High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes

Clinical differential diagnosis of early-onset dementia (EOD) includes fami lial Alzheimer disease (FAD) and hereditary prion disease. In both disease entities, postmortem brain histopathological examination is essential for u nambiguous diagnosis. Mutations in the genes encoding the presenilins (PS1 and PS2) and amyloid precursor protein (APP) are associated with FAD, where as mutations in the prion protein (PrP) gene are associated with prion dise ase. To investigate the proportion of EOD attributable to known genes, we p rospectively (i.e., antemortem) screened these four genes for mutations by sequencing genomic PCR products from patients with EOD before age 60 years. Family history for dementia was positive (PFH) in 16 patients, negative (N FH) in 17 patients, and unknown (UFH) in 3 patients. In 12 patients, we fou nd five novel mutations (in PS1, F105L; in PS2, T122P and M239I; and in PrP , Q160X and T188K) and five previously reported mutations (in APP, in three patients who were most likely unrelated, V7171; in PS1, A79V and M139V; an d in PrP, P102L and T183A) that are all considered to be disease causing. O f these 12 patients, 3 had PFH. This indicates a detection rate of 56% (3/1 6) in patients with PFH. We found two mutations (APP V717I) in two of the t hree UFH patients, and only one mutation (PrP T188K) in 1 of the 17 patient s with NFH. We conclude that because of the lack of specific antemortem dia gnostic markers for FAD and hereditary prion disease, all four genes should be included in a molecular diagnostic program in patients with EOD who had PFH.