Drug to Treat a Type of Mental Retardation Shows Promise

A small study of 30 people with the most common inherited form of mental retardation has found encouraging evidence that some symptoms of the disorder can be alleviated with drugs. Some patients with Fragile X syndrome who received an experimental drug showed reductions in repetitive behaviors, hyperactivity, inappropriate speech, and social withdrawal. However, the drug affected only patients with a particular genetic alteration—a discouraging sign, perhaps, for those without that marker, but a potentially useful tool for identifying the patients most likely to respond to treatment.

As recently as 10 years ago, the idea of reversing mental retardation was unthinkable. That's because many of these conditions result from genetic glitches that derail brain development even before birth. But recent studies with mice and other animals have given researchers hope that it may be possible to develop treatments that improve cognition and behavior in conditions like Fragile X syndrome, in which a mutation to a gene on the X chromosome makes part of the chromosome look unusually thin, and Rett syndrome, another common cause of mental retardation.

One of the hottest prospects to emerge for treating Fragile X syndrome is a class of drugs that block a receptor in the brain called metabotropic glutamate receptor 5 (mGluR5). This receptor plays a role in protein synthesis at the junctions between nerve cells, and it becomes hyperactive as a result of the gene mutation that causes Fragile X. Blocking this receptor, the thinking goes, helps restore its activity to a normal level.

Other studies have reported that mGluR5-blocking drugs appear to have only moderate side effects, such as fatigue, in humans, but the new study is the first systematic report on behavioral changes in people with Fragile X. The 30 patients, all men between the ages of 18 and 35, were part of a phase II clinical trial sponsored by the pharmaceutical company Novartis, which makes the drug, called AFQ056. Half of the patients received AFQ056 for 4 weeks, then a placebo for 4 weeks. The other half took the placebo first, then the drug. Neither the patients, their caregivers, nor the researchers knew which group a patient had been assigned to until after the study.

To assess a patient's behavior before and after treatment, the researchers, led by Sébastien Jacquemont, a medical geneticist at Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, and Baltazar Gomez-Mancilla, a neurologist at Novartis Institutes for Biomedical Research in Basel, Switzerland, had his caregiver—typically a parent—fill out a battery of standardized questionnaires. At first, the drug seemed to have had no effect, says Gomez-Mancilla. "We were really puzzled," he says.

But when the team reexamined the data, they discovered that seven patients with a particular genetic signature had shown reduced repetitive behaviors, such as rocking back and forth and clapping, and other behavioral improvements after treatment. Some parents told the researchers they'd been more able to engage and interact with their children while they were taking the drug, Gomez-Mancilla says. Some reported fewer disruptive behaviors, such as tantrums. The researchers did not see any evidence of improvements in learning and memory, Gomez-Mancilla says, but he thinks such cognitive changes might require longer treatment times.

The Fragile X patients who responded to AFQ056 all had a "fully methylated" version of the control region of theFMR1 gene, the gene that is mutated in Fragile X. Methlyation is a chemical modification to DNA that turns a gene off, and the patients who responded to the drug appeared to have a completely inactive FMR1 gene. The others had a partially active FMR1 gene. Why this would make a difference in how people respond is still an open question, Gomez-Mancilla says. The researchers report their findings online 5 January in Science Translational Medicine.

"It's hopeful, but it's still very small numbers," says Stephen Warren, a geneticist and veteran Fragile X researcher at Emory University in Atlanta. The idea of using methylation as a biomarker to determine who might respond to this type of treatment is potentially exciting, says Ben Philpot, who studies neurodevelopmental disorders at the University of North Carolina, Chapel Hill. But he shares Warren's sense of caution: "They really need to replicate this in a larger group."

That's precisely what researchers at Novartis are trying to do now. In November, they began recruiting for a larger clinical trial that will test the effects of AFQ056 in 160 people with Fragile X. This time, the researchers will test for methylation of the FMR1 gene at the outset, and patients will take the drug for 3 months.

