title: Genotype-phenotype analysis in inherited prion disease with eight octapeptide repeat insertional mutation.
abstract: A minority of inherited prion diseases (IPD) are caused by four to 12 extra octapeptide repeat insertions (OPRI) in the prion protein gene (PRNP). Only four families affected by IPD with 8-OPRI have been reported, one of them was a three-generation Swedish kindred in which four of seven affected subjects had chorea which was initially attributed to Huntington's disease (HD). Following the exclusion of HD, this phenotype was labeled Huntington disease-like 1 (HDL1). Here, we provide an update on the Swedish 8-OPRI family, describe the clinical features of one of its affected members with video-recordings, compare the four 8-OPRI families and study the effect of PRNP polymorphic codon 129 and gender on phenotype. Surprisingly, the Swedish kindred displayed the longest survival of all of the 8-OPRI families with a mean of 15.1 years from onset of symptoms. Subjects with PRNP polymorphic codon 129M in the mutated allele had significantly earlier age of onset, longer survival and earlier age of death than 129V subjects. Homozygous 129MM had earlier age of onset than 129VV. Females had a significantly earlier age of onset and earlier age of death than males. Up to 50% of variability in age of onset was conferred by the combined effect of PRNP polymorphic codon 129 and gender. An inverse correlation between early age of onset and long survival was found for this mutation.
authors.affiliation: Translational Neuropharmacology; Clinical Neuroscience; Center for Molecular Medicine; Karolinska Institute; Stockholm, Sweden; Department of Neurology; Karolinska University Hospital; Stockholm, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Paucar
authors.forename: Fengqing
authors.initials: F
authors.lastname: Xiang
authors.forename: Richard
authors.initials: R
authors.lastname: Moore
authors.forename: Ruth
authors.initials: R
authors.lastname: Walker
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Winnberg
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
mesh_terms: D000328:Adult; D005260:Female; D005838:Genotype; D006801:Humans; D006816:Huntington Disease / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D010375:Pedigree; D010641:Phenotype; D017096:Prion Diseases / Q000235:genetics*; D011328:Prions / Q000235:genetics*; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D011328:Prions
keywords: Huntington disease-like 1; Huntington’s disease; PRNP; PRNP polymorphic codon 129; base pair insertions (BPI); inherited prion disease (IPD); octapeptide repeat insertions (OPRI)