Clinical-Genetic Correlations in Familial Alzheimer's Disease Caused by Presenilin 1 Mutations

Article type: Research Article

Authors: Gómez-Tortosa, Estrella^{a; *} | Barquero, Sagrario^b | Barón, Manuel^c | Gil-Neciga, Eulogio^d | Castellanos, Fernando^e | Zurdo, Martín^e | Manzano, Sagrario^b | Muñoz, David G.^f | Jiménez-Huete, Adolfo^g | Rábano, Alberto^h | Sainz, M. José^a | Guerrero, Rosa^a | Gobernado, Isabelⁱ | Pérez-Pérez, Julián^j | Jiménez-Escrig, Adrianoⁱ

Affiliations: [a] Department of Neurology, Fundación Jiménez Díaz, Madrid, Spain | [b] Department of Neurology, Hospital Clínico Universitario San Carlos, Madrid, Spain | [c] Department of Neurology, Fundación Hospital Alcorcón, Madrid, Spain | [d] Department of Neurology, Hospital Virgen del Rocio, Seville, Spain | [e] Department of Neurology, Hospital Virgen del Puerto, Plasencia, Spain | [f] Department of Neurology, S. Michael's Hospital, Toronto, Ontario, Canada | [g] Department of Neurology, Hospital Ruber Internacional, Madrid, Spain | [h] Department of Pathology, Fundación Hospital Alcorcón, Madrid, Spain | [i] Department of Neurology, Hospital Ramón y Cajal, Madrid, Spain | [j] Secugen SL, Madrid, Spain

Correspondence: [*] Correspondence to: Estrella Gómez-Tortosa, MD, PhD, Servicio de Neurología, Fundación Jiménez Díaz, 28040 Madrid, Spain. Tel.: +34 91 550 4913; Fax: +34 91 550 4882; E-mail: [email protected].

Abstract: We describe the clinical phenotype of nine kindred with presenile Alzheimer's disease (AD) caused by different presenilin 1 (PS1) point mutations, and compare them with reported families with mutations in the same codons. Mutations were in exon 4 (Phe105Val), exon 5 (Pro117Arg, Glu120Gly), exon 6 (His163Arg), exon 7 (Leu226Phe), exon 8 (Val261Leu, Val272Ala, Leu282Arg), and exon 12 (Ile439Ser). Three of these amino acid changes (Phe105Val, Glu120Gly, and Ile439Ser) had not been previously reported. Distinct clinical features, including age of onset, symptoms and signs associated with the cortical-type dementia and aggressiveness of the disease, characterized the different mutations and were quite homogeneous across family members. Age of onset fell within a consistent range: some mutations caused the disease in the thirties (P117R, L226F, V272A), other in the forties (E120G, H163R, V261L, L282R), and other in the fifties (F105V, I439S). Associated features also segregated with specific mutations: early epileptic activity (E120G), spastic paraparesis (V261L), subcortical dementia and parkinsonism (V272A), early language impairment, frontal signs, and myoclonus (L226F), and late myoclonus and seizures (H163R, L282R). Neurological deterioration was particularly aggressive in PS1 mutations with earlier age of onset such as P117R, L226F, and E120G. With few exceptions, a similar clinical phenotype was found in families reported to have either the same mutation or different amino acid changes in the same codons. This series points to a strong influence of the specific genetic defect in the development of the clinical phenotype.

Keywords: early onset, familial Alzheimer's disease, mutations, presenilin 1

DOI: 10.3233/JAD-2010-1292

Journal: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 873-884, 2010