title: Hereditary cerebral hemorrhage with amyloidosis associated with the E693K mutation of APP.
abstract: OBJECTIVE
  To report the clinical, genetic, neuroimaging, and neuropathologic studies of patients with the hereditary cerebral hemorrhage with amyloidosis linked to the APP E693K mutation.
  
  
  METHODS
  Case series. Clinical details and laboratory results were collected by direct evaluation and previous medical records. DNA analysis was carried out in several affected subjects and healthy individuals. Neuropathologic examination was performed in 2 subjects.
  
  
  METHODS
  Southern Lombardy, Italy. Patients Individuals with and without amyloidosis in 4 unrelated Italian families (N = 37). Main Outcome Measure Genotype-phenotype relationship.
  
  
  RESULTS
  The affected individuals presented with recurrent headache and multiple strokes, followed by epilepsy and cognitive decline in most of them. The disease was inherited with an autosomal dominant trait and segregated with the APP E693K mutation. Neuroimaging demonstrated small to large hematomas, subarachnoid bleeding, scars with hemosiderin deposits, small infarcts, and leukoaraiosis. Amyloid-beta immunoreactivity was detected in the wall of leptomeningeal and parenchymal vessels and in the neuropil, whereas phosphorylated tau, neurofibrillary changes, and neuritic plaques were absent.
  
  
  CONCLUSIONS
  These findings expand the number of APP mutations linked to hereditary cerebral hemorrhage with amyloidosis, reinforcing the link between this phenotype and codon 693 of APP.
authors.affiliation: Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11-20133, Milan, Italy.
authors.forename: Orso
authors.initials: O
authors.lastname: Bugiani
authors.forename: Giorgio
authors.initials: G
authors.lastname: Giaccone
authors.forename: Giacomina
authors.initials: G
authors.lastname: Rossi
authors.forename: Michela
authors.initials: M
authors.lastname: Mangieri
authors.forename: Raffaella
authors.initials: R
authors.lastname: Capobianco
authors.forename: Michela
authors.initials: M
authors.lastname: Morbin
authors.forename: Giulia
authors.initials: G
authors.lastname: Mazzoleni
authors.forename: Chiara
authors.initials: C
authors.lastname: Cupidi
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marcon
authors.forename: Annarita
authors.initials: A
authors.lastname: Giovagnoli
authors.forename: Alberto
authors.initials: A
authors.lastname: Bizzi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Fede
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Puoti
authors.forename: Francesco
authors.initials: F
authors.lastname: Carella
authors.forename: Andrea
authors.initials: A
authors.lastname: Salmaggi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Romorini
authors.forename: Giorgio M
authors.initials: GM
authors.lastname: Patruno
authors.forename: Mauro
authors.initials: M
authors.lastname: Magoni
authors.forename: Alessandro
authors.initials: A
authors.lastname: Padovani
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
mesh_terms: D000368:Aged; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D028226:Amyloidosis, Familial / Q000150:complications / Q000235:genetics* / Q000473:pathology; D053327:Apolipoprotein E4 / Q000235:genetics; D002543:Cerebral Hemorrhage / Q000150:complications / Q000235:genetics* / Q000473:pathology; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D018698:Glutamic Acid / Q000235:genetics*; D006801:Humans; D007558:Italy; D008239:Lysine / Q000235:genetics*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053327:Apolipoprotein E4; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D018698:Glutamic Acid; D008239:Lysine