Hippocampal sclerosis dementia with the C9ORF72 hexanucleotide repeat expansion

Abstract

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are the main syndromes of the chromosome 9 ORF72 (C9ORF72) hexanucleotide repeat expansion, but studies have shown a substantial phenotypic diversity that includes psychiatric presentations. This study describes hippocampal sclerosis dementia (HSD) in carriers of the C9ORF72 mutation. We compared clinical and neuropathological features of HSD in carriers and noncarriers autopsied at Johns Hopkins. Carriers presented with amnesia, agitation, dissocial behavior, and impaired self-care, whereas noncarriers showed little agitation. The groups were not dissimilar in cognitive or motor dysfunction. Neuropathological examination of carriers showed cerebellar neuronal inclusions positive for ubiquitin, p62, and ubiquilin-2, and negative for TAR DNA-binding protein 43. Noncarriers did not have cerebellar inclusions. C9ORF72 repeat-associated non-ATG translation was confirmed by immunohistochemistry. These observations broaden the C9ORF72 phenotype and place HSD in the FTD spectrum. The amnesic phenotype of HSD, which is consistent with the focal hippocampal atrophy, should be included in clinical categorizations of FTD.

Trial registration: ClinicalTrials.gov NCT01626378.

Keywords: C9ORF72 hexanucleotide repeat expansion; Dementia; Frontotemporal dementia; Hippocampal sclerosis.

Copyright © 2014 Elsevier Inc. All rights reserved.

Figures

Figure 1

A: Hippocampus immunostained with TDP-43 antibody. Paranuclear TDP-43-positive inclusions are seen in granule cells of the fascia dentata (arrows). The cells lack nuclear TDP-43 immunoreactivity. B and C: Cerebellum granule cell layer, Cytoplasmic inclusions are abundant and immunoreactive for ubiquitin (B) and p62 (C). These inclusions are not TDP-43 immunoreactive (not shown).

Figure 2

Repeat-primed PCR analysis of genomic DNA from the brain tissue of a C9ORF72 mutation carrier demonstrates the characteristic saw tooth pattern associated with the GGGGCC hexanucleotide repeat expansion (A), which the control sample does not show (B). Immunohistochemical staining of the hippocampus CA1 region of a carrier (C) with polyclonal antibody 3154 (GP), which recognizes the GP repeat motif that is expressed in both the sense and the antisense directions. Multiple pyramidal neurons display cytoplasmic inclusions containing RAN proteins, with no similar staining seen in controls (D).