Familial Prion Disease with Alzheimer Disease-Like Tau Pathology and Clinical Phenotype

Inherited prion diseases are a heterogeneous group of autosomal dominantly inherited neurodegenerative syndromes that were originally divided into Gerstmann-Straussler-Scheinker syndrome (GSS), familial Creutzfeldt-Jacob disease (CJD), and fatal familial insomnia (FFI) based primarily on clinical and pathological characteristics. Mutations in the prion protein (PrP) gene (PRNP) were eventually found to be causative in all of these prion diseases, and since then it has become apparent that PRNP mutation-associated diseases manifest overlapping as well as distinctive clinical and pathological features.1,2 Here, we report a family with a rare PRNP mutation in which the clinical presentation, course, and initial neuropathological studies were strongly suggestive of Alzheimer disease (AD). A clinical diagnosis of early-onset AD was initially made for our proband. Ten years prior, the proband’s mother was also clinically and pathologically diagnosed with AD; the autopsy, carried out in 1987, revealed abundant neuritic plaques and neurofibrillary tangles (NFTs). After an 8-year course, consisting solely of cognitive decline, the proband expired. Her autopsy was also remarkable for abundant limbic and neocortical neuritic plaque-like structures and NFTs, consistent with a neuropathologic diagnosis of AD. However, immunohistochemical studies, which were unavailable at the time of her mother’s autopsy, demonstrated PrP, rather than Aβ, immunopositive deposits. Subsequently, we found this family to have a nonsense substitution for glutamine (Q) at position 160 (Q160X) in PRNP that results in production of truncated PrP. This mutation has been previously described in one family, although with limited clinical description and no microscopic neuropathological characterization.3 Interestingly, a similar mutation, Y145X, has also been reported with a truncated PrP and severe neurofibrillary tangle pathology.4