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

Casper Jansen, Willem Voet, Mark W. Head, Piero Parchi, Helen Yull, Aad Verrips, Pieter Wesseling, Jan Meulstee, Frank Baas, Willem A. Van Gool, James W. Ironside, Annemieke J M Rozemuller

Research output: Contribution to journalArticlepeer-review

Abstract

Human prion diseases can be sporadic, inherited or acquired by infection and show considerable phenotypic heterogeneity. We describe the clinical, histopathological and pathological prion protein (PrP Sc) characteristics of a Dutch family with a novel 7-octapeptide repeat insertion (7-OPRI) in PRNP, the gene encoding the prion protein (PrP). Clinical features were available in four, neuropathological features in three and biochemical characteristics in two members of this family. The clinical phenotype was characterized by slowly progressive cognitive decline, personality change, lethargy, depression with anxiety and panic attacks, apraxia and a hypokinetic-rigid syndrome. Neuropathological findings consisted of numerous multi- and unicentric amyloid plaques throughout the cerebrum and cerebellum with varying degrees of spongiform degeneration. Genetic and molecular studies were performed in two male family members. One of them was homozygous for valine and the other heterozygous for methionine and valine at codon 129 of PRNP. Sequence analysis identified a novel 168 bp insertion [R2-R2-R2-R2-R3g-R2-R2] in the octapeptide repeat region of PRNP. Both patients carried the mutation on the allele with valine at codon 129. Western blot analysis showed type 1 PrP Sc in both patients and detected a smaller ~8 kDa PrP Sc fragment in the cerebellum in one patient. The features of this Dutch kindred define an unusual neuropathological phenotype and a novel PRNP haplotype among the previously documented 7-OPRI mutations, further expanding the spectrum of genotype-phenotype correlations in inherited prion diseases.

Original languageEnglish
Pages (from-to)59-68
Number of pages10
JournalActa Neuropathologica
Volume121
Issue number1
DOIs
Publication statusPublished - Jan 2011

Keywords

  • Amyloidosis
  • Base pair insertion
  • Creutzfeldt-Jakob disease
  • Genetic CJD
  • Gerstmann-Sträussler-Scheinker disease
  • Neurodegeneration
  • Prion protein

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Cellular and Molecular Neuroscience

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