Novel prion protein gene mutation in an octogenarian with Creutzfeldt-Jakob disease

Background: The transmissible spongiform encephalopathies constitute a fasc inating and biologically unique group of invariably fatal neurodegenerative disorders that affect both animals and humans. Creutzfeldt-Jakob disease ( CJD), Girstmann-Straussler-Scheinker syndrome, and fatal familial insomnia represent the more common human phenotypes. Excluding the small number of i atrogenically transmitted cases, approximately 85% to 90% of patients devel op CJD without identifiable explanation, with an increasing number of diffe rent mutations in the prion protein gene (PRNP) recognized as probably caus ative in the remainder. Objective: To report on an 82-year-old woman with pathologically confirmed CJD found unexpectedly to harbor a novel mutation in PRNP. Methods: Routine clinical investigations were undertaken to elucidate the c ause of the rapidly progressive dementia and neurological decline manifeste d by the patient, including magnetic resonance imaging of the brain, electr oencephalography, and cerebrospinal fluid analysis for the 14-3-3 beta prot ein. Standard postmortem neuropathological examination of the brain was per formed, including immunocytochemistry of representative sections to detect the prion protein. Posthumous genetic analysis of the open reading frame of PRNP was performed on frozen brain tissue using polymerase chain reaction and direct sequencing. Results: Concomitant with the exclusion of alternative diagnoses, the prese nce of characteristic periodic sharp-wave complexes on the electroencephalo gram in combination with a positive result for 14-3-3 beta protein in the c erebrospinal fluid led to a confident clinical diagnosis of CJD, confirmed at autopsy. There was no family history of dementia or similar neurological illness, but patrilineal medical information was incomplete. Unexpectedly, full sequencing of the PRNP open reading frame revealed a single novel mut ation consisting of an adenine-to-guanine substitution at nucleotide 611, c ausing alanine to replace threonine at codon 188. Conclusions: In addition to expanding the range of PRNP mutations associate d with human prion diseases, we believe this case is important for the foll owing reasons. First, from an epidemiological perspective, the avoidance of occasional incorrect classification of patients manifesting neurodegenerat ive disorders that may have a genetic basis requires systematic genotyping, particularly when there are uncertainties regarding the family history. Se cond, the incidence of spongiform encephalopathy in elderly patients beyond the typical age range may be underestimated and does not preclude a geneti c basis. Finally, as a corollary, this case highlights problematic issues i n human transmissible spongiform encephalopathies, as illustrated by diseas e penetrance and age of onset in genotype-phenotype correlations.