Hippocampal sclerosis dementia with the C9ORF72 hexanucleotide repeat expansion

Olga Pletnikova; Kelly L Sloane; Alan E Renton; Bryan J Traynor; Barbara J Crain; Tammy Reid; Tao Zu; Laura P W Ranum; Juan C Troncoso; Peter V Rabins; Chiadi U Onyike

doi:10.1016/j.neurobiolaging.2014.04.009

Hippocampal sclerosis dementia with the C9ORF72 hexanucleotide repeat expansion

Neurobiol Aging. 2014 Oct;35(10):2419.e17-21. doi: 10.1016/j.neurobiolaging.2014.04.009. Epub 2014 Apr 18.

Authors

Affiliations

¹ Division of Neuropathology, Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
² Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
³ Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
⁴ Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Brain Sciences Institute, Johns Hopkins University, Baltimore, MD, USA.
⁵ Center for NeuroGenetics, Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainsville, FL, USA; Genetics Institute, Department of Neurology, College of Medicine, University of Florida, Gainesville, FL, USA.
⁶ Division of Neuropathology, Department of Pathology, Johns Hopkins University, Baltimore, MD, USA; Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
⁷ Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA. Electronic address: conyike1@johnshopkins.edu.

PMID: 24819148
PMCID: PMC4087047
DOI: 10.1016/j.neurobiolaging.2014.04.009

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.

Publication types

Clinical Trial
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
C9orf72 Protein
DNA Repeat Expansion / genetics*
Female
Frontotemporal Dementia / genetics*
Frontotemporal Dementia / pathology*
Genetic Association Studies*
Heterozygote
Hippocampus / pathology*
Humans
Male
Middle Aged
Mutation*
Proteins / genetics*
Sclerosis

Hippocampal sclerosis dementia with the C9ORF72 hexanucleotide repeat expansion

Authors

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Abstract

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