Mutations

PSEN1 G417S

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Spastic Paraparesis : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73685842 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GGT to AGT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation was found in a Japanese woman who initially presented with cognitive impairment, muscle weakness in the hands, and forgetfulness in her mid-20s (Miki et al., 2019). Over the next few years, her motor and cognitive symptoms worsened and she was suspected of having AD with parkinsonism, including spastic paraperesis. Her decline was slow, however, with a disease duration of 29 years. Her final neurological diagnosis was unclassifiable dementia.

Brain MRI at 40 years revealed diffuse cerebral atrophy, and at 44 years, single-photon emission- computed tomography (SPECT) showed hypoperfusion in the posterior part of the cingulate gyrus, precuneus, and parieto-occipital cortices.

The patient’s brother, mother, uncle, and maternal grandfather suffered from dementia and/or gait disturbance, and all died in their late ‘40s. However, no genetic data are available for these relatives.

Neuropathology
Autopsy revealed cotton- wool plaques throughout the cortex, abundant Aβ deposits in the cerebellum and spinal gray matter. Also, cerebral amyloid angiopathy, extensive neuronal loss, astrocytic and microglial markers, and extensive distribution of neocortical Lewy bodies were observed. Moreover, TDP-43 inclusions in the limbic region and temporal cortex were reported.

Biological Effect

Unkown.

Last Updated: 20 Feb 2019

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References

Paper Citations

  1. . Young adult-onset, very slowly progressive cognitive decline with spastic paraparesis in Alzheimer's disease with cotton wool plaques due to a novel presenilin1 G417S mutation. Acta Neuropathol Commun. 2019 Feb 12;7(1):19. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Young adult-onset, very slowly progressive cognitive decline with spastic paraparesis in Alzheimer's disease with cotton wool plaques due to a novel presenilin1 G417S mutation. Acta Neuropathol Commun. 2019 Feb 12;7(1):19. PubMed.

Other mutations at this position

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