Japanese siblings with missense mutation (717Val right arrow Ile) in amyloid precursor protein of early-onset Alzheimer's disease

Abstract

We report Japanese siblings with the missense mutation 717Val right arrow Ile in the amyloid precursor protein.The maternal grandmother died of an unknown dementing disorder. The proband's mother had gradually increasing amnesia beginning at age 64, which was diagnosed as Alzheimer's disease (AD). She died in a psychiatric hospital (duration of illness: 16 years). Both the proband and her elder sister were affected at about age 55 years. Disturbances of memory, judgment, and emotion, as well as personality changes, occurred first, with dementia eventually predominating. The elder sister died of pneumonia (duration of illness: 9 years). The amyloid precursor protein (APP) gene was analyzed from each sibling. Genomic DNAs obtained from blood samples were amplified by the polymerase chain reaction (PCR) method. PCR products were digested with the restriction enzyme Bcl I. The resulting restriction fragment length polymorphisms (RFLPs) showed the missense mutation 717Val right arrow Ile in both patients, but not in a normal control. DNA sequencing showed the presence of the 2149G right arrow A missense mutation only in the patients. We conclude that this familial AD may originate from the missense mutation 717Val right arrow Ile in the amyloid precursor protein gene and that the clinical picture is typical of AD, except for normal-pressure hydrocephalus and psychiatric phenomena.

NEUROLOGY 1996;46: 1721-1723