Restless Legs Scientists Find Sleep-Kicking Gene

[JohnMack]

Source: ABC News

[Be sure to see: The "RLS Gene" Story: Requip Ad Disguised as News on ABC]

Hunt for Restless Legs Gene Turns Up Possible Sleep-Kicking Culprit
By KAMAL MENGHRAJANI
ABC News Medical Unit

July 18, 2007 —

Late at night, Lynne Kaiser is awake.

It's a routine she has come to terms with over the last seven years, as her bout with restless legs syndrome (RLS) has become debilitating.

"It controls my life," she said.

Kaiser has had to go so far as to alter her occupation because RLS keeps her from holding a job during regular business hours.

"I created a job out of it. I'm an artist, so I did things I could do quietly late at night," she said. "I might go to bed from anywhere between 2 and 7 in the morning."

But by noon, her symptoms return, waking her and stealing much needed sleep for the rest of the day.

"I was not the mother I wanted to be because I didn't have the patience or the brain function or the ability to hold myself together," she said. "And God bless my husband -- I certainly wasn't the woman he married."

Kaiser's case is rare. Less than 3 percent of Americans are severely affected by RLS, and even fewer have the same troubles she does.

But what is normal about Kaiser's RLS experience is that, once she does fall asleep, she involuntarily kicks her legs.

"I own most of our bed. My husband gets about the top right eighth," she said. "Even the animals know: If they want to get into the bed, they don't lay near my legs at all."

Now, scientists may have pinpointed the gene that increases the chances that people will kick in their sleep. Their findings, which could have big implications for many RLS sufferers, are presented in the current issue of the New England Journal of Medicine.

"One of the components of RLS that is found in somewhere around 80 percent of patients was, in addition to having discomfort in the legs, that they move their legs in a dramatic fashion," said Dr. Kári Stefánsson, president of deCODE Genetics, a biotechnology company based in Reykjavik, Iceland.

The company, which has been tracking down disease genes since 1996, was heavily involved with the new study. This same company has successfully located other specific sections of DNA that contribute to diseases such as type 2 diabetes, heart attack and prostate cancer.

"The only thing that the variant does is to increase the probability of the disease," Stefánsson said, pointing out that having this form of the gene does not guarantee the leg-kicking symptom.

The study was initially done with 306 Icelanders who fit the criteria for RLS and who kicked their legs once they fell asleep -- an action known as periodic limb movements in sleep, or PLMs.

To check their work, the scientists repeated the study twice -- once again in Iceland, and another time in Atlanta -- finding the same gene variant each time.

"Once the Icelanders found it there, we wanted to make sure that we could generalize the finding," said Dr. David Rye, director of the Emory Healthcare Program in Sleep Medicine.

"Essentially we had 188 people from the Atlanta area, and we saw the exact same variant in the patients from here," he said. "It's not just chance or luck or a mistake."

Surprise Finding

Interestingly, the gene the researchers ended up discovering wasn't exactly what they set out to find. While they began in search of a gene specific to RLS, researchers instead found a link between DNA and kicking in sleep.

"It is not a gene per se for RLS, but rather for leg movements seen in individuals and families with RLS," said Dr. John Winkelman, medical director of the Sleep Health Center at Brigham and Women's Hospital. "Whether the same gene is associated with periodic leg movements in [other] contexts, we have no information from this study."

So essentially what researchers found was a gene for kicking while asleep. This version of the gene was most often found in people who had sleep-kicking problems and didn't have restless legs syndrome.

Moreover, people who had RLS and didn't kick in their sleep were no more likely to have this form of the gene than anyone else in the general population.

Restless Legs Run in the Family

About half of patients with RLS are said to have family members who also show symptoms, which has led many to believe heredity plays a role.

In fact, Kaiser said that her son also experiences symptoms of the disorder. And he isn't the only one.

"In the two weeks that we were with my grandmother before she passed, I got to see 19 of my relatives -- and 13 of us had symptoms in one form or another," Kaiser said.

"I wanted to know if there was a genetic link -- if mine was inherited and that's why it was so severe, and undoubtedly that has something to do with it."

In a separate study published this Wednesday in Nature Genetics, a group of German and Canadian researchers found three genes that were associated with symptoms of RLS. One of these is the same gene found by the researchers at deCODE and Emory.

The researchers did not make any claims as to which specific symptoms were influenced by the genes, but in one of the groups they studied, 82.1 percent of their patients who had RLS also had periodic limb movements in sleep.

Treatment Precedes Understanding, Some Say

The New England Journal of Medicine study had a secondary finding that people with this gene variant were likely to have less iron in their blood.

"Iron has important roles in the brain," said Winkelman. Iron is involved in making and using a chemical in the brain called dopamine, which helps brain cells communicate with one another.

"Dopamine is intimately involved with both sensation as well as movement," he said. "And it's probably not a coincidence that the medications that are most effective in treating RLS increase dopamine activity in the brain."

Indeed, the two most prominent drugs to treat RLS are GlaxoSmithKline's Requip and Boehringer Ingelheim's Mirapex. Both medications affect dopamine in the brain and were originally created to help patients with Parkinson's disease, a devastating movement disorder.

"They sell more Requip for restless leg than for Parkinson's. It's taken over the primary indication for why the drug was made, and that speaks for itself," said Emory's Dr. Rye.

This has led many to question the need for so many people to be on medication for RLS.

"There are people whose lives are seriously affected, but those cases are rare," said Dr. Steve Woloshin, senior research associate at the VA Outcomes Group in Vermont who wrote about RLS and disease mongering in PLoS Medicine last year.

"The paper underscores that the marketing of RLS is way ahead of the science," he said. "It seems a little crazy to launch a $27 million campaign to push RLS into America's consciousness when we don't really understand what it is, who has it, or how to decide if or when medication is needed."

