Mutations

PSEN1 L424R

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.71075T>G
Genomic Mutation Name (NT1): g.87686T>G
dbSNP ID: rs63751032
Coding/Non-Coding: Coding
Genomic Region: Exon 12
Mutation Type: Point, Missense
Codon Change: CTC to CGC

Findings

This mutation was first described in a Polish family (Pedigree J.P) affected by early-onset dementia with prominent motor impairment (Kowalska et al., 1999). The reported pedigree showed at least six affected individuals over four generations (Kowalska et al., 2004). Onset in this family was very early, ranging from 30 to 35 years of age, and deterioration was rapid, with death occurring four to five years after onset. The proband developed progressive memory and language impairment at age 30. Within a year he had also developed sporadic myoclonic jerks and left-side hemiparesis.

This mutation was also reported in a young, Polish, Caucasian woman, who at the age of 34 developed behavioral and personality changes, including apathy and aggression, as well as cognitive decline. She exhibited increasingly severe involuntary movements, including choreic movements in the upper and lower extremities. She also developed gait problems and and seizures. She had a family history of early-onset dementia accompanied by involuntary movements. Her father had died at age 37 following personality changes, memory problems, and motor disturbances. Her paternal aunt died at age 40 with similar symptoms. The proband's paternal grandfather had died in his forties with a diagnosis of "psychiatric disease". Segregation of the mutation with disease could not be assessed due to lack of DNA from family members. Huntington's disease was excluded by genetic testing, and no pathogenic mutations were observed in APP, PSEN2 or PRNP  (Klimkowicz-Mrowiec et al., 2014).

Neuropathology

Unknown. MRI showed cortical and subcortical atrophy with a thin corpus callosum (Klimkowicz-Mrowiec et al., 2014).

Biological Effect

Unknown.

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References

Paper Citations

  1. . A Polish pedigree with Alzheimer's disease determined by a novel mutation in exon 12 of the presenilin 1 gene: clinical and molecular characterization. Folia Neuropathol. 1999;37(1):57-61. PubMed.
  2. . Genetic study of familial cases of Alzheimer's disease. Acta Biochim Pol. 2004;51(1):245-52. PubMed.
  3. . Clinical Presentation of Early-Onset Alzheimer's Disease as a Result of Mutation in Exon 12 of the PSEN-1 Gene. Am J Alzheimers Dis Other Demen. 2014 Jun 6; PubMed.

Further Reading

Papers

  1. . Molecular genetics of Alzheimer's disease: presenilin 1 gene analysis in a cohort of patients from the Poznań region. J Appl Genet. 2003;44(2):231-4. PubMed.
  2. . Presenilin 1 mutations in Polish families with early-onset Alzheimer's disease. Folia Neuropathol. 2004;42(1):9-14. PubMed.

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . A Polish pedigree with Alzheimer's disease determined by a novel mutation in exon 12 of the presenilin 1 gene: clinical and molecular characterization. Folia Neuropathol. 1999;37(1):57-61. PubMed.

Other mutations at this position

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