title: Inherited prion disease with 4-octapeptide repeat insertion: disease requires the interaction of multiple genetic risk factors.
abstract: Genetic factors are implicated in the aetiology of sporadic late-onset neurodegenerative diseases. Whether these genetic variants are predominantly common or rare, and how multiple genetic factors interact with each other to cause disease is poorly understood. Inherited prion diseases are highly heterogeneous and may be clinically mistaken for sporadic Creutzfeldt-Jakob disease because of a negative family history. Here we report our investigation of patients from the UK with four extra octapeptide repeats, which suggest that the risk of clinical disease is increased by a combination of the mutation and a susceptibility haplotype on the wild-type chromosome. The predominant clinical syndrome is a progressive cortical dementia with pyramidal signs, myoclonus and cerebellar abnormalities that closely resemble sporadic Creutzfeldt-Jakob disease. Autopsy shows perpendicular deposits of prion protein in the molecular layer of the cerebellum. Identity testing, PRNP microsatellite haplotyping and genealogical work confirm no cryptic close family relationships and suggests multiple progenitor disease haplotypes. All patients were homozygous for methionine at polymorphic codon 129. In addition, at a single nucleotide polymorphism upstream of PRNP thought to confer susceptibility to sporadic Creutzfeldt-Jakob disease (rs1029273), all patients were homozygous for the risk allele (combined P=5.9×10(-5)). The haplotype identified may also be a risk factor in other partially penetrant inherited prion diseases although it does not modify age of onset. Blood expression of PRNP in healthy individuals was modestly higher in carriers of the risk haplotype. These findings may provide a precedent for understanding apparently sporadic neurodegenerative diseases caused by rare high-risk mutations.
authors: National Prion Clinic, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
authors: Diego N
authors: DN
authors: Kaski
authors: Catherine
authors: C
authors: Pennington
authors: Jon
authors: J
authors: Beck
authors: Mark
authors: M
authors: Poulter
authors: James
authors: J
authors: Uphill
authors: Matthew T
authors: MT
authors: Bishop
authors: Jaqueline M
authors: JM
authors: Linehan
authors: Catherine
authors: C
authors: O'Malley
authors: Jonathan D F
authors: JD
authors: Wadsworth
authors: Susan
authors: S
authors: Joiner
authors: Richard S G
authors: RS
authors: Knight
authors: James W
authors: JW
authors: Ironside
authors: Sebastian
authors: S
authors: Brandner
authors: John
authors: J
authors: Collinge
authors: Simon
authors: S
authors: Mead