Amyotrophic lateral sclerosis (ALS) is a rapidly progressive disorder of motor neurons in the cortex, brainstem and spinal cord, for which there is no cure.  The pathophysiological mechanisms underlying ALS remain to be fully elucidated, although approximately 10% of cases were previously regarded as familial.  Mutations in the superoxide dismuate-1 gene (SOD-1) were first reported in 1993, accounting for ~20% of all familial ALS cases.  Recently, two independent research groups have made a stunning discovery, whereby large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 gene located on chromosome 9p21 was reported to account for between 23.5-46% of familial and 21.1% of sporadic forms of ALS (DeJesus-Hernandez et al. 2011; Renton et al. 2011).   In addition to the typical ALS phenotype, this genetic mutation was also associated with frontotemporal dementia, suggesting a potential link between these two disorders.  The mechanisms by which this genetic mutation results in the AL/FTD phenotype remains to be fully elucidated, although a loss-of-function and RNA-mediated gain-of-function mechanisms have been proposed.  Further research is required to clarify the precise mechanisms mediating the neurodegenerative processes in ALS.  Resolution of such issues could be of profound therapeutic significance.

In this issue of JNNP, Dr Bryan Traynor, one of the senior authors on the original manuscript in Neuron, provides historical commentary on the discovery of this very important gene.  In addition, Khan and colleagues further expand the phenotype associated with this very important mutation by reporting a behavioural variant from of frontotemporal dementia (FTD).   This underscores the importance of this mutation in development of neurodegeneration and appears to be a game changer for the diagnosis of both ALS and FTD, having significant implications in the counselling of the so called “sporadic ALS” patients and FTD.


Traynor, B. J. Road to the chromosome 9p-linked ALS/FTD locus. Journal of Neurology, Neurosurgery & Psychiatry. 2012; 83: 356-357.

Khan, B. K., J. S. Yokoyama, L. T. Takada, et al. Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion. Journal of Neurology, Neurosurgery & Psychiatry. 2012; 83: 358-364.

DeJesus-Hernandez, M., Ian R. Mackenzie, et al. (2011). “Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS.” Neuron 72: 245-256.

Renton, Alan E., E. Majounie, et al. (2011). “A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD.” Neuron 72: 257-268.

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