Early-onset familial Alzheimer disease is caused by mutations in the amyloid precursor protein (APP), presenilin-1 (PSEN1), or presenilin-2 (PSEN2) genes. Phenotypic diversity has been reported to be associated with various mutations in PSEN1. Various mutations of PSEN1 have been reported in cases of early-onset Alzheimer disease with spastic paraparesis.
To describe a novel mutation in the PSEN1 gene associated with early-onset Alzheimer disease with spastic paraparesis.
Patient and Methods
The patient was a 27-year-old man who developed early-onset dementia with spastic paraparesis. We examined sequences of the PSEN1, PSEN2, and APP genes from the patient and his family. To detect a possible mutation effect on the production of amyloid-β peptide (Aβ), transfected HEK293 cells were examined for Aβ42 and Aβ40 production.
We found a novel mutation (Leu85Pro) in PSEN1. This mutation influenced the production of Aβ, resulting in a 2-fold elevation of Aβ42 production and of the Aβ42/40 ratio.
To our knowledge, this is the first report of very early–onset Alzheimer disease with spastic paraparesis and with the visual variant form of the disease, which is associated with visuospatial cognitive disorder. The Leu85Pro mutation in PSEN1 was pathogenic.