Corticobasal and ataxia syndromes widen the spectrum of C9ORF72 hexanucleotide expansion disease.
Recently, a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 was reported as the cause of chromosome 9p21-linked frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS). We here report the prevalence of the expansion in a hospital-based cohort and associated clinical features indicating a wider clinical spectrum of C9ORF72 disease than previously described. We studied 280 patients previously screened for mutations in genes involved in early onset autosomal dominant inherited dementia disorders. A repeat-primed polymerase chain reaction amplification assay was used to identify pathogenic GGGGCC expansions. As a potential modifier, confirmed cases were further investigated for abnormal CAG expansions in ATXN2. A pathogenic GGGGCC expansion was identified in a total of 14 probands. Three of these presented with atypical clinical features and were previously diagnosed with clinical olivopontocerebellar degeneration (OPCD), atypical Parkinsonian syndrome (APS) and a corticobasal syndrome (CBS). Further, the pathogenic expansion was identified in six FTD patients, four patients with FTD-ALS and one ALS patient. All confirmed cases had normal ATXN2 repeat sizes. Our study widens the clinical spectrum of C9ORF72 related disease and confirms the hexanucleotide expansion as a prevalent cause of FTD-ALS disorders. There was no indication of a modifying effect of the ATXN2 gene.
Department of Clinical Genetics, 4062, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. suzanne.lindquist@rh.regionh.dk
S G
SG
Lindquist
M
M
Duno
M
M
Batbayli
A
A
Puschmann
H
H
Braendgaard
S
S
Mardosiene
K
K
Svenstrup
L H
LH
Pinborg
K
K
Vestergaard
L E
LE
Hjermind
J
J
Stokholm
B B
BB
Andersen
P
P
Johannsen
J E
JE
Nielsen
D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000235:genetics*; D001259:Ataxia / Q000175:diagnosis / Q000235:genetics*; D001483:Base Sequence; D000073885:C9orf72 Protein; D015331:Cohort Studies; D042622:DNA Repeat Expansion / Q000235:genetics*; D005192:Family Health; D005260:Female; D057180:Frontotemporal Dementia / Q000175:diagnosis / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008875:Middle Aged; D011506:Proteins / Q000235:genetics*; D013577:Syndrome
D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins