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Abstract
Objective: To determine the frequency of a hexanucleotide repeat expansion in C9ORF72, a gene of unknown function implicated in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), in Australian FTD patient cohorts and to examine the clinical and neuropathologic phenotypes associated with this expansion.
Methods: We examined a clinically ascertained FTD cohort (n = 89) and a neuropathologically ascertained cohort of frontotemporal lobar degeneration cases with TDP-43 pathology (FTLD-TDP) (n = 22) for the C9ORF72 hexanucleotide repeat expansion using a repeat primed PCR assay. All expansion-positive patients were genotyped for rs3849942, a surrogate marker for the chromosome 9p21 risk haplotype previously associated with FTD and ALS.
Results: The C9ORF72 repeat expansion was detected in 10% of patients in the clinically diagnosed cohort, rising to 29% in those with a positive family history of early-onset dementia or ALS. The prevalence of psychotic features was significantly higher in expansion-positive cases (56% vs 14%). In the pathology cohort, 41% of TDP-43-positive cases harbored the repeat expansion, and all exhibited type B pathology. One of the 17 expansion-positive probands was homozygous for the “nonrisk” G allele of rs3849942.
Conclusions: The C9ORF72 repeat expansion is a relatively common cause of FTD in Australian populations, and is especially common in those with FTD-ALS, psychotic features, and a strong family history. Detection of a repeat expansion on the 9p21 putative “nonrisk” haplotype suggests that not all mutation carriers are necessarily descended from a common founder and indicates that the expansion may have occurred on multiple haplotype backgrounds.
GLOSSARY
- ALS=
- amyotrophic lateral sclerosis;
- bvFTD=
- behavioral variant frontotemporal dementia;
- CBS=
- corticobasal syndrome;
- FTD=
- frontotemporal dementia;
- FTLD-TDP=
- frontotemporal lobar degeneration with TDP-43 pathology;
- LPA=
- logopenic aphasia;
- MAS=
- Memory and Ageing Study;
- PNFA=
- progressive nonfluent aphasia;
- PSP=
- progressive supranuclear palsy;
- SMD=
- semantic dementia
Footnotes
Study funding: This study was funded by the National Health and Medical Research Council of Australia (NHMRC Project Grants 630428 to C.D.-S., 510106 to J.R.H., and 510217 to J.B.J.K. and P.R.S., and Senior Principal Research Fellowship 630434 to G.M.H.) and the Australian Research Council (Federation Fellowship FF0776229 to J.R.H.).
Editorial, page 962
See page 1002
Supplemental data at www.neurology.org
- Received December 13, 2011.
- Accepted February 7, 2012.
- Copyright © 2012 by AAN Enterprises, Inc.
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