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A novel mutation I215V in the PRNP gene associated with Creutzfeldt–Jakob and Alzheimer’s diseases in three patients with divergent clinical phenotypes

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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.

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Abbreviations

CJD:

Creutzfeldt–Jakob disease

AD:

Alzheimer’s disease

TSE:

Transmissible spongiform encephalopathies

GSS:

Gerstmann–Sträussler–Scheinker syndrome

FFI:

Fatal familial insomnia

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Acknowledgments

We thank the personnel from the Anatomic Pathology department of Hospital Clínico Universitario de Zaragoza (Zaragoza, Spain) for their assistance in the implementation of the autopsy of the three cases reported here, according to established protocols. We also thank all the physicians and epidemiological and clinical coordinators for their assistance and for notifying cases to the CJD Spanish Registry, as well as to F. Avellanal, J. Almazán, M. Ruiz, and E. Alcalde for their collaboration with the Spanish CJD surveillance system. This work was supported by grants FIS 05/0912 and PI11/03021 from the Acción Estratégica en Salud (Instituto de Salud Carlos III, Ministerio de Economía y Competitividad), the DGSP of the Spanish National Health Ministry (MC), and the Spanish CIBERNED network (JdP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflicts of interest

The authors have declared that no competing interests exist.

Author information

Author notes

  1. Natividad Cuadrado-Corrales

    Present address: CIEMAT-CIBERER, Madrid, Spain

Authors and Affiliations

  1. Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Spain

    Mercedes Muñoz-Nieto, Natividad Cuadrado-Corrales & Miguel Calero

  2. Unidad de Medicina Interna, Hospital Bajo Cinca de Fraga, Huesca, Spain

    Neus Ramonet & Marcos Díaz-Hurtado

  3. Servicio de Neurología, Hospital Miguel Servet, Zaragoza, Spain

    Juan Ignacio López-Gastón

  4. CIBERNED, Madrid, Spain

    Olga Calero, Jesús de Pedro-Cuesta & Miguel Calero

  5. Servicio de Vigilancia en Salud Pública, D.G. de Salud Pública, Consejería de Salud y Consumo, Gobierno de Aragón, Zaragoza, Spain

    José Ramón Ipiens

  6. Servicio de Anatomía Patológica, Hospital Clínico Universitario de Zaragoza, Zaragoza, Spain

    Santiago Ramón y Cajal

  7. Centro Nacional de Epidemiología, Instituto de Salud Carlos III, Madrid, Spain

    Jesús de Pedro-Cuesta

  8. Unidad de Encefalopatías Espongiformes, Centro Nacional de Microbiología, Instituto de Salud Carlos III (CNM-ISCIII), Madrid, Spain

    Miguel Calero

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  1. Mercedes Muñoz-Nieto
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Correspondence to Miguel Calero.

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Muñoz-Nieto, M., Ramonet, N., López-Gastón, J.I. et al. A novel mutation I215V in the PRNP gene associated with Creutzfeldt–Jakob and Alzheimer’s diseases in three patients with divergent clinical phenotypes. J Neurol 260, 77–84 (2013). https://doi.org/10.1007/s00415-012-6588-1

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  • DOI: https://doi.org/10.1007/s00415-012-6588-1

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