eprintid: 1523260
rev_number: 62
eprint_status: archive
userid: 608
dir: disk0/01/52/32/60
datestamp: 2016-10-30 00:35:26
lastmod: 2021-12-02 23:26:46
status_changed: 2017-01-03 11:18:31
type: article
metadata_visibility: show
creators_name: Ryan, NS
creators_name: Nicholas, JM
creators_name: Weston, PSJ
creators_name: Liang, Y
creators_name: Lashley, T
creators_name: Guerreiro, R
creators_name: Adamson, G
creators_name: Kenny, J
creators_name: Beck, J
creators_name: Chavez-Gutierrez, L
creators_name: de Strooper, B
creators_name: Revesz, T
creators_name: Holton, J
creators_name: Mead, S
creators_name: Rossor, MN
creators_name: Fox, NC
title: Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series
ispublished: pub
divisions: UCL
divisions: B02
divisions: C07
divisions: DF9
divisions: FA5
divisions: D07
divisions: F85
divisions: F86
divisions: FI1
divisions: D13
divisions: G23
keywords: Science & Technology, Life Sciences & Biomedicine, Clinical Neurology, Neurosciences & Neurology, PRECURSOR PROTEIN GENE, HUMAN GAMMA-SECRETASE, AMYLOID ANGIOPATHY, MUTATION, PRESENILIN-1, ONSET, PEDIGREE, MECHANISM, PATHOLOGY, DEMENTIA
note: © 2017 Elsevier B.V. Made available under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.
abstract: Background - The causes of phenotypic heterogeneity in familial Alzheimer’s disease with autosomal dominant inheritance are not well understood. We aimed to characterise clinical phenotypes and genetic associations with APP and PSEN1 mutations in symptomatic autosomal dominant familial Alzheimer’s disease (ADAD). Methods - 
We retrospectively analysed genotypic and phenotypic data (age at symptom onset, initial cognitive or behavioural symptoms, and presence of myoclonus, seizures, pyramidal signs, extrapyramidal signs, and cerebellar signs) from all individuals with ADAD due to APP or PSEN1 mutations seen at the Dementia Research Centre in London, UK. We examined the frequency of presenting symptoms and additional neurological features, investigated associations with age at symptom onset, APOE genotype, and mutation position, and explored phenotypic differences between APP and PSEN1 mutation carriers. The proportion of individuals presenting with various symptoms was analysed with descriptive statistics, stratified by mutation type. Findings - Between July 1, 1987, and Oct 31, 2015, age at onset was recorded for 213 patients (168 with PSEN1 mutations and 45 with APP mutations), with detailed history and neurological examination findings available for 121 (85 with PSEN1 mutations and 36 with APP mutations). We identified 38 different PSEN1 mutations (four novel) and six APP mutations (one novel). Age at onset differed by mutation, with a younger onset for individuals with PSEN1 mutations than for those with APP mutations (mean age 43·6 years [SD 7·2] vs 50·4 years [SD 5·2], respectively, p<0·0001); within the PSEN1 group, 72% of age at onset variance was explained by the specific mutation. A cluster of five mutations with particularly early onset (mean age at onset <40 years) involving PSEN1’s first hydrophilic loop suggests critical functional importance of this region. 71 (84%) individuals with PSEN1 mutations and 35 (97%) with APP mutations presented with amnestic symptoms, making atypical cognitive presentations significantly more common in PSEN1 mutation carriers (n=14; p=0·037). Myoclonus and seizures were the most common additional neurological features; individuals with myoclonus (40 [47%] with PSEN1 mutations and 12 [33%] with APP mutations) were significantly more likely to develop seizures (p=0·001 for PSEN1; p=0·036 for APP), which affected around a quarter of the patients in each group (20 [24%] and nine [25%], respectively). A number of patients with PSEN1 mutations had pyramidal (21 [25%]), extrapyramidal (12 [14%]), or cerebellar (three [4%]) signs. Interpretation - ADAD phenotypes are heterogeneous, with both age at onset and clinical features being influenced by mutation position as well as causative gene. This highlights the importance of considering genetic testing in young patients with dementia and additional neurological features in order to appropriately diagnose and treat their symptoms, and of examining different mutation types separately in future research. Funding - Medical Research Council and National Institute for Health Research.
date: 2016-12-01
date_type: published
publisher: ELSEVIER SCIENCE INC
official_url: http://dx.doi.org/10.1016/S1474-4422(16)30193-4
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
article_type_text: Article
verified: verified_manual
elements_id: 1188040
doi: 10.1016/S1474-4422(16)30193-4
language_elements: eng
lyricists_name: De Strooper, Bart
lyricists_name: Fox, Nicholas
lyricists_name: Holton, Janice
lyricists_name: Kenny, Joanna
lyricists_name: Lashley, Tammaryn
lyricists_name: Louro Guerreiro, Rita
lyricists_name: Mead, Simon
lyricists_name: Nicholas, Jennifer
lyricists_name: Revesz, Tamas
lyricists_name: Rossor, Martin
lyricists_name: Ryan, Natalie
lyricists_name: Weston, Philip
lyricists_id: BDEST57
lyricists_id: NCIFO25
lyricists_id: JHOLT26
lyricists_id: JKENN22
lyricists_id: TJOHN05
lyricists_id: RJLOU51
lyricists_id: SMEAD68
lyricists_id: JNICH85
lyricists_id: TREVE26
lyricists_id: MNROS52
lyricists_id: NRYAN07
lyricists_id: PWEST19
actors_name: Bracey, Alan
actors_id: ABBRA90
actors_role: owner
full_text_status: public
publication: LANCET NEUROLOGY
volume: 15
number: 13
pagerange: 1326-1335
pages: 10
issn: 1474-4422
citation:        Ryan, NS;    Nicholas, JM;    Weston, PSJ;    Liang, Y;    Lashley, T;    Guerreiro, R;    Adamson, G;                                     ... Fox, NC; + view all <#>        Ryan, NS;  Nicholas, JM;  Weston, PSJ;  Liang, Y;  Lashley, T;  Guerreiro, R;  Adamson, G;  Kenny, J;  Beck, J;  Chavez-Gutierrez, L;  de Strooper, B;  Revesz, T;  Holton, J;  Mead, S;  Rossor, MN;  Fox, NC;   - view fewer <#>    (2016)    Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series.                   LANCET NEUROLOGY , 15  (13)   pp. 1326-1335.    10.1016/S1474-4422(16)30193-4 <https://doi.org/10.1016/S1474-4422%2816%2930193-4>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/1523260/1/1-s2.0-S1474442216301934-main.pdf