News Release

Wednesday, September 28, 2011

Genetic mutation linked to inherited forms of ALS, dementia

NIH-supported researchers’ gene discovery provides clues to cause.

National Institutes of Health scientists and worldwide teams of researchers have identified the most common genetic cause known to date for two neurological diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The discovery offers clues to underlying mechanisms of these diseases, and may eventually contribute to the design and testing of possible therapies. The research results appeared online in Neuron on Sept. 21, 2011.

Researchers found that a mutation on a single gene, C9ORF72 on the short arm of chromosome 9, accounts for nearly 50 percent of the directly inherited, familial ALS and FTD in the Finnish population, and more than a third of familial ALS in other groups of European ancestry. The mutation, called a hexanucleotide repeat expansion, is an unusual one that involves repeating a DNA sequence over and over again. The researchers also found these mutations in Finnish people with the more common, sporadic form of ALS.

Bryan Traynor, M.D., of the Laboratory of Neurosciences at the NIH’s National Institute on Aging (NIA), led the NIH work with support from NIH's National Institute of Neurological Disorders and Stroke (NINDS). NIA and NINDS also funded work by a team from the Mayo Clinic in Florida, reported by Mayo investigator Rosa Rademakers, Ph.D., and colleagues, which independently identified the same repeat DNA sequence as a genetic cause of FTD/ALS.

"Identifying this defective gene common to both the inherited forms of ALS and FTD and the sporadic form of ALS provides important new insights into the development of these neurodegenerative diseases," said NIA Director Richard J. Hodes, M.D. "We still have much to learn about the complex interplay between genetic risk for a disorder and the other factors that determine disease onset and progression. But finding these types of mutations is critically important to a better understanding of disease mechanisms so that we can ultimately target disease biology to develop therapeutics."

"This finding highlights the importance of studying isolated populations with high rates of a specific disease. Finland has the highest rates of ALS in the world. By collecting virtually every case within the Finnish population, Traynor and colleagues were able to definitively show that this particular gene mutation plays a role in ALS development—a discovery relevant not just to that population, but critical to our basic understanding of the disorder," said NINDS Director Story Landis, Ph.D.

Both ALS, often referred to as Lou Gehrig's disease, and FTD are rapidly progressive, fatal neurological disorders that attack and kill brain cells, or neurons. People with ALS lose strength and the ability to move their arms, legs, and body, and eventually, the ability to breathe without support. About 5 percent of people with ALS have the directly inherited form of the disease. People with FTD develop erratic behavior, emotional problems, trouble communicating, or difficulty with walking and other basic movements. About 20 to 40 percent of those with FTD have a family history of the disorder. ALS and FTD can sometimes occur together in the same individual, but they also occur independently of each other.

There is growing scientific evidence that the pathologies of ALS and FTD somehow overlap. To date, a number of mutated genes have been identified as playing a role in the development of familial FTD and ALS, but not to the level of significance as the discovery of the 9p21 gene mutation. The five major genes previously identified for ALS account for approximately 25 percent of familial cases. The new discovery increases this figure to around 65 percent.

"Until now, the gene alteration responsible for the chromosome 9p-linked inherited forms of these diseases remained elusive," said Traynor. "Investigators around the world worked together to identify a common genetic cause of these fatal disorders. At NIH, our state of the art DNA sequencing facilities enabled us to rapidly generate the data needed to identify this repeat expansion."

The findings reported by Traynor and the team resulted from an international collaboration involving scientists in the United States, Canada and Europe. In the United States, participating institutions included the University of Washington School of Medicine, Seattle; Johns Hopkins University, Baltimore; Georgetown University, Washington, D.C.; and the Miller School of Medicine, University of Miami. The European collaborators included Cardiff University School of Medicine, Wales; VU University Medical Centre, Amsterdam, and Erasmus MC - University Medical Center, Rotterdam, The Netherlands; University of Manchester and University College London, England; University of Oulu and University of Helsinki, Finland; the University of Toronto; University of Würzburg, Germany; and the University of Turin, Catholic University Rome, and the University of Modena Cagliari, Italy.

The NIA leads the federal government effort conducting and supporting research on aging and the health and well-being of older people. The Institute’s broad scientific program seeks to understand the nature of aging and to extend the healthy, active years of life. For more information on research and aging, go to

NINDS is the nation's leading funder of research on the brain and nervous system. The NINDS mission is to reduce the burden of neurological disease — a burden borne by every age group, by every segment of society, by people all over the world.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit

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Renton, A.E., et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked FTD/ALS, Neuron, 10.1016/j.neuron.2011.09.010. Published online September 21, 2011.

Rademakers, R., et al. Expanded GGGGCC hexanucleotide repeat in non-coding region of C9ORF72 causes chromosome 9p-linked frontotemporal dementia and amyotrophic lateral sclerosis.DOI 10.1016/j.neuron.2011.09.011. Published online September 21, 2011.