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

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    URI
    http://hdl.handle.net/11287/593884
    Author
    Proudfoot, Malcolm
    Gutowski, Nicholas J.
    Edbauer, D.
    Hilton, D. A.
    Stephens, M.
    Rankin, Julia
    Mackenzie, I. R.
    Date
    2014-03-01
    Journal
    Acta neuropathologica
    Type
    Case Report
    Research Support, Non-U.S. Gov't
    Publisher
    Springer
    DOI
    10.1007/s00401-014-1245-7
    Metadata
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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.
    Citation
    Acta Neuropathol. 2014 Mar;127(3):451-8.
    Publisher URL
    http://dx.doi.org/10.1007/s00401-014-1245-7
    Collections
    • 2014 RD&E publications
    • Genetics and genomics
    • Neurology and neurorehabilitation

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