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

Hippocampal sclerosis dementia with the C9ORF72 hexanucleotide repeat expansion.

Pletnikova O¹, Sloane KL², Renton AE³, Traynor BJ⁴, Crain BJ¹, Reid T⁵, Zu T⁵, Ranum LP⁵, Troncoso JC⁶, Rabins PV², Onyike CU⁷.

Author information

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.

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.