Mutations

PSEN1 R269H

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Myoclonus
Genomic Mutation Name (MET1): g.49991G>A
Genomic Mutation Name (NT1): g.66597G>A
dbSNP ID: rs63750900
Coding/Non-Coding: Coding
Genomic Region: Exon 8
Mutation Type: Point, Missense
Codon Change: CGT to CAT

Findings

This mutation has been described in at least four families world-wide. The age at onset has been described as particularly variable for carriers of this mutation, ranging from mid-forties to late-sixties.

This mutation was first described in a Caucasian American man who developed memory impairment at the age of 46. He died after a nine-year course of progressive dementia and met CERAD criteria for AD. His clinical phenotype included visual and auditory hallucinations and myoclonus He did not have seizures or extrapyramidal signs. His APOE genotype was ε4/ε4. The patient’s father died at the age of 61 after a five year history of dementia. There was no further family history of dementia and segregation with disease could not be assessed (Gómez-Isla et al., 1997).

Two members of a Japanese family (Mat-1) were found to carry this mutation. They met NINCDS-ADRDA criteria for AD and had an average age at onset of 50 years. Further clinical details were not reported (Kamimura et al., 1998).

A U.K. family was identified (Family 226) with four affected individuals over three generations. The mean age of onset in this family was 53 years of age (range: 50 to 56). At least one member of this family had an autopsy-confirmed diagnosis of AD (Janssen et al., 2003).

A second U.K. family has been reported with nine affected individuals over three generations in a pattern consistent with autosomal dominant transmission. The proband presented with forgetfulness at the age of 66 and was diagnoses with probable AD. He later developed prominent visual agnosia. His mother was diagnosed with AD at the age of 67 and died two years later. She was one of seven sisters, five of whom were reported to have had AD, as did the maternal grandfather. At the age of 69, the proband’s sister also developed memory impairment consistent with AD. The proband was determined to carry the R269H mutation, but segregation with disease could not assessed due to lack of DNA from family members (Larner et al., 2007).

Neuropathology

Postmortem analysis in the first mutation carrier showed a high burden of Aβ and neurofibrillary tangles in cortical areas compared to other cases of similar age and APOE genotype (Gómez-Isla et al., 1997).

MRI in another proband showed global brain atrophy and white matter changes thought to be associated with the patient’s visual agnosia (Larner et al., 2007).

Biological Effect

Unknown.

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References

Paper Citations

  1. . A novel presenilin-1 mutation: increased beta-amyloid and neurofibrillary changes. Ann Neurol. 1997 Jun;41(6):809-13. PubMed.
  2. . Familial Alzheimer's disease genes in Japanese. J Neurol Sci. 1998 Sep 18;160(1):76-81. PubMed.
  3. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
  4. . The R269H mutation in presenilin-1 presenting as late-onset autosomal dominant Alzheimer's disease. J Neurol Sci. 2007 Jan 31;252(2):173-6. Epub 2006 Dec 26 PubMed.

Further Reading

Papers

  1. . The R269H mutation in presenilin-1 presenting as late-onset autosomal dominant Alzheimer's disease. J Neurol Sci. 2007 Jan 31;252(2):173-6. Epub 2006 Dec 26 PubMed.
  2. . The impact of different presenilin 1 andpresenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer's disease brain: evidence for other phenotype-modifying factors. Brain. 1999 Sep;122 ( Pt 9):1709-19. PubMed.

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . A novel presenilin-1 mutation: increased beta-amyloid and neurofibrillary changes. Ann Neurol. 1997 Jun;41(6):809-13. PubMed.

Other mutations at this position

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