ORIGINAL COMMUNICATION A novel mutation I215V in the PRNP gene associated with Creutzfeldt–Jakob and Alzheimer’s diseases in three patients with divergent clinical phenotypes Mercedes Mun ˜ oz-Nieto • Neus Ramonet • Juan Ignacio Lo ´pez-Gasto ´n • Natividad Cuadrado-Corrales • Olga Calero • Marcos Dı ´az-Hurtado • Jose ´ Ramo ´n Ipiens • Santiago Ramo ´n y Cajal • Jesu ´s de Pedro-Cuesta • Miguel Calero Received: 27 February 2012 / Revised: 18 May 2012 / Accepted: 12 June 2012 / Published online: 5 July 2012 Ó Springer-Verlag 2012 Abstract Genetic human prion diseases are autosomal dominant disorders associated with different mutations in the PRNP gene that are manifested as distinct clinical phenotypes. Here, we report a new pathogenic missense mutation (c.[643A [ G], p.[I215V]) in the PRNP gene associated with three pathologically confirmed cases: two of Creutzfeldt–Jakob disease (CJD) and one of Alzheimer’s disease (AD) in two different families from the same geographical region in Spain. This mutation has not been found in any of more than 2,000 control cases studied. It represents a conservative amino acid change, and the same change is observed in the PRNP gene from other species. The two CJD cases were homozygous at codon 129 (M/M), but showed divergent clinical phenotypes with onset at ages 55 and 77 years and illness durations of 15 and 6 months, respectively. The postmortem neuropathological analysis of these cases showed homogeneous features compatible with CJD. Interestingly, the AD case (a brother of one of the CJD cases) was heterozygous at codon 129 (M/V). No familiar history was documented for any of the cases, suggesting a de novo mutation, or a partial, age- dependent penetration of the mutation, perhaps related to codon 129 status. This new mutation extends the list of known pathogenic mutations responsible for genetic CJD, reinforces the clinical heterogeneity of the disease, and advocates for the inclusion of PRNP gene examination in the diagnostic workup of patients with poorly classifiable dementia, even in the absence of family history. M. Mun ˜oz-Nieto Á N. Cuadrado-Corrales Á M. Calero Centro Nacional de Microbiologı ´a, Instituto de Salud Carlos III, Majadahonda, Spain N. Ramonet Á M. Dı ´az-Hurtado Unidad de Medicina Interna, Hospital Bajo Cinca de Fraga, Huesca, Spain J. I. Lo ´pez-Gasto ´n Servicio de Neurologı ´a, Hospital Miguel Servet, Zaragoza, Spain Present Address: N. Cuadrado-Corrales CIEMAT-CIBERER, Madrid, Spain O. Calero Á J. de Pedro-Cuesta Á M. Calero CIBERNED, Madrid, Spain J. R. Ipiens Servicio de Vigilancia en Salud Pu ´blica, D.G. de Salud Pu ´blica, Consejerı ´a de Salud y Consumo, Gobierno de Arago ´n, Zaragoza, Spain S. Ramo ´n y Cajal Servicio de Anatomı ´a Patolo ´gica, Hospital Clı ´nico Universitario de Zaragoza, Zaragoza, Spain J. de Pedro-Cuesta Centro Nacional de Epidemiologı ´a, Instituto de Salud Carlos III, Madrid, Spain M. Calero (&) Unidad de Encefalopatı ´as Espongiformes, Centro Nacional de Microbiologı ´a, Instituto de Salud Carlos III (CNM-ISCIII), Madrid, Spain e-mail: mcalero@isciii.es 123 J Neurol (2013) 260:77–84 DOI 10.1007/s00415-012-6588-1