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