Mutations

PSEN1 L282V

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy
Reference Assembly: GRCh37 (105)
Position: Chr14:73664813 C>G
dbSNP ID: rs63749937
Coding/Non-Coding: Coding
Genomic Region: Exon 8
Mutation Type: Point, Missense
Codon Change: CTT to GTT

Findings

This mutation was identified in a Belgian family affected by early onset Alzheimer’s disease (Dermaut et al., 2001). The family, known as “GB”, included five affected individuals over three generations, in a pattern suggestive of autosomal-dominant transmission. The mean age of onset in the GB family was 44.3 ± 3.1 years, with mean age at death of 53.5 ± 3.3 years.

One of the two confirmed mutation carriers in this family developed symptoms at the age of 45. In addition to cognitive deficits, he developed extrapyramidal features including a shuffling gait, sporadic myoclonus in the hands, and rigidity in the upper limbs. A few years later, he developed epileptic seizure-like episodes and generalized rigidity and myoclonus. He died at age 54. His parents had died with dementia, his mother at age 54 and his father at 83 (thought to be sporadic AD).

A cousin of the proband described above was also a mutation carrier. She developed signs of cognitive impairment at age 41. She had depression and aphasia, which progressed to complete muteness. She died at the age of 49. Her father was similarly affected by AD. He developed symptoms around age 53 and died at age 57 with neuropathologically confirmed AD.

Both confirmed mutation carriers in this family had ApoE genotypes of 3/4.

Neuropathology

Neuropathology findings are available for one of the two confirmed mutation carriers. Overall, neuropathology was consistent with the diagnosis of AD. Neurofibrillary tangles were seen in the entorhinal cortex, the CA1 and CA2 regions of the hippocampus, and in the neocortex. Amyloid deposits were present both as dense-cored plaques and diffuse plaques in all regions analyzed. Activated microglia and astrocytes were associated with dense-cored plaques. The brain was notable for severe and extensive cerebral amyloid angiopathy (CAA) in all regions analyzed, including the neocortex, hippocampus, and cerebellum. Like the cored plaque amyloid pathology, the CAA deposits were associated with dystrophic neurites and inflammatory gliosis. There was severe white-matter loss in the neocortex. The cerebellum had notable amyloid pathology associated with severe CAA and loss of Purkinje cells.

A brain biopsy specimen of the above’s affected father also revealed plaques and tangles consistent with the diagnosis of AD. Severe CAA was also found in his brain.

Notably, the prominent CAA pathology found in the GB family did not appear to lead to strokes or stroke-like episodes.

Biological Effect

HEK-293 cell lines stably expressing mutant PSEN1 showed a twofold increase in the Aβ42/Aβ40 ratio compared with cells expressing wildtype PSEN1.

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References

Paper Citations

  1. . Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease due to a novel presenilin 1 mutation. Brain. 2001 Dec;124(Pt 12):2383-92. PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

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Primary Papers

  1. . Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease due to a novel presenilin 1 mutation. Brain. 2001 Dec;124(Pt 12):2383-92. PubMed.

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