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Brain 2006 129(9):2297-2317; doi:10.1093/brain/awl226
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© The Author (2006). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Inherited prion disease with six octapeptide repeat insertional mutation—molecular analysis of phenotypic heterogeneity

Simon Mead, Mark Poulter, Jon Beck, Thomas E. F. Webb, Tracy A. Campbell, Jacqueline M. Linehan, Melanie Desbruslais, Susan Joiner, Jonathan D. F. Wadsworth, Andrew King, Peter Lantos and John Collinge

MRC Prion Unit, Department of Neurodegenerative Diseases, Institute of Neurology and Department of Neuropathology, King's College Hospital London, UK

Correspondence to: John Collinge, MRC Prion Unit, Department of Neurodegenerative Diseases, Institute of Neurology, Queen Square WC1N 3BG, London E-mail: j.collinge{at}prion.ucl.ac.uk

By far the largest known kindred with an inherited prion disease caused by a prion protein (PrP) octapeptide repeat insertion mutation originates from southeast England. This extended family shows very marked phenotypic heterogeneity and provides a unique opportunity to characterize this diversity and examine possible modifying factors amongst a large number of individuals in whom prion disease has been initiated by the same defined genetic mutation. As the inherited prion diseases comprise a significant proportion of familial early-onset dementia, an appreciation of their wide range of clinical presentation is important for differential diagnosis. Genealogical and clinical record review, together with the characterization of the mutation-linked single nucleotide polymorphism and microsatellite haplotype, suggested a single founder for both this large kindred and a smaller family in the mid-18th century. Here we report the phenotype of 86 affected individuals; at least another 84 individuals are known to be at risk of inheriting the disease. Clinical onset, typically with cognitive impairment, can be strikingly early in this kindred when compared with other inherited or sporadic prion diseases. We have investigated the effect of PrP genotype, candidate genes and prion strain type on clinical, neuroradiological and neuropathological phenotype. The transmission characterisitics of prions from affected individuals resembled those of classical sporadic Creutzfeldt–Jakob disease. One surprising finding was a strong inverse correlation between age of onset and disease duration. The PrP gene polymorphic codon 129 was found to confer 41% of the variance in age of onset but interestingly this polymorphism had no effect on disease duration suggesting different molecular mechanisms are involved in determining disease onset and rate of clinical progression.

Key Words: 144 bp; CJD; early-onset dementia; insertion; OPRI; prion

Abbreviations: CJD, Creutzfeldt–Jakob disease; MRC, Medical Research Council; OPRI, octapeptide repeat insertion; PRNP, prion protein gene; PrP, prion protein; SNP, single nucleotide polymorphism

Received July 3, 2006. Revised July 27, 2006. Accepted July 27, 2006.


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