Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73219138 T>G
Position: (GRCh37/hg19):Chr14:73685846 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTG to TGG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This variant was identified in two Japanese sisters who developed early onset Alzheimer’s disease with atypical features at a very early age (Takahashi et al., 2018). Symptoms varied between the two, but both had disease onset at 18 years of age. One of them suffered from personality changes, aggression, and dementia. At 37, she developed tremors and bradykinesia. By 44, her memory and attention were severely impaired and she had akinesia, tremor, and rigospasticity in all her limbs. Her sister gradually developed dementia and place disorientation, but did not exhibit aggressive behavior. At 41, her memory and attention were moderately impaired. Like her sister, she had rigospasticity in her four limbs.

The deceased mother of the women had also suffered from personality changes, aggression, and dementia emerging at age 34, followed by parkinsonism characterized by tremors and rigidity. She died with advanced dementia.

This variant was also reported in a Japanese woman with AD whose symptoms emerged at age 34 (Islam et al., 2022 /papers/presenilin-essential-apoe-secretion-novel-role-presenilin-involved-alzheimers-disease). It is uncertain if this woman was the same patient as described above.
The variant was absent from the gnomAD variant database (v2.1.1, Feb 2022).

Neuropathology
Neuropathological data for carriers of this mutation are unavailable, but brain imaging of both carriers revealed symmetrical hyperintensities in the posterior-dominant white matter and the splenium of corpus (Takahashi et al., 2018). Moreover, SPECT imaging showed hypoperfusion in the posterior cingulate gyrus and parietal lobe. In one of the carriers, but not the other, DAT imaging revealed decreased dopamine uptake in the putamen bilaterally.

An autopsy of the carriers’ mother, who was affected but whose genotype is uncertain, revealed cotton wool plaques throughout the cortex, particularly dense in the temporal region. Lewy bodies were observed in the substantia nigra.

Biological Effect
The biological effect of this mutation is unknown. Another substitution at the same location, L418F, altered Aβ peptide production. Moreover, in one L418W carrier with an APOE3/3 genotype, blood ApoE levels were reduced compared with those of non-carriers (Islam et al., 2022). This may be due to a disruption of PSEN1’s proposed role in ApoE secretion.

The variant’s PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Feb 2022).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum because data for either a pathogenic or benign classification are lacking: it was found in a single affected family without clear evidence of cosegregation or a functional effect, and it is absent, or very rare, in the gnomAD database.

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

PM1-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

	Pathogenic (PS, PM, PP)			Benign (BA, BS, BP)
Criteria Weighting	Strong (-S)	Moderate (-M)	Supporting (-P)	Supporting (-P)	Strong (-S)	Strongest (BA)

Last Updated: 08 Mar 2022

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References

Mutations Citations

Paper Citations

Takahashi Y, Ohta Y, Sasaki R, Tadokoro K, Sato K, Shang J, Takemoto M, Hishikawa N, Yamashita T, Haraguchi T, Ikeuchi T, Abe K. A novel presenilin 1 mutation (Leu418Trp) associated with spasticity, parkinsonism, and white matter lesion in a dominant Alzheimer's family. J Neurol Sci. 2018 Apr 15;387:166-169. Epub 2018 Jan 5 PubMed.
Islam S, Sun Y, Gao Y, Nakamura T, Noorani AA, Li T, Wong PC, Kimura N, Matsubara E, Kasuga K, Ikeuchi T, Tomita T, Zou K, Michikawa M. Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis. J Neurosci. 2022 Feb 23;42(8):1574-1586. Epub 2022 Jan 5 PubMed.

Mutations

PSEN1 L418W

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