Amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD) can occur in the same family with an autosomal-dominant pattern of heritance that is linked to chromosome 9p21. Now, two studies independently report that a hexanucleotide repeat expansion in the non-coding region of C9ORF72 causes 9p21-linked ALS and FTD. Both studies initially identified this genetic expansion in families with an established history of 9p21-linked ALS, FTD and/or FTD–ALS (a phenotype with characteristics of both diseases). Subsequently, DeJesus-Hernandez et al. showed that in a clinical series of patients, this expansion was the most common genetic cause of familial and sporadic ALS, and a major cause of familial FTD. Meanwhile, Renton et al. showed that the hexanucleotide expansion underlay ∼21% of sporadic cases and 46% of familial cases of ALS in a Finnish cohort of patients. The mechanism by which this expansion causes disease is unclear — although, together, the studies show that it may have an effect on C9ORF72 expression and lead to the formation of nuclear RNA foci.
ORIGINAL RESEARCH PAPERS
DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 21 Sep 2011 (doi:10.1016/j.neuron.2011.09.011)
Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS–FTD. Neuron 21 Sep 2011 (doi:10.1016/j.neuron.2011.09.010)
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Yates, D. Expanding ALS and FTD genetics. Nat Rev Neurosci 12, 616 (2011). https://doi.org/10.1038/nrn3134
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DOI: https://doi.org/10.1038/nrn3134
