Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations.
The identification of a hexanucleotide repeat expansion in the C9ORF72 gene as the cause of chromosome 9-linked frontotemporal dementia and motor neuron disease offers the opportunity for greater understanding of the relationship between these disorders and other clinical forms of frontotemporal lobar degeneration. In this study, we screened a cohort of 398 patients with frontotemporal dementia, progressive non-fluent aphasia, semantic dementia or mixture of these syndromes for mutations in the C9ORF72 gene. Motor neuron disease was present in 55 patients (14%). We identified 32 patients with C9ORF72 mutations, representing 8% of the cohort. The patients' clinical phenotype at presentation varied: nine patients had frontotemporal dementia with motor neuron disease, 19 had frontotemporal dementia alone, one had mixed semantic dementia with frontal features and three had progressive non-fluent aphasia. There was, as expected, a significant association between C9ORF72 mutations and presence of motor neuron disease. Nevertheless, 46 patients, including 22 familial, had motor neuron disease but no mutation in C9ORF72. Thirty-eight per cent of the patients with C9ORF72 mutations presented with psychosis, with a further 28% exhibiting paranoid, deluded or irrational thinking, whereas <4% of non-mutation bearers presented similarly. The presence of psychosis dramatically increased the odds that patients carried the mutation. Mutation bearers showed a low incidence of motor stereotypies, and relatively high incidence of complex repetitive behaviours, largely linked to patients' delusions. They also showed a lower incidence of acquired sweet food preference than patients without C9ORF72 mutations. Post-mortem pathology in five patients revealed transactive response DNA-binding protein 43 pathology, type A in one patient and type B in three. However, one patient had corticobasal degeneration pathology. The findings indicate that C9ORF72 mutations cause some but not all cases of frontotemporal dementia with motor neuron disease. Other mutations remain to be discovered. C9ORF72 mutations are associated with variable clinical presentations and pathology. Nevertheless, the findings highlight a powerful association between C9ORF72 mutations and psychosis and suggest that the behavioural characteristics of patients with C9ORF72 mutations are qualitatively distinct. Mutations in the C9ORF72 gene may be a major cause not only of frontotemporal dementia with motor neuron disease but also of late onset psychosis.
Cerebral Function Unit, Greater Manchester Neuroscience Centre, Salford Royal Foundation Trust, Salford, M6 8HD, UK. julie.snowden@manchester.ac.uk
Julie S
JS
Snowden
Sara
S
Rollinson
Jennifer C
JC
Thompson
Jennifer M
JM
Harris
Cheryl L
CL
Stopford
Anna M T
AM
Richardson
Matthew
M
Jones
Alex
A
Gerhard
Yvonne S
YS
Davidson
Andrew
A
Robinson
Linda
L
Gibbons
Quan
Q
Hu
Daniel
D
DuPlessis
David
D
Neary
David M A
DM
Mann
Stuart M
SM
Pickering-Brown
D000328:Adult; D017668:Age of Onset; D000368:Aged; D001344:Autopsy; D001519:Behavior / Q000502:physiology; D001921:Brain / Q000473:pathology; D000073885:C9orf72 Protein; D002531:Cerebellum / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics / Q000523:psychology; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D003710:Demography; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D008526:Medulla Oblongata / Q000473:pathology; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000235:genetics / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009483:Neuropsychological Tests; D011506:Proteins / Q000235:genetics*; D011618:Psychotic Disorders / Q000209:etiology / Q000523:psychology; D013116:Spinal Cord / Q000473:pathology
D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D011506:Proteins; D004247:DNA