Two groups of scientists working independently of each other have discovered a gene mutation that causes amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. Both teams found that mutations to the same gene can also cause a common type of dementia called frontotemporal dementia (FTD). The findings add to growing evidence that these two 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 twitch, some muscle stiffness, or occasionally slurred speech—but then paralysis spreads across 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 strange and inappropriate behavior, especially in social situations, as well as difficulty with decision-making, language, and other cognitive functions.
Despite these differences, there are signs of overlap. Clinicians have noticed that people with one disorder sometimes have symptoms of the other, and some families seem to have more than their share of both. In 2006, researchers linked a region of chromosome 9 to both ALS and FTD. The findings suggested that a mutated gene in this region was responsible for many cases of both conditions, but scientists did not pinpoint a specific gene.
The ensuing race to find the gene was "very intense," says Rosa Rademakers, a neurogeneticist at the Mayo Clinic Florida in Jacksonville, who led one of several teams that joined the pursuit. "Within the ALS and FTD fields, this was a result that everyone was waiting for."
In papers published online today in Neuron, Rademakers's team  and another group led by Bryan Traynor , a neurologist specializing in ALS at the National Institute on Aging in Bethesda, Maryland, identify the same genetic culprit, mutations in an obscure gene called C9ORF72. Virtually nothing is known about its function. Both teams found that a repeated string of six nucleotides—the building blocks of DNA that make up the "letters" of the genetic code—in this gene can cause ALS or FTD. Whereas healthy people in both studies had no more than about 20 repeats, those with ALS or FTD often had hundreds if not thousands.
Traynor's team examined hundreds of patients and control subjects in Finland, where ALS is nearly twice as common as in other Caucasian populations. They found that C9ORF72 mutations accounted for 46% of familial cases of ALS and about 21% of "sporadic" cases in which the patient reported no family history of the disorder. In comparison, the next most common genetic cause of ALS, mutations of the SOD1 gene, is responsible for about 15% of familial cases in other European populations, Traynor says.
Rademakers's team studied patients at several clinics in the United States and Canada. They found that C9ORF72 mutations explained about 22% of familial cases of ALS 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 the sporadic cases of both disorders.
"This is a big step forward because it's such a common mutation," says John Trojanowski, who studies neurodegenerative disorders at the University of Pennsylvania. His group has found that ALS and FTD share common cellular features , including a misfolded protein called TDP-43 that forms clusters inside neurons. Trojanowski says the new work points in a similar direction. "These findings add further compelling evidence to the concept ... that ALS and [FTD] are mechanistically related disorders at either ends of a clinical and pathological spectrum."
Still, many important questions remain. Neither team has found an explanation for why some people with C9ORF72 mutations get ALS whereas others get FTD. And it's not clear how the mutations would cause either disease. It may be that the protein encoded by C9ORF72 performs some yet-to-be-discovered essential function that gets disrupted, Traynor says. Or maybe the function of C9ORF72 doesn't matter. Another possibility, Traynor says, is that the repeated nucleotides cause a toxic buildup of messenger RNA, a key player in the cellular machinery for reading out DNA to make protein.