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Inherited prion disease with 5-OPRI

Phenotype modification by repeat length and codon 129

From the MRC Prion Unit and Department of Neurodegenerative Disease (S.M., T.E.F.W., T.A.C., J.B., J.M.L., S.J., J.D.F.W., S.W., J.C.), Institute of Neurology, and Department of Clinical Neuropathology (L.D., A.K.), King's College Hospital, London, UK; and Neuropathology Unit (S.R.), Department of Anatomical Pathology, University of Stellenbosch, and Neurology Division (J.H.), Groote Schuur Hospital and University of Cape Town, South Africa.

Address correspondence and reprint requests to Dr. J. Collinge, MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London, UK WC1N 3BG j.collinge{at}prion.ucl.ac.uk

Background: Humanprion diseases have sporadic, acquired and inherited etiologies and show considerable phenotypic heterogeneity. An individual inherited prion disease offers an opportunity to study the determinants of this clinicopathologic heterogeneity among individuals with the same causal mutation.

Methods: We report clinical and pathologic data from three families with different 5-octapeptide repeat insertion (5-OPRI) mutations of the prion protein gene (PRNP), extending the reported phenotypic range of this mutation.

Results: The proband of a South African family presented with a rapidly progressive dementia and atypical pathology associated with kuru-like prion protein plaques. The original mutation in this family probably occurred on a PRNP allele encoding a 1-octapeptide repeat deletion polymorphism. This has not been previously reported as a precursor allele in over 30 other OPRI mutation kindreds. An English family with a genetically distinct mutation but identical protein product showed clinical onsets that varied 30 years between father and daughter, an effect that may be explained by their genotypes at PRNP codon 129. A patient from Northern Ireland with a phenotype of sporadic Creutzfeldt–Jakob disease presenting with visual disturbance was unexpectedly found to have a 5-OPRI.

Conclusions: When these cases were combined with the existing world literature, the mean age at onset for patients with 5-octapeptide repeat insertion (5-OPRI) was significantly later than that for patients with 6-OPRI, but both mutations exhibit a similar powerful disease modifying effect of PRNP codon 129.

Deceased.

This work was undertaken at UCLH/UCL, which received a portion of funding from the Department of Health's NIHR Biomedical Research Centres. The research was also funded by the Medical Research Council, UK.

Disclosure: The authors report no conflicts of interest.

Received November 10, 2006. Accepted in final form March 21, 2007.

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