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Clin Genet. 2013 Mar;83(3):279-83. doi: 10.1111/j.1399-0004.2012.01903.x. Epub 2012 Jul 4.

Corticobasal and ataxia syndromes widen the spectrum of C9ORF72 hexanucleotide expansion disease.

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1
Department of Clinical Genetics, 4062, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. suzanne.lindquist@rh.regionh.dk

Abstract

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.

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