About 1 out of 10 cases of ALS appear to be linked to repeat expansions in the C9orf72 gene, the most common form of the disease identified to date. 

Researchers are working hard to how these repeat sequences may contribute to ALS in hopes to create a treatment for people with C9 ALS.  And, develop tools to anticipate their needs.

A genetic test is now available - enabling clinicians to confirm the diagnosis. Cutting-edge imaging techniques are beginning to emerge - paving the way to predicting outcomes. And, the first potential treatment strategy, developed in partnership with ISIS pharmaceuticals, entered the pipeline.

Ahead of the 2014 meeting of the American Academy of Neurology (AAN), ALS Today takes a look back at key advances in C9 ALS in this interactive timeline. Click on the timeline to learn more about emerging strategies to diagnose, track and treat this form of the disease.


To learn more about C9orf72 ALS, check out ALS on cloud C9. To find out more about emerging treatment strategies for the disease, check out  ALS Antisense and Sensibility.

Image credits: Mark Lythgoe PhD & Chloe Hutton PhD, Wellcome Images; Jonathan Charles, Flickr; George Shuklin, Wikimedia Commons;  Judith Stoffer, National Institute of Genome Sciences; Stephen Neidle PhD, American Chemical Society; European Journal of Human Genetics, Nature Publishing Group; Nature Chemical Biology, Nature Publishing Group and Despicable Me 2 (Viva Press).


Akimoto, C. et al. (2014) A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories.  Journal of Medical Genetics doi:10.1136/jmedgenet-2014-102360Abstract  |  Full Text  

Haeusler, A.R. et al. (2014) C9orf72 nucleotide repeat structures initiate molecular cascades of disease.  Nature 507(7491), 195-200. Abstract  |  Full Text  (Subscription Required)

van Blitterswijk, M. et al. (2014) TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia.  Acta Neuropathologica 127(3), 397-406.  Abstract  |  Full Text (Subscription Required)

Gallagher, M.D. et al. (2014) TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions. Acta Neuropathologica 127(3), 407-418.  Abstract  |  Full Text (Subscription Required)

Cistaro, A. et al. (2014) The metabolic signature of C9ORF72-related ALS: FDG PET comparison with nonmutated patients. European Journal of Nuclear and Molecular Imaging doi: 10.1007/s00259-013-2667-5 Abstract  |  Full Text  (Subscription Required)

Van Laere, K., Vanhee, A., Verschueren, J., De Coster, L., Driesen, A., Dupont, P., Robberecht, W. and Van Damme, P.  (2014) Value of 18Fluorodeoxyglucose-Positron-Emission Tomography in Amyotrophic Lateral Sclerosis: A Prospective Study.  JAMA Neurology doi: 10.1001/jamaneurol.2014.62.  Abstract  |  Full Text (Subscription Required)

Farg, M.A. et al. (2014) C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Human Molecular Genetics doi: 10.1093/hmg/ddu068 Abstract  |  Full Text

Waite, A.J., Bäumer, D., East, S., Neal, J., Morris, H.R., Ansorge, O., Blake and D.J. (2014) Reduced C9orf72 protein levels in frontal cortex of amyotrophic lateral sclerosis and frontotemporal degeneration brain with the C9ORF72 hexanucleotide repeat expansion. Neurobiology of Aging doi: 10.1016/j.neurobiolaging.2014.01.016. Abstract  |  Full Text (Subscription Required)

Lee, Y.B. et al. (2013) Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic.  Cell Reports 5(5), 1178-1186.Abstract | Full Text

Donnelly, C.J. et al. (2013) RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 80(2), 415-428. Abstract  |  Full Text (Subscription Required)

Sareen, D. et al. (2013) Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Science Translational Medicine 5(208), 208ra149. Abstract  |  Full Text  (Subscription Required)

