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Atypical Creutzfeldt-Jakob disease in an American family with an insert mutation in the PRNP amyloid precursor gene

From the Laboratory of CNS Studies (Drs. Brown, Goldfarb, Nieto, Godec, Gibbs, and Gajdusek), and the Laboratory of Molecular and Cellular Neurobiology (Section of Receptor Biochemistry and Molecular Biology) (Dr. McCombie), NINDS, NIH, Bethesda, MD; the Department of Neurology (Drs. Squillacote and Sheremata), University of Miami School of Medicine, Miami, FL; and the Lehigh Valley Hospital Center (Dr. Little), Allentown, PA.

An American family of English origin with an unusually early onset and long-duration form of Creutzfeldt-Jakob disease (CJD) had a heterozygous insert mutation in the region of repeating octapeptide coding sequences between codons 51 and 91 of the PRNP gene on chromosome 20. Affected members were 23 to 35 years old at the onset of illnesses that lasted from 4 to 13 years, yet experimental transmission of disease from the proband (11-year duration) produced a typically brief incubation period and duration of illness in each of three inoculated primates. Also, the PrP amyloid protein that accumulates in CJD brain was only barely detectable in extracted brain tissue from one case with massive spongiform change and was undetectable in another case with no spongiform change, perhaps because of epitope shielding by a configurational change in the protein induced by the mutation. Analysis of this and other families with similar inserts suggests that such mutations in the PRNP gene not only predispose to CJD, but also modify its phenotypic expression.

Address correspondence and reprint requests to Dr. Paul Brown, Building 36, Room 5B21, National Institutes of Health, Bethesda, MD 20892.

Received April 17, 1991. Accepted for publication in final form July 29, 1991.

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