Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Reference Assembly: GRCh37/hg19
Position: Chr14:73664820 C>T
dbSNP ID: rs63750863
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCA to CTA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was identified in a Japanese woman with dementia and parkinsonism (Tabira et al., 2002). Family history was unknown. Her symptoms started at age 32 with spastic paraparesis leading to falls. She later developed dysarthria (difficulty pronouncing words) and dementia. She died at age 54.

This variant was also reported in a whole-exome sequencing study of 38 Chinese patients with dementia (Xu et al., 2018). The proband fulfilled the diagnostic criteria for dementia due to either AD or frontotemporal dementia. At age 39, he presented with short-term memory impairment, acalculia, and disrupted language fluency. In the following two years, he developed slow responses to external stimuli and limb bradykinesia. Five family members, spanning three generations, were affected, with several developing bradykinesia and dying in their 40s.

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

Neuropathology

Autopsy examination of the Japanese woman showed cortical atrophy, enlarged ventricles, and neuronal loss, especially in the hippocampus, substantia nigra, and locus coeruleus. Abundant amyloid pathology was observed, notably cotton-wool plaques in the cerebral cortex, basal ganglia, brainstem, and spinal cord. Some cored plaques were seen, mainly in the hippocampus and cerebral cortex, where neurofibrillary tangles were also observed. Neuritic changes and glial activation were mild, and prion staining was absent. Vacuolar changes were noted in the cerebral cortex, along with amyloid angiopathy in vessel walls (Tabira et al., 2002).

Brain imaging of the Chinese patient revealed multiple, bilateral white matter hyperintensities beside the lateral ventricles and in the subcortical area of the frontal and parietal lobes (Xu et al., 2018). No lobar atrophy was observed. Of note, there was no amyloid accumulation as assessed by PET-PiB imaging. 

Biological Effect

The biological effect of this variant is unknown but 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).

Pathogenicity

Alzheimer's Disease : Likely Pathogenic

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. Tabira T, Chui DH, Nakayama H, Kuroda S, Shibuya M. Alzheimer's disease with spastic paresis and cotton wool type plaques. J Neurosci Res. 2002 Nov 1;70(3):367-72. PubMed.
2. Xu Y, Liu X, Shen J, Tian W, Fang R, Li B, Ma J, Cao L, Chen S, Li G, Tang H. The Whole Exome Sequencing Clarifies the Genotype- Phenotype Correlations in Patients with Early-Onset Dementia. Aging Dis. 2018 Aug;9(4):696-705. PubMed.
3. 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

Learn More

1. Japanese Familial Alzheimer's Disease Database