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Case Report/Case Series |

Expanded C9ORF72 Hexanucleotide Repeat in Depressive Pseudodementia

Kevin F. Bieniek, BSc1,2; Marka van Blitterswijk, MD, PhD1; Matthew C. Baker, BSc1; Leonard Petrucelli, PhD1; Rosa Rademakers, PhD1; Dennis W. Dickson, MD1
[+] Author Affiliations
1Department of Neuroscience, Mayo Clinic, Jacksonville, Florida
2Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, Minnesota
JAMA Neurol. 2014;71(6):775-781. doi:10.1001/jamaneurol.2013.6368.
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Importance  Expanded hexanucleotide repeats in C9ORF72 are a common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. Repeat expansions have also been detected infrequently in other disorders, including Alzheimer disease, dementia with Lewy bodies, and parkinsonian disorders.

Observations  A consecutive series of 31 cases from the brain bank for neurodegenerative disorders at Mayo Clinic was screened to assess the incidence of the expanded C9ORF72 repeat in cases of depressive pseudodementia. The presence of the hexanucleotide repeat was established using immunohistochemistry with a highly disease-specific antibody (C9RANT), and was further validated in carriers using repeat-primed polymerase chain reaction and Southern blotting. Two individuals harbored the C9ORF72 repeat expansion. Both patients were men with refractory depression. One patient experienced drug-induced parkinsonism and sudden-onset dementia, while the other patient had a more insidious disease course suspected to be Alzheimer disease.

Conclusions and Relevance  This report increases the range of clinicopathologic presentations of C9ORF72 expanded hexanucleotide repeat to include psychiatric disorders such as depressive pseudodementia.

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Figure 1.
Macroscopic Features of C9ORF72-Associated Pseudodementia in Patients

A and B, Fixed left hemibrain of the patients with pseudodementia both show no cortical atrophy. Coronal sections show a thick cortical ribbon, corpus callosum, and a normal-appearing thalamus and hippocampus with no ventricular enlargement in patient 1 (C) and minimal enlargement in patient 2 (D). E and F, There is visible pigment in the substantia nigra (midbrain; upper) and locus ceruleus (pons; lower) of both individuals.

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Figure 2.
Patients With Pseudodementia Meet Diagnostic Criteria for C9ORF72 Hexanucleotide Repeat Expansion

A, Repeat-primed polymerase chain reaction shows stutter amplification of the GGGGCC repeat in the pseudodementia cases (patient 1, upper; patient 2, middle), but not in non-carrier negative controls (lower). B, Neuronal cytoplasmic inclusions immunoreactive for C9RANT antibodies are seen in primary neurons of the hippocampus (upper panels) and granule cells of the cerebellum (lower panels) of the pseudodementia cases (patient 1, left panels; patient 2, middle panels) but not in other non-carrier pseudodementia controls (right panels) (10 µm bars). C, Southern blotting of cerebellar tissue from the pseudodementia cases (in duplicate; patient 1 in lanes 3 and 4; patient 2 in lanes 5 and 6), two positive frontotemporal dementia controls (lanes 7 and 8), and two negative non-carrier controls (lanes 9 and 10) reveals a wild-type (WT) non-expanded allele at 2.5 kilobases (kb) for the cases and all controls as well as an expanded allele at approximately 8.5 kb (1000-1400 repeat units) for the cases and positive controls.

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