ORIGINAL COMMUNICATION Spongiform encephalopathy in siblings with no evidence of protease-resistant prion protein or a mutation in the prion protein gene Daniela Varges • Walter J. Schulz-Schaeffer • Wiebke M. Wemheuer • Insa Damman • Matthias Schmitz • Maria Cramm • Kai Kallenberg • Katayoon Shirneshan • Manar Elkenani • Susanne Markwort • Michael Faist • Ju ¨ rgen Kohlhase • Otto Windl • Inga Zerr Received: 10 July 2012 / Revised: 6 March 2013 / Accepted: 14 March 2013 / Published online: 2 April 2013 Ó Springer-Verlag Berlin Heidelberg 2013 Abstract We discuss relevant aspects in two siblings with a neurodegenerative process of unclear aetiology who developed progressive dementia with global aphasia and hyperoral behaviour at the ages of 39 and 46 years and who died 6 and 5 years after disease onset. The cases were reported to the National Reference Center for TSE Surveillance in Go ¨ttingen, Germany. Detailed clinical examinations, CSF, blood samples, and copies of the important diagnostic tests (magnetic resonance imaging, electroencephalogram, laboratory tests) were obtained. Further neuropathological and genetic analyses were performed. Cerebral magnetic resonance imaging of both siblings showed prominent changes in signal intensity, especially in the left medial temporal cortex, but also the hippocampal formation. Neuropathological examination revealed spongiform changes, neuronal loss, and astro- cytic gliosis, which are typical in Creutzfeldt–Jakob dis- ease. However, no prion protein deposits were detectable by immunohistochemical analysis, Western blot, or PET blot, though abundant tau protein deposits were observed. A mutation in the coding region of the prion protein genes of both siblings was excluded. A detailed search of the literature revealed no other cases with a similar clinical and neuropathological appearance. While the disease aetiology remains unclear, the findings point to a neurodegenerative process and most likely a genetic disease. Keywords Dementia Á Creutzfeldt–Jakob disease Á MRI Á Prion protein Á Tau Á Early onset dementia D. Varges (&) Á M. Schmitz Á I. Zerr National Reference Center for TSE Surveillance, Department of Neurology, University Medical Center Go ¨ttingen, Robert-Koch Str. 40, 37075 Go ¨ttingen, Germany e-mail: d.varges@med.uni-goettingen.de W. J. Schulz-Schaeffer Á W. M. Wemheuer Á I. Damman Department of Neuropathology, University Medical Center Go ¨ttingen, Go ¨ttingen, Germany M. Cramm Á I. Zerr German Center for Neurodegenerative Diseases (DZNE), Department of Neurology, University Medical Center Go ¨ttingen, Robert-Koch Str. 40, 37075 Go ¨ttingen, Germany K. Kallenberg Department of Neuroradiology, University Medical Center Go ¨ttingen, Go ¨ttingen, Germany K. Shirneshan Department of Hematology and Oncology, University Medical Center Go ¨ttingen, Go ¨ttingen, Germany M. Elkenani Institute of Human Genetics, University Medical Center Go ¨ttingen, Go ¨ttingen, Germany S. Markwort Department of Psychiatry, Hospital Schlu ¨chtern, Schlu ¨chtern, Germany M. Faist Department of Neurology, Albert-Ludwigs-University Freiburg, Freiburg, Germany J. Kohlhase Center for Human Genetics, Freiburg, Germany O. Windl Molecular Pathogenesis and Genetics Department, Veterinary Laboratories Agency, New Haw, UK 123 J Neurol (2013) 260:1871–1879 DOI 10.1007/s00415-013-6897-z