[Familial Alzheimer's disease connected with mutation in presenilin gene 1 (P117L)].

We describe a Polish family with Alzheimer's disease in some of its members. Two sisters were observed and examined--also neuropathologically in the Institute of Psychiatry and Neurology in Warsaw. The disease onset was in our patients at 32 and 33 years. The first symptoms were memory loss and disorientation. Later on myoclonus and extrapyramidal stiffness were noted in both cases. Neurovisualizing examinations performed in both sisters showed diffuse brain atrophy. The symptoms increased rapidly and in short time (several months) the patients became mute and bedbound. They died at age 35 and 37 years. We were informed that the father of the patients suffered from very similar illness and died at age of 37 years and their older brother had the some symptoms and died at the age of 28 years. Post-mortem brain examination disclosed in the both hospitalized cases diffuse atrophy of the cerebral hemispheres, particularly severe in the temporal lobes. Microscopically senile plaques of various types were found in the cortex. The density of the plaques was very high but Alzheimer's fibrillary degeneration was found occasionally only. The amyloid burden in cortex of the examined brains, estimated as the measure of parenchymal amyloidosis beta, was two to six-fold higher in most areas compared with changes in sporadic AD and Down-syndrome cases. DNA was isolated from blood and tissue of both cases and from blood of their 8 children as well. In both patients mutation in presenilin 1 (PS1) gene of Prol 117 Leu was found and it was discovered that 4 persons of their progeniture were carriers of this mutation. The described mutation causes one of the earliest so far reported onset and death in FAD kindreds. Presenilin isolated from both cases and transfected into cultures of murine neuroblastoma and human kidneys provoked production of beta amyloid with increased A-beta 42/40 ratio.