Hereditary cerebral hemorrhage with amyloidosis associated with the E693K mutation of APP.
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.
Bugiani
Orso
O
Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11-20133, Milan, Italy.
Giaccone
Giorgio
G
Rossi
Giacomina
G
Mangieri
Michela
M
Capobianco
Raffaella
R
Morbin
Michela
M
Mazzoleni
Giulia
G
Cupidi
Chiara
C
Marcon
Gabriella
G
Giovagnoli
Annarita
A
Bizzi
Alberto
A
Di Fede
Giuseppe
G
Puoti
Gianfranco
G
Carella
Francesco
F
Salmaggi
Andrea
A
Romorini
Alessandro
A
Patruno
Giorgio M
GM
Magoni
Mauro
M
Padovani
Alessandro
A
Tagliavini
Fabrizio
F
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
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