The Clinical phenotype of two missense mutations in the presenilin I gene in Japanese patients

Abstract

We report the clinical and neuropathologic phenotypes associated with two different missense mutations in the presenilin 1 (PS‐1) gene in Japanese patients with early‐onset familial Alzheimer's disease (FAD). In the Ah4/JPN1 pedigree a missense mutation (C→T) was found at nucleotide 1102, which is predicted to cause an alanine‐to‐valine missense substitution at codon 260. In this family, the disease had a mean age of onset of 40.3 years and an indolent course (range, 8–19 years). Neuropathologic studies in 3 members of this pedigree showed widespread senile plaques, neurofibrillary tangles, and neuronal loss, as well as abundant perivascular subpial amyloid deposits in the Virchow‐Robin spaces and the presence of Pick‐like intraneuronal inclusions in the dentate gyrus. In the second pedigree, transmitting a C→T nucleotide substitution at position 1027, leading to the missense mutation of alanine to valine at codon 285, the disease had a later onset (mean, 51 years) but a more rapid course. Comparison of the disease phenotypes associated with other missense mutations in exon 9 of PS‐1 reveals no clinical or pathological phenotype, which uniquely distinguishes Alzheimer's disease associated with PS‐1 mutations from other forms of early‐onset FAD, implying that direct mutation screening is required to identify these cases.