Mutations

PSEN1 A434C

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1):
Genomic Mutation Name (NT1):
dbSNP ID: rs63750528, rs63750341
Coding/Non-Coding: Coding
Genomic Region: Exon 12
Mutation Type: Point, Double
Codon Change: GCT to TGT

Findings

This mutation is a double point mutation involving two nucleotides within a codon (GCT>TGT). Individuals within the family had variable clinical presentations. Five individuals were affected by Alzheimer’s disease, three of which had an early-onset form. Two individuals had late onset AD, most likely sporadic, developing at age 66 and 78 years of age. In the three cases with the early-onset form, symptoms started very early. The proband developed progressive emotional lability, depression and apathy at age 29. He became increasingly forgetful and irritable and developed behavioral disturbances. Severe dementia was present by age 31. Other symptoms included myoclonus, aphasia, visual and auditory hallucinations, and generalized tonic-clonic seizures. A sibling had a similar disease course, starting at age 28; both were confirmed mutation carriers. The mutation is thought to have arisen in their parent, who also had early-onset disease (onset at age 35), but genetic analysis was not possible (Devi et al., 2000).

An unrelated individual with presumed AD has been reported, but clinical details were unavailable (Rogaeva et al., 2003).

Neuropathology

Postmortem examination of one mutation carrier showed numerous diffuse and neuritic plaques throughout the neocortex, the latter with dense amyloid cores. Neurofibrillary tangles and Hirano bodies were also abundant in the neocortex. Plaques and tangles were found in the amygdala and nucleus basalis. Moderate cell loss and gliosis were evident in the hippocampus, amygdala, and nucleus basalis. The neuropathology was consistent with AD (Devi et al., 2000).

Biological Effect

Unknown.

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References

Paper Citations

  1. . Novel presenilin 1 mutations associated with early onset of dementia in a family with both early-onset and late-onset Alzheimer disease. Arch Neurol. 2000 Oct;57(10):1454-7. PubMed.
  2. . PS1 Alzheimer's disease family with spastic paraplegia: the search for a gene modifier. Neurology. 2003 Oct 14;61(7):1005-7. PubMed.

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Novel presenilin 1 mutations associated with early onset of dementia in a family with both early-onset and late-onset Alzheimer disease. Arch Neurol. 2000 Oct;57(10):1454-7. PubMed.

Other mutations at this position

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