A novel mutation (G217D) in the Presenilin 1 gene ( PSEN1) in a Japanese family: presenile dementia and parkinsonism are associated with cotton wool plaques in the cortex and striatum.

We report a family of Japanese origin that has five individuals from two generations affected by an illness characterized by dementia, a stooped posture and an antiflexion gait with an onset in the fourth or fifth decade of life. Two siblings had a clinical phenotype characterized by dementia and Parkinsonism with stooped posture, rigidity and bradykinesia. Neuropathological alterations in both patients included numerous 'cotton wool' plaques (CWPs), senile plaques, severe amyloid angiopathy, neurofibrillary tangles, neuronal rarefaction and gliosis. CWPs were present throughout the cerebral cortex as well as in the caudate nucleus, putamen, claustrum, thalamus, substantia innominata and colliculi. These plaques contained a small quantity of argyrophilic and tau-immunopositive neurites as well as glial fibrillary acidic protein-immunopositive elements. They were mildly fluorescent with thioflavin S and immunopositive using monoclonal antibodies recognizing amyloid beta (A beta) ending at residue 42. The main constituents of CWPs were neuropil elements and extracellular amyloid fibrils. These neuropil elements were small dendrites including spines, axon terminals containing synaptic vesicles and astrocytic processes. Dendrites occasionally contained bundles of paired helical filaments. Dendrites and axons often had an irregular outline and appeared as degenerating osmiophilic processes containing electron-dense mitochondria. Genetic analysis of the proband's affected sibling revealed a novel nucleotide substitution (G to A) in exon 8 of the Presenilin 1 ( PSEN1) gene. This nucleotide change results in a glycine to aspartic acid substitution at residue 217 of the PSEN1 protein. This study provides further evidence of clinical and pathological heterogeneity in dementing illnesses associated with PSEN1 mutations.