Creutzfeldt-Jakob disease with a novel four extra-repeat insertional mutation in the PrP gene

Objective: To investigate the role of a short insertional mutation in the p rion protein (PrP) gene (PRNP) in prion disease pathogenesis. Background: T he genetic forms of Creutzfeldt-Jakob disease (CJD) are associated with poi nt or insertional mutations in PRNP. Whereas patients with five, six, seven , eight, and nine extra octapeptide repeats show an autosomal dominant patt ern of inheritance and features of CJD, Gerstmann-Straussler-Scheinker dise ase, or atypical dementia, patients with one, two, or four extra repeats ha ve typical CJD and lack a family history of neurologic disorder. Methods: A genetic, neuropathologic, and biochemical study was carried out in a 65-ye ar-old patient with clinical features of sporadic CJD. Results: A novel fou r extra-repeat insertional mutation of PRNP was found in the patient and in his 59-year-old healthy sister. The patient showed spongiosis, nerve cell loss, and gliosis associated with diffuse PrP immunoreactivity in the cereb ral cortex, subcortical gray structures, and cerebellum. A peculiar aspect was the presence of focal PrP deposits in the basal ganglia and hypothalamu s, superimposed to diffuse PrP immunoreactivity. The biochemical analysis r evealed that both mutant and wild-type PrP participated in the pathologic p rocess, and that the protease-resistant core of the altered PrP isoforms wa s distinct from that observed in sporadic, acquired, and other genetic form s of CJD. Conclusion: These findings support the view that the four extra-r epeat insertion in PRNP is a pathogenic mutation with low penetrance rather than a benign polymorphism, and suggest that this mutation results in the formation of a distinct PrP conformer.