Mutations

PSEN1 A260G

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Cerebral Amyloid Angiopathy :
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73664748 C>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GCT to GGT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This amino acid substitution was first reported in a family with Alzheimer’s disease, including eight affected members with a mean age of onset of 53 and a mean disease duration of 13 years (Ryman et al., 2014). The underlying genetic alteration was not reported.

Subsequently, the mutation was found in an Italian family that included two symptomatic carriers and one asymptomatic carrier, suggesting incomplete penetrance (Piaceri et al., 2020). The proband was a woman who experienced memory deficits beginning at age 53 and whose cognitive abilities deteriorated rapidly after age 55. She developed severe behavioral disturbances, including delusions and aggression. The proband’s mother and one of the proband’s aunts suffered from rapidly progressive dementia with parkinsonism leading to death in less than five years. Another aunt also suffered from dementia, but progression was slower.

Two of three of the proband’s siblings carried the mutation, but only one was symptomatic. The symptomatic carrier, a 54-year-old woman, developed cognitive deficits at 54, with left-sided rigidity and bradykinesia. Like her sister, she deteriorated rapidly, developing overt dementia, behavioral disturbances, parkinsonism, and myoclonus. Strikingly, the other sibling carrying the mutation remained healthy until the end of the study, at which time he was 64. The noncarrier sibling, a 67-year-old woman, also remained healthy. All genotyped members were APOE3 homozygotes.

Neuropathology
Neuropathology is unavailable, but cerebrospinal fluid biomarkers for AD, including Aβ42, total tau, and phospho-tau, were consistent with AD in two patients (Piaceri et al., 2020). Moreover, brain MRI of one patient revealed mild cortical and hippocampal atrophy, severe vascular leukencephalopathy, multiple microbleeds, and superficial siderosis. The patient was diagnosed with cerebral amyloid angiopathy. In another patient at an early stage of disease, no significant atrophy was detected by MRI, but vascular leukencephalopathy without microbleeds or superficial siderosis was reported.

Biological effect
The biological effect of this mutation is unknown. Piaceri and colleagues speculate that DNA methylation may contribute to its pathogenicity because the two symptomatic women carrying the mutation had global levels of DNA methylation that were higher than that of the asymptomatic carrier (Piaceri et al., 2020). The methylation level of the noncarrier sibling was similar to that of the symptomatic carriers.

Last Updated: 30 Apr 2020

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References

Paper Citations

  1. . Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology. 2014 Jul 15;83(3):253-60. Epub 2014 Jun 13 PubMed.
  2. . Incomplete penetrance in familial Alzheimer's disease with PSEN1 Ala260Gly mutation. Neurol Sci. 2020 Apr 23; PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology. 2014 Jul 15;83(3):253-60. Epub 2014 Jun 13 PubMed.
  2. . Incomplete penetrance in familial Alzheimer's disease with PSEN1 Ala260Gly mutation. Neurol Sci. 2020 Apr 23; PubMed.

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