A novel presenilin 1 mutation (Ala275Val) as cause of early-onset familial Alzheimer disease

TY - JOUR

T1 - A novel presenilin 1 mutation (Ala275Val) as cause of early-onset familial Alzheimer disease

AU - Lüdecke, Daniel

AU - Becktepe, Jos S

AU - Lehmbeck, Jan T

AU - Finckh, Ulrich

AU - Yamamoto, Raina

AU - Jahn, Holger

AU - Boelmans, Kai

N1 - Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

PY - 2014/4/30

Y1 - 2014/4/30

N2 - Mutations in the presenilin 1 (PS1) gene (PSEN1) are associated with familial Alzheimer disease (FAD). Here, we report on a 50-year-old patient presenting with progressive deterioration of his short-term memory and a family history of early-onset dementia. Diagnostic workup included a neuropsychological examination, structural magnetic resonance (MR) imaging, cerebrospinal fluid (CSF) biomarkers including total tau, phosphorylated tau, and Aβ42 levels, as well as sequencing relevant fragments of the genes PSEN1, PSEN2, and APP. Additionally, we were able to obtain archival paraffin-embedded cerebellar tissue from the patient's father for cosegregation analysis. Clinical, neuropsychological and MR imaging data were indicative of early-onset Alzheimer disease. Furthermore, CSF biomarkers showed a typical pattern for Alzheimer disease. DNA sequencing revealed a heterozygous nucleotide transition (c.824C>T) in exon 8 of PSEN1, leading to an amino acid change from alanine to valine at codon 275 (Ala275Val). The same mutation was found in an archival brain specimen of the patient's demented father, but not in a blood sample of the non-demented mother. This mutation alters a conserved residue in the large hydrophilic loop of PS1, suggesting pathogenic relevance. Cosegregegation analysis and the structural as well as the presumed functional role of the mutated and highly conserved residue suggest FAD causing characteristics of the novel PSEN1 mutation Ala275Val.

AB - Mutations in the presenilin 1 (PS1) gene (PSEN1) are associated with familial Alzheimer disease (FAD). Here, we report on a 50-year-old patient presenting with progressive deterioration of his short-term memory and a family history of early-onset dementia. Diagnostic workup included a neuropsychological examination, structural magnetic resonance (MR) imaging, cerebrospinal fluid (CSF) biomarkers including total tau, phosphorylated tau, and Aβ42 levels, as well as sequencing relevant fragments of the genes PSEN1, PSEN2, and APP. Additionally, we were able to obtain archival paraffin-embedded cerebellar tissue from the patient's father for cosegregation analysis. Clinical, neuropsychological and MR imaging data were indicative of early-onset Alzheimer disease. Furthermore, CSF biomarkers showed a typical pattern for Alzheimer disease. DNA sequencing revealed a heterozygous nucleotide transition (c.824C>T) in exon 8 of PSEN1, leading to an amino acid change from alanine to valine at codon 275 (Ala275Val). The same mutation was found in an archival brain specimen of the patient's demented father, but not in a blood sample of the non-demented mother. This mutation alters a conserved residue in the large hydrophilic loop of PS1, suggesting pathogenic relevance. Cosegregegation analysis and the structural as well as the presumed functional role of the mutated and highly conserved residue suggest FAD causing characteristics of the novel PSEN1 mutation Ala275Val.

KW - Age of Onset

KW - Alzheimer Disease

KW - Brain

KW - Female

KW - Humans

KW - Magnetic Resonance Imaging

KW - Male

KW - Middle Aged

KW - Mutation

KW - Pedigree

KW - Presenilin-1

U2 - 10.1016/j.neulet.2014.02.034

DO - 10.1016/j.neulet.2014.02.034

M3 - SCORING: Journal article

C2 - 24582897

VL - 566

SP - 115

EP - 119

JO - NEUROSCI LETT

JF - NEUROSCI LETT

SN - 0304-3940

ER -