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

2.50
Hdl Handle:
http://hdl.handle.net/11287/593884
Title:
Early dipeptide repeat pathology in a frontotemporal dementia kindred with C9ORF72 mutation and intellectual disability
Authors:
Proudfoot, Malcolm; Gutowski, Nicholas J.; Edbauer, D.; Hilton, D. A.; Stephens, M.; Rankin, Julia; Mackenzie, I. R.
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:
Springer
Journal:
Acta neuropathologica
Issue Date:
1-Mar-2014
URI:
http://hdl.handle.net/11287/593884
DOI:
10.1007/s00401-014-1245-7
PubMed ID:
24445903
Additional Links:
http://dx.doi.org/10.1007/s00401-014-1245-7
Type:
Case Report; Research Support, Non-U.S. Gov't
Language:
eng
ISSN:
1432-0533 (Electronic) 0001-6322 (Linking)
Appears in Collections:
Neurology; 2014 RD&E publications; Clinical Genetics (Peninsula Genetics)

Full metadata record

DC FieldValue Language
dc.contributor.authorProudfoot, Malcolmen
dc.contributor.authorGutowski, Nicholas J.en
dc.contributor.authorEdbauer, D.en
dc.contributor.authorHilton, D. A.en
dc.contributor.authorStephens, M.en
dc.contributor.authorRankin, Juliaen
dc.contributor.authorMackenzie, I. R.en
dc.date.accessioned2016-01-19T12:36:19Zen
dc.date.available2016-01-19T12:36:19Zen
dc.date.issued2014-03-01en
dc.identifier.citationActa Neuropathol. 2014 Mar;127(3):451-8.en
dc.identifier.issn1432-0533 (Electronic) 0001-6322 (Linking)en
dc.identifier.pmid24445903en
dc.identifier.doi10.1007/s00401-014-1245-7en
dc.identifier.urihttp://hdl.handle.net/11287/593884en
dc.description.abstractFamilial 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.en
dc.language.isoengen
dc.publisherSpringeren
dc.relation.urlhttp://dx.doi.org/10.1007/s00401-014-1245-7en
dc.titleEarly dipeptide repeat pathology in a frontotemporal dementia kindred with C9ORF72 mutation and intellectual disabilityen
dc.typeCase Reporten
dc.typeResearch Support, Non-U.S. Gov'ten
dc.identifier.journalActa neuropathologicaen

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