Objective: To define the clinicopathologic, genetic, and pathogenic prion protein (PrP) characteristics associated with a novel mutation of the prion protein gene (PRNP). Methods: The coding segment of PRNP from the proband and family members was sequenced and the brain of the proband was histologically studied. The Western blot profile of the proteinase K (PK) resistant fraction of PrP, an approximation of its conformation, or "PrP-type," was determined. Results: We detected a novel mutation at codon 105 of PRNP that results in a serine (S) substitution of proline (P) (P105S), in a young woman who developed progressive aphasia, behavioral changes, dementia, and parkinsonism, lasting 10 years to her death. Histopathologic findings included an intense focus of multicentric PrP-plaques within the hippocampus, punctate plaques scattered throughout the cerebellum, and intense spongiform degeneration focally within the putamen, suggesting a variant of Gerstmann-Sträussler- Scheinker syndrome (GSS). However, PrP-typing revealed two PK-resistant PrP fragments (∼21 and 26 kDa), a pattern not previously detected in GSS. Conclusions: This mutation is the third sequence variation at codon 105 of PRNP. The unusual phenotype and PrP-type distinguishes this genetic prion disease from typical Gerstmann-Sträussler-Scheinker syndrome and other codon 105 substitutions, suggesting that, in addition to the loss of proline at this position, the PrP conformation and phenotype is dependent on the specific amino acid substitution. © 2008 by AAN Enterprises, Inc.