Mutations

PSEN1 G206D

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.44636G>A
Genomic Mutation Name (NT1): g.61242G>A
dbSNP ID: rs63750082
Coding/Non-Coding: Coding
Genomic Region: Exon 7
Mutation Type: Point, Missense
Codon Change: GGT to GAT

Findings

This mutation was identified in a French pedigree, referred to as ALZ 219, with five individuals affected by early-onset Alzheimer’s disease. At least one affected mutation carrier met criteria for probable AD according to NINCDS-ADRDA criteria. Symptom onset in this family clustered at 32 to 34 years of age. The mutation reportedly segregated with disease, although details of the analysis were not described. Note: this mutation was originally reported as G206N (Raux et al., 2005).

An additional family with three affected siblings has been reported. Disease in this family manifested as a rapidly progressing dementia syndrome with features consistent with frontotemporal dementia. The proband developed symptoms at age 39, starting with behavioral changes, depression, and memory and attention deficits. She subsequently developed gait disturbances and bradykinesia. Within a year she had developed seizures and violent behavior. A diagnosis of frontotemporal dementia was suspected, but a biopsy of the frontal cortex  revealed neuropathology more consistent with AD. The proband’s sister developed progressive memory impairment at age 37. Like her sister she also developed seizures. The sisters reportedly had a third affected sibling although clinical details were not available. There was no indication of cognitive impairment in either parent; the father had died at age 60 from liver cancer and the mother died at an unspecified young age. Both siblings carried the mutation. No mutations in APP, PSEN2 or MAPT were detected (Wu et al., 2011).

Neuropathology

Biopsy of the frontal cortex showed abundant amyloid and tau deposits consistent with a diagnosis of AD. MRI of one proband showed atrophy of the temporal lobe and mild paraventricular white matter hyperintensities along with dilation of the third and lateral ventricles. MRI of the proband’s sister showed frontal, parietal and temporal lobe atrophy more prominent on the left. SPECT imaging showed decreased perfusion in the frontotemporal area, again, especially on the left (Wu et al., 2011).

Biological Effect

Unknown.

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References

Paper Citations

  1. . Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.
  2. . Clinical phenotype of G206D mutation in the presenilin 1 gene in pathologically confirmed familial Alzheimer's disease. J Alzheimers Dis. 2011;25(1):145-50. PubMed.

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.

Other mutations at this position

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