Neuroscience Letters 566 (2014) 115–119
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
A novel presenilin 1 mutation (Ala275Val) as cause of early-onset familial Alzheimer disease Daniel Luedecke a , Jos S. Becktepe a , Jan T. Lehmbeck a , Ulrich Finckh b , Raina Yamamoto b , Holger Jahn a , Kai Boelmans a,∗ a b
Department of Psychiatry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany MVZ Dr. Eberhard & Partner, Dortmund, Germany
h i g h l i g h t s • • • •
We found a novel PSEN1 Ala275Val mutation in a patient with early-onset dementia. Neuropsychological examination, CSF and imaging biomarkers were indicative of AD. The same missense mutation was found in his father’s brain tissue. Ala275Val mutation affects a conserved domain of the hydrophilic loop in PS1.
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Article history: Received 15 November 2013 Received in revised form 22 January 2014 Accepted 17 February 2014 Keywords: Early-onset Alzheimer disease Presenilin 1 Missense mutation Cosegregation analysis
a b s t r a c t 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 A42 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. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Alzheimer disease (AD) is currently the most frequent form of dementia in the world [1]. The clinical spectrum of AD usually becomes noticeable in most patients at age 65 or older (sporadic or late-onset AD, LO-AD). In these cases, LO-AD is considered to have a multifactorial etiology. In contrast, in a small percentage
∗ Corresponding author at: Department of Psychiatry, Memory Clinic, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg, Germany. Tel.: +49 040 7410 54237; fax: +49 040 7410 59643. E-mail address: [email protected] (K. Boelmans). http://dx.doi.org/10.1016/j.neulet.2014.02.034 0304-3940/© 2014 Elsevier Ireland Ltd. All rights reserved.
of AD cases (
Contents lists available at ScienceDirect
Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
A novel presenilin 1 mutation (Ala275Val) as cause of early-onset familial Alzheimer disease Daniel Luedecke a , Jos S. Becktepe a , Jan T. Lehmbeck a , Ulrich Finckh b , Raina Yamamoto b , Holger Jahn a , Kai Boelmans a,∗ a b
Department of Psychiatry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany MVZ Dr. Eberhard & Partner, Dortmund, Germany
h i g h l i g h t s • • • •
We found a novel PSEN1 Ala275Val mutation in a patient with early-onset dementia. Neuropsychological examination, CSF and imaging biomarkers were indicative of AD. The same missense mutation was found in his father’s brain tissue. Ala275Val mutation affects a conserved domain of the hydrophilic loop in PS1.
a r t i c l e
i n f o
Article history: Received 15 November 2013 Received in revised form 22 January 2014 Accepted 17 February 2014 Keywords: Early-onset Alzheimer disease Presenilin 1 Missense mutation Cosegregation analysis
a b s t r a c t 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 A42 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. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Alzheimer disease (AD) is currently the most frequent form of dementia in the world [1]. The clinical spectrum of AD usually becomes noticeable in most patients at age 65 or older (sporadic or late-onset AD, LO-AD). In these cases, LO-AD is considered to have a multifactorial etiology. In contrast, in a small percentage
∗ Corresponding author at: Department of Psychiatry, Memory Clinic, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg, Germany. Tel.: +49 040 7410 54237; fax: +49 040 7410 59643. E-mail address: [email protected] (K. Boelmans). http://dx.doi.org/10.1016/j.neulet.2014.02.034 0304-3940/© 2014 Elsevier Ireland Ltd. All rights reserved.
of AD cases (
