Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity, Parkinsonism : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73673096 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ACA to GCA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 9

Findings

This mutation was identified in a Scottish-Italian man who also carried the PSEN1 A434T mutation (Ryan et al., 2016).  He developed memory impairment and a gait disorder at age 42. Both his mental and motor symptoms worsened rapidly, resulting in severe cognitive impairment, development of various pyramidal and extrapyramidal signs, and death at age 47.  Family history was limited, but his father had cognitive impairment and a shuffling gait before death due to brain hemorrhage at age 34.

Neuropathology
Autopsy revealed AD pathology with cotton wool plaques, diffuse amyloid deposits, and severe amyloid angiopathy. Moreover, brain MRI showed extensive white matter hyperintensities and generalized atrophy before death.

Biological Effect
The mutation site is conserved across species and a different substitution at the same residue has been associated with AD. The mutation was predicted to be possibly damaging by Polyphen, and “neutral” by Provean. It was classified as possibly pathogenic by Ryan and colleagues.

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References

Mutations Citations

1. PSEN1 A434T

Paper Citations

1. Ryan NS, Nicholas JM, Weston PS, Liang Y, Lashley T, Guerreiro R, Adamson G, Kenny J, Beck J, Chavez-Gutierrez L, de Strooper B, Revesz T, Holton J, Mead S, Rossor MN, Fox NC. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series. Lancet Neurol. 2016 Dec;15(13):1326-1335. Epub 2016 Oct 21 PubMed.

Further Reading

No Available Further Reading