Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia
Reference Assembly: GRCh37/hg19
Position: Chr14:73659479 C>T
dbSNP ID: rs63750487
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTC to TTC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This presenilin-1 mutation has been reported in at least four individuals from disparate countries. It is associated with an early and aggressive disease phenotype, with atypical behavioral and psychiatric disturbances. Patients initially presented with psychiatric symptoms in their early 30s, followed by rapid cognitive decline and dementia.

The L226F mutation was first detected in a Polish man who had been diagnosed with frontotemporal dementia at the age of 33; however, postmortem examination later revealed Alzheimer’s disease. Clinically, he met Lund and Manchester consensus criteria (1994) for FTD. His disease presented with prominent behavioral symptoms, including inertia, social disinhibition, and repetitive and stereotyped behavior. He later developed severe deterioration of short-term memory. He died mute at the age of 38. His mother had also developed cognitive deterioration at the age of 33 and died at 44 with unspecified dementia. Segregation of the mutation with disease could not be assessed due to lack of DNA from family members (Zekanowski et al., 2006).

This mutation was also identified in a Spanish woman. She developed symptoms at the age of 33, including dysarthria, nonfluent speech, depression, and frontal signs. By the age of 36 she had developed mild parkinsonism, including bilateral tremor, limb bradykinesia, and reflex myoclonus. She died at the age of 42. Her father had also died at 42 following a six-year course of cognitive deterioration. Segregation of the mutation with disease could not be assessed due to lack of DNA samples (Gómez-Tortosa et al., 2010). 

In addition, the L226F mutation was identified in a Korean woman with early onset AD (Bagyinszky et al., 2016). Her symptoms started at age 37 with anxiety and paranoia and then progressed into severe cognitive and memory deficits which affected activities of daily living. Her speech deteriorated, becoming nonfluent and then mute. Her movements slowed and she developed muscle rigidity. She was bedridden for 18 months before her death at age 44. This mutation may have arisen de novo. Her family members were not carriers and there were no other known cases of dementia in her small family tree.

A woman of South American origin living in Italy was also identified as a carrier (Bartesaghi et al., 2020). At age 30, two years after the onset of affective symptoms, she was diagnosed with postpartum depression with psychotic symptoms. She later developed severe anxiety and memory loss. Cognitive function declined quickly. Family history was unknown because she had been adopted.

This variant is absent from the gnomAD and ExAC variant databases (Dec 2020).

Neuropathology

Despite a clinical diagnosis of FTD at the time of his death, postmortem examination of the Polish man with this mutation revealed definite AD according to CERAD and NIA-Reagan criteria (Zekanowski et al., 2006).

Neuropathology was not assessed in the Spanish woman with this mutation; however, CT showed diffuse cortical atrophy, especially in the parietal lobes (Gómez-Tortosa et al., 2010). Likewise, neuropathological assessment was not available for the Korean woman; however, MRI showed bilateral atrophy in the hippocampus as well as in the parietal cortex. PET imaging showed severe hypometabolism in the parietal cortex (Bagyinszky et al., 2016).

The carrier of South American ancestry had cerebrospinal fluid levels of Aβ, tau, and phosphorylated tau consistent with AD (Bartesaghi et al., 2020). In addition, MRI revealed temporoparietal and bilateral hippocampal atrophy, and FDG-PET showed bilateral hypometabolism in the precuneus and posterior cingulate, as well as in the temporoparietal and frontal cortices. As assessed by florbetaben-PET, a diffuse β-amyloid signal was observed in the cortex, with intense labeling in the basal ganglia.

Biological Effect

When expressed in HEK293 cells co-expressing APP with the Swedish mutation, mutant presenilin-1 resulted in increased Aβ42, Aβ40, and Aβ42/Aβ40, compared with cells expressing wild-type presenilin-1 (Bialopiotrowicz et al., 2012). Similar results were obtained in vitro using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate (Sun et al., 2017). Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve) predicted this variant is damaging (Xiao et al., 2021, Bagyinszky et al., 2016).

Pathogenicity

Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

Comments

1. • Takaomi Saido
     RIKEN Center for Brain Science
   • Posted: 25 Mar 2006
   • Paper: Two novel presenilin 1 gene mutations connected with frontotemporal dementia-like clinical phenotype: genetic and bioinformatic assessment.

   This study and others imply that some of the PS mutations may induce pathological gain-of-function phenotypes.

   View all comments by Takaomi Saido

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References

Paper Citations

1. Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups. J Neurol Neurosurg Psychiatry. 1994 Apr;57(4):416-8. PubMed.
2. Zekanowski C, Golan MP, Krzyśko KA, Lipczyńska-Łojkowska W, Filipek S, Kowalska A, Rossa G, Pepłońska B, Styczyńska M, Maruszak A, Religa D, Wender M, Kulczycki J, Barcikowska M, Kuźnicki J. Two novel presenilin 1 gene mutations connected with frontotemporal dementia-like clinical phenotype: genetic and bioinformatic assessment. Exp Neurol. 2006 Jul;200(1):82-8. PubMed.
3. Gómez-Tortosa E, Barquero S, Barón M, Gil-Neciga E, Castellanos F, Zurdo M, Manzano S, Muñoz DG, Jiménez-Huete A, Rábano A, Sainz MJ, Guerrero R, Gobernado I, Pérez-Pérez J, Jiménez-Escrig A. Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations. J Alzheimers Dis. 2010;19(3):873-84. PubMed.
4. Bagyinszky E, Park SA, Kim HJ, Choi SH, An SS, Kim SY. PSEN1 L226F mutation in a patient with early-onset Alzheimer's disease in Korea. Clin Interv Aging. 2016;11:1433-1440. Epub 2016 Oct 12 PubMed.
5. Bartesaghi F, Rosci CE, Rassiga C, Barbieri V, Gambini O, Floro S, D'Arrigo AM, Del Sole A, Scarpini EA, Galimberti D, Priori A. Psychiatric Disorders in Alzheimer Disease With the Presenilin-1 L226F Mutation. Cogn Behav Neurol. 2020 Dec;33(4):278-282. PubMed.
6. Bialopiotrowicz E, Szybinska A, Kuzniewska B, Buizza L, Uberti D, Kuznicki J, Wojda U. Highly Pathogenic Alzheimer's Disease Presenilin 1 P117R Mutation Causes a specific Increase in p53 and p21 Protein Levels and Cell Cycle Dysregulation in Human Lymphocytes. J Alzheimers Dis. 2012 Jan 1;32(2):397-415. PubMed.
7. Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
8. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

Other Citations

1. Swedish mutation

Further Reading