Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640338 A>T
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: AAT to TAT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

The proband developed symptoms at age 32, starting with forgetfulness and confusion. By age 39 she had spasticity in both arms. She later developed other motor symptoms including a gait abnormality, described as “wide based” and “scissoring.” She enrolled in the Dominantly Inherited Alzheimer Network (DIAN) study and participated in neuropsychological testing and quantitative brain imaging. Her father had died at age 48 after being in a severe stage of dementia for three years. His cognitive symptoms began rapidly at age 42 and were accompanied by visual and auditory hallucinations. His clinical diagnosis of AD was confirmed by autopsy. He had a seizure disorder as a child. There were no other known cases of dementia in the family (Natelson Love et al., 2016).

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, May 2021).

Neuropathology

The proband’s MRI showed decreased volume in many regions, including the bilateral precuneus, hippocampus, entorhinal cortex, parahippocampal cortex, lateral occipital cortex, and amygdala, among others. FDG-PET showed decreased metabolism in many regions, including the bilateral precuneus, posterior cingulate, and lateral orbitofrontal cortices. The left hippocampus had striking hypermetabolism. PiB-PET imaging showed amyloid in the brainstem, striatum, temporal lobes, parietal lobes, and occipital lobes, among other areas. Video-EEG telemetry monitoring showed epileptiform activity in both frontal lobes.

The autopsy report of the proband’s father confirmed his AD diagnosis. Findings included striking cerebral atrophy, especially in the frontal and temporal lobes, the hippocampus, and the amygdala, whereas the basal ganglia, subthalamic nucleus, red nucleus, and substantia nigra were relatively spared. White matter was moderately reduced. Neuritic plaques ranged from “moderate” to “frequent” resulting in a CERAD designation of C. There were numerous neurofibrillary tangles in the hippocampal formation and the neocortex, resulting in a Braak and Braak stage of V/VI. No Lewy bodies were observed.

Biological Effect

When expressed in 7PA2 Chinese hamster ovarian cells stably overexpressing human APP, the N135Y mutation in PSEN1 produced less secreted Aβ40 and had a higher Aβ42/Aβ40 ratio than cells expressing wild-type presenilin-1.

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).

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References

Paper Citations

1. Natelson Love M, Clark DG, Cochran JN, Den Beste KA, Geldmacher DS, Benzinger TL, Gordon BA, Morris JC, Bateman RJ, Roberson ED. Clinical, imaging, pathological, and biochemical characterization of a novel presenilin 1 mutation (N135Y) causing Alzheimer's disease. Neurobiol Aging. 2017 Jan;49:216.e7-216.e13. Epub 2016 Oct 3 PubMed.
2. 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