For RLS sufferer Kaiser, for whom these medications no longer work, living with RLS and PLMs requires her to take life one day at a time. And through it all, her husband, Bruce, is still by her side.

"We don't go to the number of parties or functions that we used to -- but I love her madly, so to me, it is what it is."

Dr. Rye has reported receiving consulting and lecture fees from Boehringer Ingelheim and GlaxoSmithKline. With respect to deCODE Genetics, Dr. Stefansson has a financial interest in the diagnostic products and patents that may result from this study. Dr. Winkelman has reported receiving financial support for research, as well as consulting and lecture fees, from Boehringer Ingelheim and GlaxoSmithKline. Dr. Woloshin has declared no conflicts of interest.

[JohnMack]

I couldn't believe my eyes and my ears last night when ABC News devoted significant airtime to a story that it claimed "will put and end to criticism of Restless leg Syndrome" or something to that effect.

In reality, this "news" item was a direct to consumer ad (DTC) for Requip, except without the fair balance!

But, more than that, the study behind the news is seriously mired in conflict of interest. Not only that, this study is likely to cause the greatest off-label scandal in history!

For more on this, see today's post to Pharma Marketing Blog.

[JohnMack]

Source: Bloomberg.com

By John Lauerman

Scientists have linked certain genes to heart and eye disease, as well as the sleep-robbing restless leg syndrome, in four studies using new DNA screening tools that have led to a flurry of discoveries on the causes of illness.

One gene variant doubles the risk of age-related macular degeneration, the most common cause of blindness in developed countries, researchers said. A separate study found several common DNA variations that can raise heart disease risk in millions of people.

The findings are the latest made possible by genetic tools from two California-based companies, Affymetrix Inc. and Illumina Inc., that can analyze as many as 900,000 genetic variations in 48 hours. Scientists using the devices have found potential explanations for diseases in dozens of previously unexplored genes in the last few years.

``These studies represent an important advance in medicine,'' wrote Jeffrey Drazen, editor of the New England Journal of Medicine, in an editorial. ``They convey novel, unbiased information about the heritable basis of disease at a level of detail that has not been possible previously.''

Three of the studies are published in the New England Journal, and a fourth is in the journal Nature Genetics.

For some rare disorders, a faulty gene can act like an ``on'' switch that determines a person's fate from conception. In most common diseases, however, genes are just one of many puzzle pieces -- along with influences such as diet and exposure to chemicals -- that result in illness.

Markers

The tools made by Santa Clara-based Affymetrix and San Diego-based Illumina identify markers that show which variant of a gene is present in an individual. These markers are called single nucleotide polymorphisms, or ``snips.''

``This amounts to a full-employment act for cell biologists and physiologists to understand what these screens are telling us,'' Drazen said in a phone interview today. ``Understanding how these genetic variants lead to disease won't be easy.''

One study in the New England Journal pointed to a series of genes that raise patients' risk of coronary artery disease, a type of damage to the heart's blood vessels that affects 15 million Americans and often leads to heart attacks. The study confirmed earlier research from the U.K. and Germany pointing to the same genes, and identified at least four new genetic variants that may also be linked to heart disease.

The results ``are likely to uncover unanticipated mechanisms in heart disease and will ultimately enhance our ability to care for patients,'' said Anthony Rosenzweig, a Harvard Medical School cardiologist in an editorial.

Macular Degeneration

John Yates and Tina Sepp of the Cambridge Institute for Medical Research in the U.K. led the study of genes involved in macular degeneration, a deterioration of the macula, the most sensitive part of the eye. Comparing gene screens of 505 patients with those of 351 healthy people, they found that one version of an immune gene called C3 can increase the risk of macular degeneration from 70 percent to 160 percent.

The higher risk is associated with a variant of the gene called C3F that might increase inflammation in the eye. People who get two copies of the gene are more likely to get the disease than those who get one copy or none.

``It's exciting,'' said Margaret DeAngelis, a Harvard Medical School genetic epidemiologist at the Massachusetts Eye and Ear Institute in Boston, in a telephone interview today. ``Our group is looking at every gene and associated pathway, and this group got to it first.''

Genome screening is also giving new insights into poorly understood disorders such as restless leg syndrome, an urge to move one's legs at night that often disrupts patients' sleep. Some researchers have questioned whether the disease, described in doctors' writings as long as 350 years ago, has any physiological basis.

Restless Leg

Papers published in the New England Journal by researchers from DeCode Genetics Inc. of Iceland and in Nature Genetics by Max Planck Institute of Psychiatry scientists point to a gene called BTBD9 on chromosome 6 as a partial explanation for the disorder. The Max Planck paper, published in Nature Genetics, found three additional genes at other locations that raise the risk of the disorder.

Some scientists had said that restless leg syndrome was a myth, pointing out that it was far more common in developed countries in the West, where health care is more available than in developing Eastern nations. The BTBD9 variant is also more common in people of European descent, which may explain why the disease occurs in the West, said Kari Stefansson, DeCode's chief executive officer.

``What is probably behind the difference in the frequency of diagnosis is the distribution in the risk variant,'' he said today in telephone interview.

Juliane Winkelmann, a neurologist at the Institute of Human Genetics and the Max Planck Institute who led the study in Nature Genetics, said her findings suggest that genes involved in the formation of the nervous system in the embryo play a role in restless leg syndrome.

``The discovery of a role for these genes is completely surprising,'' she said today in a telephone interview. She plans to follow up with animal and test tube studies to determine whether restless leg syndrome begins early in an organism's development.

To contact the reporter on this story: John Lauerman in Boston at jlauerman@bloomberg.net