Abstract
The insertion of additional 168 base pair containing seven octapeptide repeats in the prion protein (PrP) gene region spanning residues 51–91 is associated with inherited prion disease. In 2008, we reported the clinical features of a novel de novo seven-octapeptide repeat insertion (7-OPRI) mutation coupled with codon 129 methionine (M) homozygosity in the PrP gene of a 19-year-old man presenting with psychosis and atypical dementia, and 16-year survival. Here, we describe the histopathological and PrP molecular properties in the autopsied brain of this patient. Histopathological examination revealed widespread brain atrophy, focal spongiform degeneration (SD), cortical PrP plaques, and elongated PrP formations in the cerebellum. Overall, these histopathological features resemble those described in a Belgian pedigree with 7-OPRI mutation except for the presence of PrP plaques in our case, which are morphologically different from the multicore plaques described in some OPRI mutations and in Gerstmann–Sträussler–Scheinker (GSS) syndrome. The comparative characterization of the detergent-soluble and detergent-insoluble PrP in our patient and in sporadic Creutzfeldt–Jakob disease (CJD) revealed distinct molecular signatures. Proteinase K digestion of the pathogenic, disease-associated PrP (PrPD) revealed PrPD type 1 in the cerebral cortex and mixed PrPD types 1 and 2 in the cerebellum. Altogether, the present study outlines the importance of assessing the phenotypical and PrP biochemical properties of these rare conditions, thereby widening the spectrum of the phenotypic heterogeneity of the 7-OPRI insertion mutations. Further studies are needed to determine whether distinct conformers of PrPD are associated with two major clinico-histopathological phenotypes in prion disease with 7-OPRI.
Highlights
Human prion diseases can be classified into three groups according to etiology: sporadic, genetic, and acquired by infection (Gambetti et al, 2003; Puoti et al, 2012)
We carried out a description of the histopathological and biochemical features of a novel de novo 7-octapeptide repeat insertion (OPRI) mutation in a patient presenting with early onset behavioral changes and long survival (Mauro et al, 2008)
The age at onset (19 years) and disease duration (16 years) are in line with the clinical data reported in families with 7-OPRI mutation coupled with methionine at prion protein (PrP)-codon 129 of the mutated allele
Summary
Human prion diseases can be classified into three groups according to etiology: sporadic, genetic, and acquired by infection (Gambetti et al, 2003; Puoti et al, 2012). While the sporadic form represents the most common human prion disease and accounts for about 85–90% of cases, genetic forms have been described in 10–15% of cases and are typically associated with point mutations in the coding region of the prion protein (PrP) gene (Gambetti et al, 2011; Bonda et al, 2016). Insertion mutations involve a region consisting of 27 base pairs (bp) nonapeptide (R1) followed by four 24-bp octapeptide repeats (R2, R2, R3, and R4) with slight variations at the nucleotide level (Goldfarb et al, 1991) These repeats lie in the portion of the PrP gene encompassing codons 51 and 91, a region matching the copper-binding domain of the protein. An exception to the aforementioned clinical phenotypes is represented by a Chinese patient with cis-M PrP-codon 129 who exhibited memory impairment at age 44 and relatively short disease duration of 4 years. Biochemical characterization of PrP harvested from detergent-soluble and detergent-insoluble fractions unveiled a distinctive signature of the prion protein
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