Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3, BS3
Clinical Phenotype: Alzheimer's Disease, Ataxia, Spastic Paraparesis
Position: (GRCh38/hg38):Chr14:73198111 C>T
Position: (GRCh37/hg19):Chr14:73664819 C>T
dbSNP ID: rs63750324
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCA to TCA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was found in four members of an Italian family in which affected members presented with dementia, spastic paraparesis, and white-matter lesions (Marrosu et al., 2006). Memory impairment and personality changes characterized the onset of disease, which ranged between 32 and 45 years of age. In addition, motor impairments, including spastic paraparesis, emerged early on. All mutation carriers had an APOE 3/3 genotype.

This variant was also identified in a Chinese Han family spanning three generations with one member affected by an atypical form of Alzheimer’s disease (AD) (Xia et al., 2022). The proband was a woman who initially suffered from depression and postural abnormalities starting at age 30, and a year later developed memory loss and slow movements. These symptoms progressed and she also developed mood swings, irritability, and speech impairment. At 36, her motor abilities deteriorated further, with increasing slowness, instability, and rigidity similar to that seen in Parkinson’s disease. She had trouble walking and a neurological exam at age 37 revealed cerebellar dysfunction, ataxia, and both pyramidal and extrapyramidal signs.

The proband’s unaffected six-year-old daughter was also found to carry the mutation. The proband’s sister, son, and nephew were unaffected non-carriers. Except for the proband and daughter, family member ages were not reported.

The mutation was absent from 96 Italian patients with sporadic multiple sclerosis and 96 unrelated, healthy controls (Marrosu et al., 2006), as well as from 50 healthy Chinese (Xia et al., 2022). It was also absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology

Neuropathological data are unavailable. However, 18F-florbetapir PET imaging of the Chinese proband indicated extensive Aβ deposition in the cerebral cortex, cerebellum, and putamen (Xia et al., 2022). Also, MRI showed atrophy in the temporal lobe and hippocampus. Cerebrospinal fluid biomarkers were consistent with AD, including decreased Aβ42 and Aβ42/Aβ40 ratio, as well as increased levels of tau and p-tau181.

Moreover, MRI scans of four individuals from the Italian family revealed disseminated white-matter lesions reminiscent of those found in multiple sclerosis (Marrosu et al., 2006). Areas of hyperintensity in the frontal and temporal lobes were similar to those seen in cerebral autosomal-dominant arteriopathy (CADASIL), but no subcortical lacunar lesions typical of CADASIL were observed. Two subjects demonstrated multiple microbleeds in lobar regions (Floris et al., 2015).

Biological Effect

In an in vitro assay using the APP-C99 substrate, the mutant protein produced Aβ40 and Aβ42 peptides at levels similar to those generated by wild-type PSEN1. Accordingly, the Aβ42/Aβ40 ratio was similar to controls (Sun et al., 2017).

P284 is phylogenetically conserved, however (Xia et al., 2022) and several in silico algorithms, including CADD, predicted P284S is damaging (Xiao et al., 2021, Xia et al., 2022).

Pathogenicity

Alzheimer's Disease : Likely Pathogenic*

*Carriers of this variant had heterogenous phenotypes, some atypical for AD.

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

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References

Paper Citations

1. Marrosu MG, Floris G, Costa G, Schirru L, Spinicci G, Cherchi MV, Mura M, Mascia MG, Cocco E. Dementia, pyramidal system involvement, and leukoencephalopathy with a presenilin 1 mutation. Neurology. 2006 Jan 10;66(1):108-11. PubMed.
2. Xia M, Gao C, Wang H, Shang J, Liu R, You Y, Zang W, Zhang J. Novel PSEN1 (P284S) Mutation Causes Alzheimer's Disease with Cerebellar Amyloid β-Protein Deposition. Curr Alzheimer Res. 2022;19(7):523-529. PubMed.
3. Floris G, Di Stefano F, Cherchi MV, Costa G, Marrosu F, Marrosu MG. Multiple Spontaneous Cerebral Microbleeds and Leukoencephalopathy in PSEN1-Associated Familial Alzheimer's Disease: Mirror of Cerebral Amyloid Angiopathy?. J Alzheimers Dis. 2015;47(3):535-8. PubMed.
4. 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.
5. 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.

External Citations

1. gnomAD v2.1.1

Further Reading

No Available Further Reading