An inherited prion disease with a PrPP105L mutation - Clinicopathologic and PrP heterogeneity

Objective: To clarify a clinical and neuropathologic phenotype of an inheri ted prion disease associated with a missense mutation at codon 105 in the p rion protein (PrP) gene that was originally described as a variant of Gerst mann-Straussler-Scheinker disease demonstrating spastic paraparesis. Method s: Two siblings from a Japanese family are described. PrP gene analyses, ne uropathologic studies with immunohistochemistry, and Western blot analysis of the PrP were performed. Results: Both patients showed a missense (prolin e-->leucine) mutation at codon 105 and a methionine/valine polymorphism at codon 129 of the PrP gene. Clinically, Patient 1 presented with progressive spastic: paraparesis, ataxia, and dementia. Patient 2, the sister of Patie nt 1, showed prominent action myoclonus and dementia. Neuropathologically, multiple PrP-positive amyloid plaques and diffuse PrP deposition in the dee p cortical layers were found in the cerebral cortex with primarily frontal dominant atrophy in both patients. Tau-positive pathologic structures inclu ding neurofibrillary tangles, neuropil threads, and dystrophic neurites aro und the plaques were abundant in the brain of Patient 2. In contrast, the t au pathology was scarce in Patient 1. Western blot analysis of the brain sh owed different patterns of detergent-insoluble PrP fragments between the pa tients. Conclusions: Despite the identical codon 105 mutation and codon 129 polymorphism of the PrP gene, remarkable clinical and neuropathologic diff erences, and PrP heterogeneity were present between the affected siblings. The phenotypic variability might be related to PrP heterogeneity.