A novel presenilin-1 mutation (Leu85Pro) in early-onset Alzheimer disease with spastic paraparesis.
BACKGROUND
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.


OBJECTIVE
To describe a novel mutation in the PSEN1 gene associated with early-onset Alzheimer disease with spastic paraparesis.


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-beta peptide (Abeta), transfected HEK293 cells were examined for Abeta42 and Abeta40 production.


RESULTS
We found a novel mutation (Leu85Pro) in PSEN1. This mutation influenced the production of Abeta, resulting in a 2-fold elevation of Abeta42 production and of the Abeta42/40 ratio.


CONCLUSIONS
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.
Ataka
Suzuka
S
Department of Neurology, Osaka City University Medical School, Osaka, Japan.
Tomiyama
Takami
T
Takuma
Hiroshi
H
Yamashita
Takenari
T
Shimada
Hiroyuki
H
Tsutada
Tsuyoshi
T
Kawabata
Koichi
K
Mori
Hiroshi
H
Miki
Takami
T
D000328:Adult; D017668:Age of Onset; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000235:genetics; D004252:DNA Mutational Analysis; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D020336:Paraparesis, Spastic / Q000209:etiology*; D017354:Point Mutation; D053764:Presenilin-1; D014786:Vision Disorders / Q000209:etiology
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1