Genetic Mutation and ALS and Dementia

Genetic mutation linked to inherited forms of ALS, dementia

New Understanding Into the Causes of ALS and Dementia

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.