Lagier-Tourenne, C. et al. (2013) Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proceedings of the National Academy of Sciences 110(47), E4530-E4539.  Abstract  |  Full Text  (Subscription Required)

Almeida, S. et al.  (2013) Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. Acta Neuropathologica 126(3), 385-399. Abstract  |  Full Text

van Blitterswijk, M. et al. (2013) C9ORF72 repeat expansions in cases with previously identified pathogenic mutations.  Neurology 81(15), 1332-1341.  Abstract Full Text

van Blitterswijk, M. et al. (2013) Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): a cross-sectional cohort study.  Lancet Neurology 12(10), 978-988.Abstract Full Text  (Subscription Required)

Panda, S.K., Wefers, B., Ortiz, O., Floss, T., Schmid, B., Haass, C., Wurst, W. and Kühn, R. (2013) Highly efficient targeted mutagenesis in mice using TALENs. Genetics 195(3), 703-713.  Abstract  | Full Text (Subscription Required)

Brettschneider, J. et al. (2013) Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Annals of Neurology 74(1), 20-38. Abstract  |  Full Text (Subscription Required)

Bede, P., Bokde, A.L., Byrne, S., Elamin, M., McLaughlin, R.L., Kenna, K., Fagan, A.J., Pender, N., Bradley, D.G. and Hardiman, O. (2013)  Multiparametric MRI study of ALS stratified for the C9orf72 genotype. Neurology 81(4), 361-369. Abstract  |  Full Text  (Subscription Required)

Xi, Z. et al. (2013) Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion. American Journal of Human Genetics 92(6), 981-989.  Abstract  |  Full Text

Xu, Z. et al. (2013) Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration.  Proceedings of the National Academy of Sciences 110(19), 7778-7783.  Abstract  |  Full Text

Mori, K. et al. (2013) hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations.Acta Neuropathologica 125(3), 1178-1186. Abstract  |Full Text (Subscription Required)

Mori, K. et al. (2013) The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339(6125), 1335-1338. Abstract  |  Full Text  (Subscription Required)

Ash, P.E. et al. (2013) Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77(4) 639-646. Abstract  |  Full Text (Subscription Required)

Williams, K.L., Fifita, J.A., Vucic, S., Durnall, J.C., Kiernan, M.C., Blair, I.P. and Nicholson, G.A. (2013) Pathophysiological insights into ALS with C9ORF72 expansions. Journal of Neurology, Neurosurgery and Psychiatry 84(8), 931-935. Abstract  |  Full Text (Subscription Required)

Gómez-Tortosa, E. et al. (2013) C9ORF72 hexanucleotide expansions of 20-22 repeats are associated with frontotemporal deterioration. Neurology 80(4), 366-370. Abstract  |  Full Text  (Subscription Required)

Reddy, K., Zamiri, B., Stanley, S.Y., Macgregor, R.B. Jr and Pearson, C.E. (2013) The disease-associated r(GGGGCC)n repeat from the C9orf72 gene forms tract length-dependent uni- and multimolecular RNA G-quadruplex structures. Journal of Biological Chemistry 288(14), 9860-9866. Abstract  |  Full Text

Fratta, P., Mizielinska, S., Nicoll, A.J., Zloh, M., Fisher, E.M., Parkinson, G. and Isaacs, A.M. (2012)  C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Scientific Reports 2, 2016.  Abstract  |  Full Text

van Blitterswijk, M. et al. (2012) Evidence for an oligogenic basis of amyotrophic lateral sclerosis. Human Molecular Genetics 21(17), 3776-3784. Abstract  |  Full Text

Majounie, E., et al. (2012) Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurology 11(4), 323-330. Abstract  |  Full Text

DeJesus-Hernandez, M., et al. (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72(2), 245-256.  Abstract  |  Full Text

Renton, A. E., et al. (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72(2), 257-268. Abstract  |  Full Text

Vance, C. et al. (2006) Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. Brain 129(4), 868-876. Abstract | Full Text