CODON Y218N

GERSTMANN STRAUSSLER SCHEINKER

Gerstmann-Straussler-Scheinker (GSS) disease is a prion disease associated with prion protein gene (PRNP) mutations. We report a novel PRNP mutation (Y218N) associated with GSS disease in a pathologically confirmed case and in two other affected family members. The clinical features of these cases met criteria for possible Alzheimer disease and possible frontotemporal dementia. Neuropathologic analysis revealed deposition of proteinase KY resistant prion protein (PrPres), widespread hyperphosphorylated tau pathology, abnormal accumulation of mitochondria in the vicinity of PrPres deposits, and expression of mutant ubiquitin (UBB+1) in neurofibrillary tangles and dystrophic neurites.

Prion protein immunoblotting using 3F4 and 1E4 antibodies disclosed multiple bands ranging from approximately 20 kd to 80 kd and lower bands of 15 kd and approximately 10 kd, the latter only seen after a long incubation. These bands were partially resistant to proteinase K pretreatment. This pattern differs from those seen in Creutzfeldt-Jakob disease and resembles those reported in other GSS cases. The approximately 10 kd band was recognized with antiYPrP C-terminus antibodies but not with antiYN terminus antibodies, suggesting PrP truncation at the N terminal.
This new mutation extends the list of known mutations responsible for GSS disease and reinforces its clinical eterogeneity.
Genetic examination of the PRNP gene should be included in the workup of patients with poorly classifiable dementia.