; Paris 13 University (E.P.), Sorbonne Paris Cité, UFR SMBH Bobigny; and PROTECT (E.P.), INSERM, Paris Diderot University, Bondy, France.
Background And Objective:
To report a triplication of the amyloid-β precursor protein (APP) locus along with relative messenger RNA (mRNA) expression in a family with autosomal dominant early-onset cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD).
Methods:
Four copies of the APP gene were identified by quantitative multiplex PCR of short fluorescent fragments, fluorescent in situ hybridization (FISH), and array comparative genomic hybridization. APP mRNA levels were assessed using reverse-transcription-digital droplet PCR in the proband's whole blood and compared with 10 controls and 9 APP duplication carriers.
Results:
Beginning at age 39 years, the proband developed severe episodic memory deficits with a CSF biomarker profile typical of AD and multiple lobar microbleeds in the posterior regions on brain MRI. His father had seizures and recurrent cerebral hemorrhage since the age of 37 years. His cerebral biopsy showed abundant perivascular amyloid deposits, leading to a diagnosis of CAA. In the proband, we identified 4 copies of a 506-kb region located on chromosome 21q21.3 and encompassing the whole APP gene without any other gene. FISH suggested that the genotype of the proband was 3 copies/1 copy corresponding to an APP locus triplication, which was consistent with the presence of 2 APP copies in the healthy mother and with the paternal medical history. Analysis of the APP mRNA level showed a 2-fold increase in the proband and a 1.8 fold increase in APP duplication carriers compared with controls.
Discussion:
Increased copy number of APP is sufficient to cause AD and CAA, with likely earlier onset in case of triplication compared with duplication.
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