Case Report: Histopathology and Prion Protein Molecular Properties in Inherited Prion Disease With a De Novo Seven-Octapeptide Repeat Insertion

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.

[1]  R. Occhipinti,et al.  Co-existence of PrPD types 1 and 2 in sporadic Creutzfeldt-Jakob disease of the VV subgroup: phenotypic and prion protein characteristics , 2020, Scientific Reports.

[2]  T. Prior,et al.  A case report of genetic prion disease with two different PRNP variants , 2020, Molecular genetics & genomic medicine.

[3]  D. Scheie,et al.  A Novel Eight Octapeptide Repeat Insertion in PRNP Causing Prion Disease in a Danish Family. , 2019, Journal of neuropathology and experimental neurology.

[4]  B. Ghetti,et al.  Gerstmann-Sträussler-Scheinker disease revisited: accumulation of covalently-linked multimers of internal prion protein fragments , 2019, Acta Neuropathologica Communications.

[5]  S. Capellari,et al.  Recent advances in the histo‐molecular pathology of human prion disease , 2019, Brain pathology.

[6]  M. Geschwind,et al.  Genetic PrP Prion Diseases. , 2018, Cold Spring Harbor perspectives in biology.

[7]  C. Duyckaerts,et al.  Iatrogenic Creutzfeldt-Jakob disease with Amyloid-β pathology: an international study , 2018, Acta Neuropathologica Communications.

[8]  S. Manjila,et al.  Human prion diseases: surgical lessons learned from iatrogenic prion transmission. , 2016, Neurosurgical focus.

[9]  P. Gambetti,et al.  Protease-sensitive prions with 144-bp insertion mutations , 2013, Aging.

[10]  A. Bizzi,et al.  Sporadic human prion diseases: molecular insights and diagnosis , 2012, The Lancet Neurology.

[11]  Piero Parchi,et al.  Molecular pathology, classification, and diagnosis of sporadic human prion disease variants. , 2012, Folia neuropathologica.

[12]  F. Baas,et al.  A novel seven-octapeptide repeat insertion in the prion protein gene (PRNP) in a Dutch pedigree with Gerstmann–Sträussler–Scheinker disease phenotype: comparison with similar cases from the literature , 2010, Acta Neuropathologica.

[13]  W. Surewicz,et al.  Molecular biology and pathology of prion strains in sporadic human prion diseases , 2010, Acta Neuropathologica.

[14]  J. V. van Swieten,et al.  Inherited Creutzfeldt–Jakob disease in a Dutch patient with a novel five octapeptide repeat insertion and unusual cerebellar morphology , 2009, Journal of Neurology, Neurosurgery & Psychiatry.

[15]  J. Langeveld,et al.  Co-existence of scrapie prion protein types 1 and 2 in sporadic Creutzfeldt-Jakob disease: its effect on the phenotype and prion-type characteristics. , 2009, Brain : a journal of neurology.

[16]  B. Ghetti,et al.  Incidence and spectrum of sporadic Creutzfeldt–Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification , 2009, Acta Neuropathologica.

[17]  Xiao-Fan Wang,et al.  A Patient With Creutzfeldt-Jakob Disease With an Insertion of 7 Octa-Repeats in the PRNP Gene: Molecular Characteristics and Clinical Features , 2008, The American journal of the medical sciences.

[18]  A. Leonardi,et al.  A novel insertional mutation in the prion protein gene: clinical and bio-molecular findings , 2008, Journal of Neurology, Neurosurgery, and Psychiatry.

[19]  S. Mead,et al.  Inherited prion disease with 5-OPRI , 2007, Neurology.

[20]  X. Wang,et al.  Creutzfeldt–Jakob disease in a Chinese patient with a novel seven extra-repeat insertion in PRNP , 2007, Journal of Neurology, Neurosurgery & Psychiatry.

[21]  P. Lantos,et al.  Inherited prion disease with six octapeptide repeat insertional mutation--molecular analysis of phenotypic heterogeneity. , 2006, Brain : a journal of neurology.

[22]  R. Castellani,et al.  Classification of sporadic Creutzfeldt-Jakob disease revisited. , 2006, Brain : a journal of neurology.

[23]  H. Budka,et al.  Prion disease with a 144 base pair insertion: unusual cerebellar prion protein immunoreactivity , 2005, Acta Neuropathologica.

[24]  Shu G. Chen,et al.  Identification of Novel Proteinase K-resistant C-terminal Fragments of PrP in Creutzfeldt-Jakob Disease* , 2003, Journal of Biological Chemistry.

[25]  Shu G. Chen,et al.  Sporadic and familial CJD: classification and characterisation. , 2003, British medical bulletin.

[26]  C. Masters,et al.  Novel prion protein insert mutation associated with prolonged neurodegenerative illness , 2003, Neurology.

[27]  F. Tagliavini,et al.  Creutzfeldt-Jakob disease with a novel extra-repeat insertional mutation in the PRNP gene. , 2003, Neurology.

[28]  R. Petersen,et al.  Creutzfeldt–Jakob disease associated with a deletion of two repeats in the prion protein gene , 2002, Neurology.

[29]  S. Mead,et al.  Two-octapeptide repeat deletion of prion protein associated with rapidly progressive dementia , 2001, Neurology.

[30]  C. van Broeckhoven,et al.  Familial Creutzfeldt-Jakob disease in a patient carrying both a presenilin 1 missense substitution and a prion protein gene insertion , 2000, Journal of Neurology.

[31]  F. Tagliavini,et al.  Sporadic Creutzfeldt-Jakob disease: Co-occurrence of different types of PrPSc in the same brain , 1999, Neurology.

[32]  P Brown,et al.  Classification of sporadic Creutzfeldt‐Jakob disease based on molecular and phenotypic analysis of 300 subjects , 1999, Annals of neurology.

[33]  H. Budka,et al.  Different patterns of truncated prion protein fragments correlate with distinct phenotypes in P102L Gerstmann-Sträussler-Scheinker disease. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[34]  E. Pegoraro,et al.  Familial prion disease with a novel 144-bp insertion in the prion protein gene in a Basque family , 1997, Neurology.

[35]  D. C. Henckel,et al.  Case report. , 1995, Journal.

[36]  M. Palmer,et al.  Deletions in the prion protein gene are not associated with CJD. , 1993, Human molecular genetics.

[37]  J. Collinge.  Inherited prion diseases. , 1993, Advances in neurology.

[38]  W. Sheremata,et al.  Atypical Creutzfeldt‐Jakob disease in an American family with an insert mutation in the PRNP amyloid precursor gene , 1992, Neurology.

[39]  J. Tateishi.  [Recent advances in the research of Creutzfeldt-Jakob disease (CJD) and Gerstmann-Strüssler syndrome (GSS)]. , 1991, Rinsho shinkeigaku = Clinical neurology.

[40]  D. Goldgaber,et al.  Transmissible familial Creutzfeldt-Jakob disease associated with five, seven, and eight extra octapeptide coding repeats in the PRNP gene. , 1991, Proceedings of the National Academy of Sciences of the United States of America.