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 prion protein (PrP) gene (PRNP) in prion disease pathogenesis. Background: The genetic forms of Creutzfeldt-Jakob disease (CJD) are associated with point or insertional mutations in PRNP. Whereas patients with five, six, seven, eight, and nine extra octapeptide repeats show an autosomal dominant pattern of inheritance and features of CJD, Gerstmann-Straussler-Scheinker disease, or atypical dementia, patients with one, two, or four extra repeats have typical CJD and lack a family history of neurologic disorder. Methods: A genetic, neuropathologic, and biochemical study was carried out in a 65-year-old patient with clinical features of sporadic CJD. Results: A novel four 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 cerebral cortex, subcortical gray structures, and cerebellum. A peculiar aspect was the presence of focal PrP deposits in the basal ganglia and hypothalamus, superimposed to diffuse PrP immunoreactivity. The biochemical analysis revealed that both mutant and wild-type PrP participated in the pathologic process, and that the protease-resistant core of the altered PrP isoforms was distinct from that observed in sporadic, acquired, and other genetic forms of CJD. Conclusion: These findings support the view that the four extra-repeat 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.