High Prevalence of Pathogenic Mutations in Patients with Early-Onset Dementia Detected by Sequence Analyses of Four Different Genes

Abstract

Clinical differential diagnosis of early-onset dementia (EOD) includes familial Alzheimer disease (FAD) and hereditary prion disease. In both disease entities, postmortem brain histopathological examination is essential for unambiguous diagnosis. Mutations in the genes encoding the presenilins (PS1 and PS2) and amyloid precursor protein (APP) are associated with FAD, whereas mutations in the prion protein (PrP) gene are associated with prion disease. To investigate the proportion of EOD attributable to known genes, we prospectively (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 (NFH) in 17 patients, and unknown (UFH) in 3 patients. In 12 patients, we found 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, V717I; in PS1, A79V and M139V; and in PrP, P102L and T183A) that are all considered to be disease causing. Of these 12 patients, 9 had PFH. This indicates a detection rate of 56% (9/16) in patients with PFH. We found two mutations (APP V717I) in two of the three UFH patients, and only one mutation (PrP T188K) in 1 of the 17 patients with NFH. We conclude that because of the lack of specific antemortem diagnostic 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.

Prion disease genetics

“…Mutation screening of dementia has shown that prion disease is a frequent cause of inherited early onset dementia. Finckh et al, 14 for example, tested four genes (APP, PSEN1, PSEN2 and PRNP) in 36 patients with familial early onset dementia and found PRNP accounted for 4/12 mutation positive cases. A general epidemiological account of IPD is problematic, however, for a number of reasons.…”

Detailed Characterization of Neuroprotection by a Rescue Factor Humanin against Various Alzheimer's Disease-Relevant Insults

“…Three kinds of known mutant genes cause familial AD (FAD): mutants of amyloid precursor protein (APP), presenilin (PS) 1, and PS2 (Shastry and Giblin, 1999). The most frequent causes for FAD are the mutations in PS1, whereas only a few mutations were found in PS2 (Cruts and Van Broeckhoven, 1998;Finckh et al, 2000). Among FAD-linked mutations of APP, V642 mutations to I, F, and G are the most popular cause (Hardy, 1992).…”

Binding of bovine T194A PrPCby PrPSc-specific antibodies

“…27,29 In these individuals immunization with a prion vaccine would seem a rationale course of action. We previously conducted experiments to confirm that antibodies produced in response to the conformations that are structurally consistent with the diseaseassociated folding pattern.…”

“…27 For example, an inherited prion disease in humans is associated with the mutation T183A. 28,29 This mutation has been suggested to disrupt glycosylation, 28 promote structural instability and misfolding 30,31 and accelerate conversion of the α-helical to β-sheet rich conformation. 32 Independent of the specific mechanism, this mutation correlates with early onset spontaneous prion disease.…”

“…32 Independent of the specific mechanism, this mutation correlates with early onset spontaneous prion disease. 28,29 The low occurrence of prion diseases in the human population makes it highly unlikely that a prion vaccine would ever be administered to the general population. Instead, such a vaccine might be strategically administered to high risk individuals, such as those working with prions or be utilized as a therapeutic vaccine for persons genetically predisposed to prion diseases.…”