APP Mutations in Cerebral Amyloid Angiopathy with or without Cortical Calcifications: Report of Three Families and a Literature Review

Article type: Research Article

Authors: Sellal, François^{a; b} | Wallon, David^{c; d; e; f} | Martinez-Almoyna, Laurent^g | Marelli, Cecilia^h | Dhar, Abhinavⁱ | Oesterlé, Héléneⁱ | Rovelet-Lecrux, Anne^{e; f} | Rousseau, Stéphane^{d; f} | Kourkoulis, Christina E.^{j; k} | Rosand, Jon^{j; k} | DiPucchio, Zora Y.^{j; k} | Frosch, Matthew^l | Gombert, Claudine^g | Audoin, Bertrand^m | Miné, Manuèle^{n; o} | Riant, Florence^{n; o} | Frebourg, Thierry^{e; f; p} | Hannequin, Didier^{c; d; e; f; p} | Campion, Dominique^{d; e; f; q} | Greenberg, Steven M.^{j; k} | Tournier-Lasserve, Elisabeth^{n; o} | Nicolas, Gaël^{d; e; f; p; *}

Affiliations: [a] Department of Neurology and Consultation Mémoire de Ressource et de Recherche, Hôpitaux Civils de Colmar, Colmar, France | [b] Strasbourg University, INSERM U-1118, Faculty of Medicine, Strasbourg, France | [c] Department of Neurology, Rouen University Hospital, Rouen, France | [d] CNR-MAJ, Rouen University Hospital, Rouen, France | [e] Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France | [f] Normandy Center for Genomic and Personalized Medicine, Rouen, France | [g] Neurology Department, Centre Hospitalier, Aix-en-Provence, France | [h] Service de Neurologie, CMRR, CHRU Gui de Chauliac, Montpellier, France | [i] Radiology Service, Hospital of Moenchsberg, Mulhouse, France | [j] J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, USA | [k] Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, USA | [l] Neuropathology Service, C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital and Harvard Medical School, Boston, USA | [m] Aix-Marseille Université, CNRS, CRMBM UMR 7339, Marseille, France/APHM, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie, Marseille, France | [n] AP-HP, Service de génétique moléculaire neurovasculaire, Hôpital Lariboisiére, Paris, France | [o] Inserm, U1161, Université Paris 7 Diderot, Paris, France | [p] Department of Genetics, Rouen University Hospital, Rouen, France | [q] Department of Research, Rouvray Psychiatric Hospital, Sotteville-Lés-Rouen, France

Correspondence: [*] Correspondence to: Gaël Nicolas, Department of Genetics, Rouen University Hospital, 1, rue de Germont, 76031 Rouen, France. Tel.: +33 235148280; Fax: +33 235148237; E-mail: gaelnicolas@hotmail.com.

Abstract: 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.

Keywords: Alzheimer’s disease, amyloid-β, APP, calcification, cerebral amyloid angiopathy, mutation

DOI: 10.3233/JAD-160709

Journal: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 37-46, 2017