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From the Division of Neuropathology (Drs. Capellari, Parchi, Petersen, and Gambetti), Institute of Pathology, Case Western Reserve University, Cleveland, OH; Laboratory of Neuropathology (Dr. Vital) and Department of Neurology (Drs. Ferrer, Jarnier, and Julien), CHU Bordeaux, France; and Department of Molecular Genetics and Biochemistry (Dr. Pegoraro), University of Pittsburgh, Pittsburgh, PA.
Address correspondence and reprint requests to Prof. Jean Julien, Centre Hospitalier Universitaire de Bordeaux, Service de Neurologie, Hôpital du Haut-Leveque-USN, Avenue de Magellan, 33604 PESSAC, France.
Three members of a Basque family carrying a novel six R2 octapeptide repeat 144-bp insertion in the prion protein gene (PRNP) showed a slowly progressive dementia associated with cerebellar signs, myoclonic jerks, and seizures. Although postmortem examination revealed only focal and minimal spongiform degeneration in one subject with a 4-year course, significant astrogliosis and neuronal loss were associated with pronounced spongiform degeneration in the patient with a duration of symptoms of 10 years. Prion protein (PrP)-immunoreactive patches with a unique morphology were present in the molecular layer of the cerebellum in both subjects. Western blot analysis demonstrated the presence of protease-resistant prion protein (PrPres) with the same characteristics (size and ratio of the three differently glycosylated isoforms) of that found in typical sporadic Creutzfeldt-Jakob disease (CJD129M/M, PrPres type 1). The amount of PrPres correlated with presence and severity of spongiform degeneration in the cerebral cortex. The findings suggest that a relatively low rate of PrPres deposition is the cause of the lack of spongiform degeneration in subjects carrying a 144-bp insertion in PRNP. The presence of PrP-immunoreactive patches with unique morphology in the molecular layer of the cerebellum is a hallmark of certain prion encephalopathies with insertional mutations and is useful in the diagnosis of this subtype of human prion disease.
Supported in part by NIH grants AG08012, AG08155, and AG08992; the Britton Fund; and Biomed 2 CT96-0856 and PL 962034.
Received October 16, 1996. Accepted in final form January 14, 1997.
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