title: The clinical phenotype of two missense mutations in the presenilin I gene in Japanese patients.
abstract: We report the clinical and neuropathologic phenotypes associated with two different missense mutations in the presenilin 1 (PS-1) gene in Japanese patients with early-onset familial Alzheimer's disease (FAD). In the AM/JPN1 pedigree a missense mutation (C-->T) was found at nucleotide 1102, which is predicted to cause an alanine-to-valine missense substitution at codon 260. In this family, the disease had a mean age of onset of 40.3 years and an indolent course (range, 8-19 years). Neuropathologic studies in 3 members of this pedigree showed widespread senile plaques, neurofibrillary tangles, and neuronal loss, as well as abundant perivascular subpial amyloid deposits in the Virchow-Robin spaces and the presence of Pick-like intraneuronal inclusions in the dentate gyrus. In the second pedigree, transmitting a C-->T nucleotide substitution at position 1027, leading to the missense mutation of alanine to valine at codon 285, the disease had a later onset (mean, 51 years) but a more rapid course. Comparison of the disease phenotypes associated with other missense mutations in exon 9 of PS-1 reveals no clinical or pathological phenotype, which uniquely distinguishes Alzheimer's disease associated with PS-1 mutations from other forms of early-onset FAD, implying that direct mutation screening is required to identify these cases.
authors.affiliation: Centre for Research in Neurodegenerative Diseases, Department of Medicine Division of Neurology, University of Toronto, Ontario, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Ikeda
authors.forename: V
authors.initials: V
authors.lastname: Sharma
authors.forename: S M
authors.initials: SM
authors.lastname: Sumi
authors.forename: E A
authors.initials: EA
authors.lastname: Rogaeva
authors.forename: P
authors.initials: P
authors.lastname: Poorkaj
authors.forename: R
authors.initials: R
authors.lastname: Sherrington
authors.forename: L
authors.initials: L
authors.lastname: Nee
authors.forename: T
authors.initials: T
authors.lastname: Tsuda
authors.forename: N
authors.initials: N
authors.lastname: Oda
authors.forename: M
authors.initials: M
authors.lastname: Watanabe
authors.forename: M
authors.initials: M
authors.lastname: Aoki
authors.forename: M
authors.initials: M
authors.lastname: Shoji
authors.forename: K
authors.initials: K
authors.lastname: Abe
authors.forename: Y
authors.initials: Y
authors.lastname: Itoyama
authors.forename: S
authors.initials: S
authors.lastname: Hirai
authors.forename: G D
authors.initials: GD
authors.lastname: Schellenberg
authors.forename: T D
authors.initials: TD
authors.lastname: Bird
authors.forename: P H
authors.initials: PH
authors.lastname: St George-Hyslop
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D001921:Brain / Q000473:pathology; D005260:Female; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D016874:Neurofibrillary Tangles / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D053764:Presenilin-1
chemical_list: D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1