Different clinical phenotypes in siblings with a presenilin-1 P264L mutation

Mutations in the presenilin-1 gene (PSEN1) have been identified in autosomal dominant early-onset cases of Alzheimer's disease (AD).

To investigate different clinical phenotypes of siblings possessing the same heterozygous P264L mutation in the PSEN1 gene.

We evaluated clinical features, neuroimaging results, and neuropsychological examinations. The PSEN1 gene and other dementia-related gene mutations were screened.

We clinically diagnosed the proband as atypical AD with frontotemporal dementia features and diagnosed the elder brother of the proband as typical AD, based on neuropsychological symptoms and a brain imaging examination including amyloid imaging data. A heterozygous P264L mutation in the PSEN1 gene was identified in both siblings.

This study is one of few reports of AD siblings possessing the same mutation but exhibiting different clinical phenotypes in a Japanese family possessing a P264L mutation in the PSEN1 gene. The current results suggest that unknown modifiers, including both genetic and epigenetic factors, may alter the pathological and clinical phenotypes of a genetically predetermined disease.