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 I (PSEN1), and presenilin 2 (PSEN2) genes. Most cases are due to mutations in the PSEN1 gene, whereas mutations in the APP and PSEN2 genes are rare. Objective: To describe a novel mutation in the PSEN2 gene 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 the APP, PSEN1, I PSEN2, and tau (TAU) genes was performed. Apolipoprotein E (APOE) was also genotyped. Results: We found a missense mutation at codon 430 of the PSEN2 gene 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 mouse PSEN1 and mouse PSEN2 homologues. No influence of the APOE genotype was observed. Conclusions: We have found a novel mutation in the PSEN2 gene in a family with early-onset Alzheimer disease. The variation in the age at onset confirms that PSEN2 mutations are associated with variable clinical expression.