Brain Advance Access first published online on August 30, 2008
This version published online on September 1, 2008
Brain, doi:10.1093/brain/awn202
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series
1MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, 2National Prion Clinic and National Hospital for Neurology & Neurosurgery, Queen Square, London, WC1N 3BG, 3Department of Medicine (Neuroscience), Monash University, Melbourne, Australia, 4Department of Neurology, University of California, San Francisco (UCSF), San Francisco, CA, USA and 5Department of Clinical Genetics, Churchill Hospital and Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DU, UK
Correspondence to:
Prof. John Collinge, Department of Neurodegenerative Disease and MRC Prion Unit, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK E-mail: j.collinge{at}prion.ucl.ac.uk
The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers.
Key Words: P102L; sCJD; early-onset dementia; Gerstmann-Sträussler-Scheinker syndrome; prion disease
Abbreviations: APOE, apolipoprotein E; GSS, Gerstmann-Sträussler-Scheinker syndrome; IPD, inherited prion disease; NCS, nerve conduction studies; OPRI, octapeptide repeat insertion; PRNP, human prion protein gene; PrPc, prion protein (cellular isoform); PrPSc, prion protein (scrapie isoform); sCJD, sporadic Creutzfeldt-Jakob disease
Received May 14, 2008. Revised July 29, 2008. Accepted July 30, 2008.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  E. A. Asante, I. Gowland, A. Grimshaw, J. M. Linehan, M. Smidak, R. Houghton, O. Osiguwa, A. Tomlinson, S. Joiner, S. Brandner, et al. Absence of spontaneous disease and comparative prion susceptibility of transgenic mice expressing mutant human prion proteins J. Gen. Virol., March 1, 2009; 90(3): 546 - 558. [Abstract] [Full Text] [PDF]
|
|