Two groups of scientists working independently of each other have discovered a genetic mutation that causes amyotrophic lateral sclerosis (ALS) known as the disease of Lou Gehrig. Both teams found that mutations of the same gene can also cause a common type of dementia called frontotemporal dementia (FTD). The results add to the growing evidence that these devastating disorders have more in common than meets the eye.
ALS robs patients of the ability to control their bodies. The first symptoms can be subtle, a tic, some muscle stiffness, or speech, but then occasionally mumbled paralysis spreads throughout the body. Most patients die of respiratory failure within 5 years. FTD is a very different beast. The most common type of dementia after Alzheimer's disease, it triggers a strange and inappropriate behavior, particularly in social situations, and difficulty with decision making, language, and other cognitive functions.
Despite these differences, there are overlapping signs. Clinicians have observed that people with a disorder may have symptoms of the other, and some families seem to have more than their share of both. In 06, researchers have linked a region of chromosome 9 in both ALS and FTD. The results suggest that a gene mutated in this region was responsible for many cases of the two conditions, but scientists PinPoint a specific gene.
The race that followed to find the gene was "very intense," said Rosa Rademakers, Neurogeneticist at Mayo Clinic Florida in Jacksonville, who led one of several teams that joined the lawsuit. "In areas of ALS and FTD, it was a result that everyone expected."
In papers published online today Neuron , the team of Rademakers and another group led by Bryan Traynor, a neurologist specializing in ALS at the National Institute on aging in Bethesda, Maryland, identified the same genetic culprit, mutations in an obscure gene called C9ORF72 . Do virtually nothing is known about its function . both teams found that repeated string of six-nucleotide building blocks of DNA that make up the "letters" of the genetic code in this gene can cause ALS or FTD. While healthy people in both studies had no more than 20 repetitions, those with ALS or FTD often were hundreds if not thousands.
the team reviewed hundreds Traynor patients and control subjects in Finland, where the SLA is almost twice as common as in other Caucasian populations. They found that C9ORF72 mutations accounted for 46% of familial ALS cases and about 21% of cases "sporadic" in which the patient reported no family history of the disease. In comparison, the proximate cause genetic most common of ALS gene mutations SOD1 , is responsible for about 15% of familial cases in other European populations, says Traynor.
Rademakers team studied patients in several clinics in the United States and Canada. They found that C9ORF72 mutations accounts for about 22% of familial ALS cases and 12% of familial cases of FTD, far more than any of a handful of other genetic risk factors they examined in the same patients. C9ORF72 mutations accounted for 3% to 4% of sporadic cases of both disorders.
"This is a great step forward because it is such a common mutation," said John Trojanowski, studying neurodegenerative disorders at the University of Pennsylvania. His group found that ALS and FTD share common cellular features, including a misfolded protein called TDP-43 which form clusters inside neurons. Trojanowski said that the new points working in a similar direction. "These results add another convincing proof that the concept ... and ALS [FTD] are mechanistically related disorders at both ends of a clinical and pathological spectrum."
Yet, many important questions remain. No team has found an explanation for why some people C9ORF72 ALS mutations while others get FTD. And it is unclear how mutations cause the disease is. It may be that the protein encoded by C9ORF72 performs an essential function that is yet to be discovered, that gets disturbed, says Traynor. Or perhaps the function of C9ORF72 does not matter. Alternatively, Traynor said, is that repeated nucleotides cause toxic accumulation of messenger RNA, a key player in the cellular machinery for the reading of the DNA for the manufacture of proteins.
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