Progressive amnestic dementia, hippocampal sclerosis, and mutation in C9ORF72.
The most common cause of familial frontotemporal lobar degeneration with TAR DNA-binding protein-43 pathology (FTLD-TDP) has been found to be an expansion of a hexanucleotide repeat (GGGGCC) in a noncoding region of the gene C9ORF72. Hippocampal sclerosis (HpScl) is a common finding in FTLD-TDP. Our objective was to screen for the presence of C9ORF72 hexanucleotide repeat expansions in a pathologically confirmed cohort of "pure" hippocampal sclerosis cases (n = 33), outside the setting of FTLD-TDP and Alzheimer's disease (AD). Using a recently described repeat-associated non-ATG (RAN) translation (C9RANT) antibody that was found to be highly specific for c9FTD/ALS, we identified a single "pure" HpScl autopsy case with a repeat expansion in C9ORF72 (c9HpScl). Mutation screening was also performed with repeat-primed polymerase chain reaction and further confirmed with Southern blotting. The c9HpScl patient had a 14-year history of a slowly progressive amnestic syndrome and a clinical diagnosis of probable AD. Neuropsychological testing revealed memory impairment, but no deficits in other cognitive domains. Autopsy showed hippocampal sclerosis with TDP-43 immunoreactive neuronal inclusions relatively limited to limbic lobe structures. Neuritic pathology immunoreactive for p62 was more frequent than TDP-43 in amygdala and hippocampus. Frequent p62-positive neuronal inclusions were present in cerebellar granule neurons as is typical of C9ORF72 mutation carriers. There was no significant FTLD or motor neuron disease. C9RANT was found to be sensitive and specific in this autopsy-confirmed series of HpScl cases. The findings in this patient suggest that the clinical and pathologic spectrum of C9ORF72 repeat expansion is wider than frontotemporal dementia and motor neuron disease, including cases of progressive amnestic dementia with restricted TDP-43 pathology associated with HpScl.
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Melissa E
ME
Murray
Kevin F
KF
Bieniek
M
M
Banks Greenberg
Mariely
M
DeJesus-Hernandez
Nicola J
NJ
Rutherford
Marka
M
van Blitterswijk
Ellis
E
Niemantsverdriet
Peter E
PE
Ash
Tania F
TF
Gendron
Naomi
N
Kouri
Matt
M
Baker
Ira J
IJ
Goodman
Leonard
L
Petrucelli
Rosa
R
Rademakers
Dennis W
DW
Dickson
D000368:Aged; D000369:Aged, 80 and over; D000647:Amnesia / Q000235:genetics*; D015139:Blotting, Southern; D001921:Brain / Q000473:pathology; D000073885:C9orf72 Protein; D004247:DNA / Q000235:genetics; D003704:Dementia / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation / Q000235:genetics*; D009483:Neuropsychological Tests; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics*; D012598:Sclerosis; D057177:TDP-43 Proteinopathies / Q000473:pathology; D014015:Tissue Banks; D019680:Trinucleotide Repeat Expansion; D014888:Wechsler Scales
D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins; D004247:DNA