APP Mutations in Cerebral Amyloid Angiopathy with or without Cortical Calcifications: Report of Three Families and a Literature Review.
BACKGROUND
Specific APP mutations cause cerebral amyloid angiopathy (CAA) with or without Alzheimer's disease (AD).


OBJECTIVE
We aimed at reporting APP mutations associated with CAA, describe the clinical, cerebrospinal fluid AD biomarkers, and neuroimaging features, and compare them with the data from the literature.


METHODS
We performed a retrospective study in two French genetics laboratories by gathering all clinical and neuroimaging data from patients referred for a genetic diagnosis of CAA with an age of onset before 66 years and fulfilling the other Boston revised criteria. We studied the segregation of mutations in families and performed a comprehensive literature review of all cases reported with the same APP mutation.


RESULTS
We screened APP in 61 unrelated French patients. Three mutations, located in the Aβ coding region, were detected in five patients from three families: p.Ala692Gly (Flemish), p.Glu693Lys (Italian), and p.Asp694Asn (Iowa). Patients exhibited CAA and progressive cognitive impairment associated with cortical calcifications in the Iowa and Italian mutation carriers, but not the patient carrying the Flemish mutation.


CONCLUSIONS
This is the first evidence of cortical calcification in patients with an APP mutation other than the Iowa mutation. We discuss the radiological, cerebrospinal fluid, and clinical phenotype of patients carrying these mutations in the literature.
['Sellal|François|F|', 'Wallon|David|D|', 'Martinez-Almoyna|Laurent|L|', 'Marelli|Cecilia|C|', 'Dhar|Abhinav|A|', 'Oesterlé|Héléne|H|', 'Rovelet-Lecrux|Anne|A|', 'Rousseau|Stéphane|S|', 'Kourkoulis|Christina E|CE|', 'Rosand|Jon|J|', 'DiPucchio|Zora Y|ZY|', 'Frosch|Matthew|M|', 'Gombert|Claudine|C|', 'Audoin|Bertrand|B|', 'Miné|Manuèle|M|', 'Riant|Florence|F|', 'Frebourg|Thierry|T|', 'Hannequin|Didier|D|', 'Campion|Dominique|D|', 'Greenberg|Steven M|SM|', 'Tournier-Lasserve|Elisabeth|E|', 'Nicolas|Gaël|G|']
D016564:Amyloid beta-Protein Precursor D002114:Calcinosis D016657:Cerebral Amyloid Angiopathy D002540:Cerebral Cortex D005192:Family Health D006801:Humans D009154:Mutation
APP mutation cerebral amyloid angiopathy calcification Alzheimer’s disease amyloid-β