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Early dipeptide repeat pathology in a frontotemporal dementia kindred with C9ORF72 mutation and intellectual disability

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Abstract

Familial cases of frontotemporal dementia (FTD) provide an opportunity to study the pathophysiology of this clinically diverse condition. The C9ORF72 mutation is the most common cause of familial FTD, recent pathological descriptions challenge existing TDP-43 based hypotheses of sporadic FTD pathogenesis. Non-ATG dependent translation of the hexanucleotide expansion into aggregating dipeptide repeat (DPR) proteins may represent a novel pathomechanism. We report detection of the DPR aggregates very early in C9ORF72 FTD development and also describe childhood intellectual disability as a clinical feature preceding dementia. The index case presented with psychiatric symptoms, progressing into typical FTD. Autopsy revealed extensive neuronal DPR aggregates but only minimal TDP-43 pathology. Her intellectually disabled elder son, also carrying the C9ORF72 mutation, died aged 26 years and at autopsy only DPR aggregates without TDP-43 were found. A second son also has intellectual disability, his C9ORF72 status is unknown, but chromosomal microarray revealed no other cause of disability. These cases both extend the existing phenotype of C9ORF72 mutation and highlight the potential significance of DPR translation early in disease development.

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Acknowledgments

MP is supported by the Guarantors of Brain. DE is supported by the Helmholtz Young Investigator program (HZ-NG-607) and by a grant of the Centres of Excellence in Neurodegeneration Research (CoEN). IM is supported by Canadian Institutes of Health Research (74580) and the Pacific Alzheimer’s Research Foundation (C06-01).

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Authors and Affiliations

  1. Department of Neurology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK

    Malcolm Proudfoot & Nick J. Gutowski

  2. University of Exeter Medical School, Exeter, UK

    Nick J. Gutowski

  3. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany

    Dieter Edbauer

  4. Adolf Butenandt Institute, Biochemistry, Ludwig-Maximilians University, Munich, Germany

    Dieter Edbauer

  5. Munich Cluster of Systems Neurology (SyNergy), Munich, Germany

    Dieter Edbauer

  6. Department of Cellular and Anatomical Pathology, Derriford Hospital, Plymouth, UK

    David A. Hilton

  7. Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK

    Mark Stephens

  8. Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK

    Julia Rankin

  9. Department of Pathology, University of British Columbia and Vancouver General Hospital, Vancouver, Canada

    Ian R. A. Mackenzie

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  1. Malcolm Proudfoot
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  2. Nick J. Gutowski
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  3. Dieter Edbauer
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  4. David A. Hilton
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  7. Ian R. A. Mackenzie
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Correspondence to Malcolm Proudfoot.

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Proudfoot, M., Gutowski, N.J., Edbauer, D. et al. Early dipeptide repeat pathology in a frontotemporal dementia kindred with C9ORF72 mutation and intellectual disability. Acta Neuropathol 127, 451–458 (2014). https://doi.org/10.1007/s00401-014-1245-7

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  • DOI: https://doi.org/10.1007/s00401-014-1245-7

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