Mutations

PSEN1 L424H

Overview

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

Findings

This mutation was first reported in a French pedigree known as ALZ 161, which included three individuals affected by early onset dementia. Onset ranged from 38 to 42 years of age. Further clinical details were not reported (Raux et al., 2005).

This mutation was also found in an individual with early onset dementia presenting with a complex clinical phenotype, described as variant AD with features resembling frontotemporal dementia as well as dementia with Lewy bodies. The patient first developed symptoms at age 37, starting with depression, anxiety, personality changes, and social inhibition. Visual and auditory hallucinations followed, along with progressive cognitive deterioration affecting memory, attention, and executive function. She later developed extrapyramidal signs, notably bradykinesia and rigidity. At the time of the report, the patient was 41 years of age and required extensive medical care. Her family history was unknown and segregation with disease could not be analyzed. No mutations were detected in PSEN2 (exons 4, 5, and 7), MAPT, or APP. The L424H mutation was absent in 100 age-matched controls as well as 50 individuals with early onset AD and 100 with late-onset AD (Zekanowski et al., 2006).

Neuropathology

Unknown. MRI showed generalized cerebral atrophy. SPECT imaging showed diffuse cerebral hypoperfusion (Zekanowski et al., 2006).

Biological Effect

In silico modeling suggested little movement of the surrounding amino acids in mutant presenilin-1 compared to the wild-type protein (Zekanowski et al., 2006).

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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. . Two novel presenilin 1 gene mutations connected with frontotemporal dementia-like clinical phenotype: genetic and bioinformatic assessment. Exp Neurol. 2006 Jul;200(1):82-8. 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.
  2. . Two novel presenilin 1 gene mutations connected with frontotemporal dementia-like clinical phenotype: genetic and bioinformatic assessment. Exp Neurol. 2006 Jul;200(1):82-8. PubMed.

Other mutations at this position

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