New genetic mutation is the most common cause of familial forms of frontotemporal dementia and ALS

September 21, 2011

JACKSONVILLE, Fla. -- North American investigators led by neuroscientists at Mayo Clinic in Florida have found a genetic abnormality they say is the most common cause of two different but related familial forms of neurodegenerative disease -- frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. In the Sept. 21 online issue of Neuron, they say an unusual mutation -- a short DNA sequence repeated hundreds to thousands of times -- was found in almost 12 percent of familial FTD and more than 22 percent of familial ALS samples studied.

The defect is also the strongest genetic risk factor found to date for the more common, non-inherited, sporadic forms of these diseases. It was found in 3 percent of sporadic FTD and 4 percent of sporadic ALS samples in Mayo's large clinical patient series.

"This finding has the potential to lead to significant insights into how both of these neurodegenerative diseases develop, and may give us much needed leads into new ways to treat our patients," says senior investigator Rosa Rademakers, Ph.D., a neuroscientist at the Mayo Clinic campus in Florida.

After Alzheimer's disease, FTD is the second most common form of early onset neurodegenerative dementia. It is characterized by changes in personality, behavior and language due to loss of gray matter in the brain's frontal lobe. ALS destroys motor neuron cells that control essential muscle activity such as speaking, walking, breathing and swallowing, and is typically fatal within 3-5 years of onset.

Researchers have recently found similarity between the two disorders: Up to half of ALS patients experience symptoms of FTD, and, similarly, up to half of FTD patients develop clinical symptoms of motor neuron dysfunction seen in ALS. Both diseases can also occur in the same family.

Several research teams, including one at Mayo Clinic in Florida, recently discovered an important clue to a genetic link. Genetic studies pointed to a region on chromosome 9 for inherited as well as sporadic forms of ALS and FTD, but no one was able to find the mutation until now.

"Since all routine methods of genetic analysis had failed to find the genetic defect in this region, we suspected the defect could be a rare DNA repeat expansion, so we specifically searched for one," says lead investigator Mariely DeJesus-Hernandez. The Mayo-led research team found an area of DNA that in healthy individuals is normally repeated only 2 to 23 times, but in ALS or FTD patients is repeated 700-1,600 times.

The repeat of C and G (two of the four nucleotides that make up the genetic code) was found in a gene called C9ORF72, which has no known function and its role in disease remains a mystery. "We believe that when the defective gene is transcribed into a messenger RNA molecule, the expanded repeat section causes the RNA to bind tightly to certain proteins, forming clumps within the brain cells," Dr. Rademakers says.

"By binding these proteins, the abnormal RNA may prevent these proteins from carrying out their normal functions in the cell," she says. "We don't have a complete picture yet of how this leads to FTD and ALS, but we have an exciting new direction in which to find out."

A team from the National Institutes of Health has independently identified the same repeat expansion as the genetic cause of FTD/ALS, and its study is reported in the same issue of Neuron.

Dr. Rademakers says this genetic defect explains a substantial number of patients with familial FTD and ALS. "More importantly, this is the only common gene that has been found that clearly affects both diseases," Dr. Rademakers says. Why some patients develop FTD and others ALS, despite carrying the same genetic defect, remains unknown and will be an important area of future research.
In addition to researchers at Mayo Clinic in Florida and in Minnesota, contributors to the study included investigators from the University of British Columbia, the University of California, San Francisco, and the University of California, Los Angeles. The authors declare no conflicts of interest.

The research at Mayo Clinic in Florida was financed by the National Institute on Aging, National Institute on Neurological Diseases and Stroke, and the ALS Association.About Mayo Clinic

Mayo Clinic is a nonprofit worldwide leader in medical care, research and education for people from all walks of life. For more information, visit and

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