Mutations

PSEN1 L420R

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genome Build: 105
Position: Chr14:73685852 T>G
dbSNP ID: rs63750802
Coding/Non-Coding: Coding
Genomic Region: Exon 12
Mutation Type: Point, Missense
Codon Change: CTT to CGT

Findings

This mutation was first identified in a family affected by early onset Alzheimer’s disease (Shrimpton et al., 2007). Disease in this family was characterized by seizures and cotton-wool plaques, but not spastic paraparesis. The proband, who also had rheumatoid arthritis, began to develop short-term memory loss in his late 30s. He became disoriented and developed irrational behavior. As the disease progressed, seizures developed, and he died at age 48, about a decade after onset. The reported pedigree shows that his mother and sister were also affected. The mutation appears to segregate with disease; it was detected in both the proband and his affected sister.

The mutation was later identified in a member of a Japanese family affected by familial Alzheimer’s disease with parkinsonism (Niwa et al., 2013). The proband developed cognitive impairment at age 31 after a motorcycle accident. By 39 she had also developed a parkinsonism gait and posture. She died at age 43, 12 years after symptom onset. Six other family members were affected by severe dementia and parkinsonism, including the proband’s father, her three siblings, and two daughters. Onset for all began in their 30s or 40s. Segregation with disease could not be determined, as DNA was available only from one of the proband’s affected daughters.

Neuropathology

Autopsy showed amyloid pathology in the neocortex and hippocampus. The majority of plaques were large, round, non-cored plaques (i.e., cotton-wool plaques), although some rare cored plaques were also observed. Tau pathology was most pronounced in the hippocampus and entorhinal cortex, and included neurofibrillary tangles and neuropil threads. Some amyloid angiopathy was also noted (Shrimpton et al., 2007).

Similarly, autopsy of the Japanese proband showed extensive amyloid pathology throughout the neocortex and hippocampus. Large cotton-wool plaques were abundant. Neurofibrillary tangles, neuropil threads, neuronal loss, and gliosis were also observed. The substantia nigra was atrophic, but α-synuclein staining was negative and Lewy bodies were not observed. Cerebral amyloid angiopathy affected arterioles in the neocortex, and capillaries in the neocortex and subcortical nuclei (Niwa et al., 2013).

Biological Effect

Unknown.

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References

Paper Citations

  1. . A presenilin 1 mutation (L420R) in a family with early onset Alzheimer disease, seizures and cotton wool plaques, but not spastic paraparesis. Neuropathology. 2007 Jun;27(3):228-32. PubMed.
  2. . Clinical and neuropathological findings in a patient with familial Alzheimer disease showing a mutation in the PSEN1 gene. Neuropathology. 2012 Aug 12; PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database
  2. Japanese Familial Alzheimer's Disease Database

Primary Papers

  1. . A presenilin 1 mutation (L420R) in a family with early onset Alzheimer disease, seizures and cotton wool plaques, but not spastic paraparesis. Neuropathology. 2007 Jun;27(3):228-32. PubMed.

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