title: Inherited prion disease with six octapeptide repeat insertional mutation--molecular analysis of phenotypic heterogeneity.
abstract: 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 characteristics 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.
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Diseases, Institute of Neurology, King's College Hospital, London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
authors.forename: Mark
authors.initials: M
authors.lastname: Poulter
authors.forename: Jon
authors.initials: J
authors.lastname: Beck
authors.forename: Thomas E F
authors.initials: TE
authors.lastname: Webb
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Campbell
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Linehan
authors.forename: Melanie
authors.initials: M
authors.lastname: Desbruslais
authors.forename: Susan
authors.initials: S
authors.lastname: Joiner
authors.forename: Jonathan D F
authors.initials: JD
authors.lastname: Wadsworth
authors.forename: Andrew
authors.initials: A
authors.lastname: King
authors.forename: Peter
authors.initials: P
authors.lastname: Lantos
authors.forename: John
authors.initials: J
authors.lastname: Collinge
mesh_terms: D000328:Adult; D017668:Age of Onset; D001057:Apolipoproteins E / Q000235:genetics; D003062:Codon / Q000235:genetics; D004251:DNA Transposable Elements / Q000235:genetics; D005192:Family Health; D005260:Female; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D050505:Mutant Proteins; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010455:Peptides / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018620:PrPSc Proteins / Q000235:genetics; D017096:Prion Diseases / Q000235:genetics* / Q000473:pathology / Q000635:transmission; D011328:Prions / Q000235:genetics*; D012737:Sex Factors; D013997:Time Factors
chemical_list: D001057:Apolipoproteins E; D003062:Codon; D004251:DNA Transposable Elements; D050505:Mutant Proteins; D010455:Peptides; D018620:PrPSc Proteins; D011328:Prions