Familial frontotemporal dementia associated with C9orf72 repeat expansion and dysplastic gangliocytoma.
A hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 gene (C9orf72) was recently identified as the most common genetic cause of frontotemporal dementia/amyotrophic lateral sclerosis. Here we describe the clinical, pathologic, and genetic features of a Finnish C9orf72 expansion carrier, who developed a dysplastic gangliocytoma (Lhermitte-Duclos disease), a rare hamartoma/overgrowth syndrome of cerebellar granule cells associated with mutations in the phosphatase and tensin homolog gene. In addition to the dysplastic gangliocytoma, the patient showed typical transactive response DNA-binding protein with Mr 43 kD (TDP-43) pathology mainly in the cortex and the substantia nigra and numerous p62-positive/TDP-43-negative inclusions in the cerebellar granule cells. His sister carried the same gene defect and showed a similar type of TDP-43/p62 pathology in her brain. Our findings confirm that the clinical and pathologic picture of C9orf72 mutation carriers is more heterogeneous than originally thought and warrants further studies on the possible involvement of phosphatase and tensin homolog gene pathway in the specific cerebellar granule cell pathology associated with C9orf72 expansion.
Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Institute of Neurology, University College London, Queen Square, London, UK.
Raffaele
R
Ferrari
Mia
M
Kero
Kin
K
Mok
Anders
A
Paetau
Pentti J
PJ
Tienari
Olli
O
Tynninen
John
J
Hardy
Parastoo
P
Momeni
Auli
A
Verkkoniemi-Ahola
Liisa
L
Myllykangas
D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D000073885:C9orf72 Protein; D002531:Cerebellum / Q000473:pathology; D042622:DNA Repeat Expansion / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics*; D018303:Ganglioglioma / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics / Q000502:physiology; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000502:physiology; D011506:Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000070876:Tensins
D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D008840:Microfilament Proteins; D011506:Proteins; D000070876:Tensins; D010744:Phosphoric Monoester Hydrolases
C9orf72; Dysplastic gangliocytoma; Familial FTD; Pathology; Sequencing