A novel seven-octapeptide repeat insertion in the prion protein gene (PRNP) in a Dutch pedigree with Gerstmann–Stra¨ussler– Scheinker disease phenotype: comparison with similar cases from the literature

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 (PrPSc) 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 multiand 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 PrPSc in both patients and detected a smaller *8 kDa PrPSc fragment in the cerebellum in one patient. The features of this Dutch kindred define an unusual neuropathological C. Jansen  A. J. M. Rozemuller Dutch Surveillance Centre for Prion Diseases, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands W. Voet  A. Verrips Department of Neurology, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands M. W. Head  H. Yull  J. W. Ironside National Creutzfeldt-Jakob Disease Surveillance Unit, University of Edinburgh, Edinburgh, UK P. Parchi Dipartimento di Scienze Neurologiche, Universita` di Bologna, Via Foscolo 7, 40123 Bologna, Italy P. Wesseling Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands J. Meulstee Department of Clinical Neurophysiology, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands F. Baas Department of Neurogenetics, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands W. A. van Gool Department of Neurology, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands A. J. M. Rozemuller Netherlands Brain Bank and Department of Pathology, VU University Medical Centre, de Boelelaan 1117, 1081 HV Amsterdam, The Netherlands C. Jansen (&) Department of Pathology, Dutch Surveillance Centre for Prion Diseases, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands e-mail: c.jansen@umcutrecht.nl 123 Acta Neuropathol (2011) 121:59–68 DOI 10.1007/s00401-010-0656-3 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.