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New gene for ALS–FTD

Increasing evidence suggests that amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a disease spectrum. An overlapping phenotype is commonly seen while, at autopsy, the transactive response DNA binding protein 43 (TDP-43) is the most common abnormal protein underlying these disorders. Familial ALS-FTD has been strongly linked to a locus on chromosome 9p21 since 2006, however it is only very recently that the culprit gene has been identified. Two independent reports published recently in Neuron show that a GGGGCC hexanucleotide expansion in the noncoding region of the C9ORF72 gene on chromosome 9p21 is the most common cause of familial ALS–FTD. Renton et al carried out next-generation sequencing of the chromosome 9p21 region in a Finnish cohort of ALS patients as well as in a Dutch and an unrelated UK ALS–FTD family that had previously been linked to chromosome 9p21. In a separate study, DeJesus-Hernandez et al sequenced DNA from a large American-Canadian ALS–FTD kindred and later to verify their findings, analyzed a further 696 patients with clinical ALS, FTD, or pathologically diagnosed FTLD–TDP. In each of these reports, the GGGGCC repeat length in healthy controls was fewer than 23 hexanucleotide units, whereas in ALS–FTD patients the repeat length was estimated as between 250–1600 units. While the mechanism of disease is unclear, both groups postulated that the repeat expansion gives rise to the accumulation of toxic RNA which impairs gene transcription. The pathogenic C9ORF72 repeat expansion was present in 23%–46% of familial ALS cases and in 11.7% of familial FTD cases, making it the most common genetic abnormality in these neurodegenerative diseases. In addition, the repeat expansion also accounted for 21.1% of sporadic cases of ALS in the Finnish population. Further studies are warranted to uncover the range of phenotypes associated with this expansion as well as the potential for anticipation and spontaneous mutation.