Novel presenilin 1 mutations associated with early onset of dementia in a family with both early-onset and late-onset Alzheimer disease

Two children of an adult with early-onset, autopsy-confirmed Alzheimer dise ase (AD) developed dementia in their late 20s and mere subsequently found t o have novel mutations in codon 434 of the presenilin 1 (PS1) gene on chrom osome 14, a G-to-T substitution at nucleotide 1548 and a C-to-G substitutio n at nucleotide 1549. The younger of the 2 children had AD confirmed at pos tmortem examination. The disease course in these 3 individuals was characte rized by cognitive and behavioral problems accompanied by myoclonus, seizur es, and aphasia within 5 years after onset. Two grandparents had clinically diagnosed AD with stroke beginning at ages 78 and 66 years, but neither ha d a PS1 mutation. No other living family member tvas demented, nor did any other family member have the PS1 mutation. We conclude that the affected pa rent of the proband was a likely recent founder for these never mutations i n PS1. The family demonstrates the clinical and genetic heterogeneity of AD .