A novel mutation in the PSEN2 gene (T430M) associated with variable expression in a family with early-onset Alzheimer disease

Background Autosomal dominant early-onset Alzheimer disease is a heterogeneous condition that has been associated with mutations in 3 different genes: the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes. Most cases are due to mutations in thePSEN1gene, whereas mutations in theAPPandPSEN2genes are rare. Objective To describe a novel mutation in thePSEN2gene associated with early-onset autosomal dominant Alzheimer disease. Patients and Methods The proband was a 49-year-old individual who displayed progressive dementia beginning at age 45 years. One of the parents and one of the grandparents had developed dementia at ages 64 years and 60 years, respectively, and 1 sibling had mild cognitive impairment. Some family members also had Tourette syndrome. Mutation analysis of theAPP,PSEN1,PSEN2,and tau (TAU) genes was performed. Apolipoprotein E (APOE) was also genotyped. Results We found a missense mutation at codon 430 of thePSEN2gene that predicts a threonine-to-methionine substitution. This mutation was detected in the affected individuals and in 1 cognitively healthy sibling. The mutation was absent in 260 control chromosomes. The normal amino acid was conserved in the human and mousePSEN1and mousePSEN2homologues. No influence of theAPOEgenotype was observed. Conclusions We have found a novel mutation in thePSEN2gene in a family with early-onset Alzheimer disease. The variation in the age at onset confirms thatPSEN2mutations are associated with variable clinical expression.