ScienceShot: Impacts Leave Marks on Rings of Saturn and Jupiter

Whizzing asteroids and comets have battered Earth and all the other solid bodies of our solar system over the eons, but the ethereal rings of the giant planets seemed immune. No longer. In two papers published online today in Science, researchers report that comet impacts in recent decades have left their mark on the rings of both Saturn and Jupiter. In August 2009, the orbiting Cassini spacecraft caught sight of 20-meter-high corrugations rippling across 1500 kilometers of Saturn's inner C ring (regular, narrow bright bands, above), which is only about 10 meters thick. The corrugations turn out to be one continuous wave spiraling outward like the groove in a vinyl LP record. And in 2007, the New Horizons spacecraft on its way to Pluto imaged two wave sets spiraling through each other in the faint, dusty ring of Jupiter. One Jovian wave appears to be still on the move 13 years after fragments from comet Shoemaker-Levy 9 hit the ring on their way to pummeling Jupiter in 1994. But for any impacting object to hit a tenuous ring hard enough to tilt it and set off such reverberations, both teams agree, it would first have to disintegrate into a cloud of fine debris that can hit a broad area of ring. That's just what Jupiter's gravity did to Shoemaker-Levy 9. 

News Release : Scientists Find Part of New Zealand's Submerged "Pink Terraces"

They were called the Eighth Wonder of the World. Until the late 19^th century, New Zealand’s Pink and White Terraces along Lake Rotomahana on the North Island, attracted tourists from around the world, interested in seeing the beautiful natural formations created by a large geothermal system. But the eruption of Mt. Tarawera on June 10, 1886, buried the terraces in sediment and caused the lake basin to enlarge, engulfing the land where the terraces stood. For more than a century, people have speculated whether any part of the Pink and White Terraces survived the eruption.

This week, scientists from New Zealand’s GNS Science, one of several government laboratories, in collaboration with engineers and scientists from Woods Hole Oceanographic Institution (WHOI) and colleagues from Lamont-Doherty Earth Observatory of Columbia University and NOAA-PMEL, located portions of the long-lost Pink Terraces.

The research team, using autonomous underwater vehicles (AUVs) to map the bottom of Lake Rotomahana, are certain they have found the lower portions of the Pink Terraces on the lake floor. Project leader Cornel de Ronde, of GNS Science, said the team was elated by the discovery.

“The first sidescan sonar image gave a hint of a terraced structure so we scanned the area twice more and we are now 95 percent certain we are seeing the bottom two tiers of the Pink Terraces,” de Ronde said. 

Side-scan sonar and bathymetric data collected by two REMUS 100 AUVs clearly show crescent-shaped terraced structures in about 60 meters of water where the Pink Terraces were located prior to 1886. They are covered by a brownish lake sediment.

The free-swimming REMUS vehicles were developed by WHOI with funding from the US Navy and were operated by Amy Kukulya and Robin Littlefield of the WHOI Oceanographic Systems Laboratory (OSL) who travelled to New Zealand for the expedition.  Dan Fornari, a scientist with the WHOI Geology & Geophysics department, helped lead the expedition and, along with Marshall Swartz of the WHOI Physical Oceanography department, developed the underwater camera system used in the lake.

After detecting areas of interest with the AUV’s sonar systems, the team used the underwater camera system, developed with funds from the U.S. National Science Foundation, to capture images of the lake floor where they were able to photograph some of the stepped terrace edges.

Dr. de Ronde said the rest of the Pink Terraces were either destroyed during the eruption, or are still concealed under thick sediment not able to be penetrated by high-frequency AUV sonars.

The scientists found no sign of the larger White Terraces in the part of the lake that matched their location prior to 1886. The two terraces, part of a very large on-land geothermal system, were separated by several hundred meters prior to the eruption.  

There are very few examples of large land-based geothermal systems that have been torn apart by an eruption and become inundated in this way. Scientists hope the data collected during this expedition will help them better understand how geothermal systems respond to disruptions of this kind.

“It was very gratifying to take the tools and knowledge we’ve developed for ocean research and apply them to work in the lake, especially for a scientific project with so much Maori cultural significance.”

In 2009, WHOI signed a memorandum of understanding with GNS and New Zealand’s National Institute for Water and Atmospheric Research (NIWA) to expand research and technology development collaborations across the scientific disciplines in the southwest Pacific and within New Zealand territorial waters.  In addition to the work in Lake Rotomahana, the organizations are also collaborating on deep ocean research on the Kermadec Seamounts north of New Zealand’s North Island using the Sentry AUV and TowCam deep-sea imaging system.

“We hope the success in Lake Rotomahana is the first of many scientific collaborations in this part of the world where there are many interesting research problems to investigate.”

The project was a collaboration involving GNS Science, Woods Hole Oceanographic Institution in Massachusetts, Lamont-Doherty Earth Observatory at Columbia University in New York, the National Oceanic and Atmospheric Administration in Seattle, and the University of Waikato.

After this week’s discovery, de Ronde paid tribute to colleagues from WHOI, saying “This result would not have been possible without the team from Woods Hole Oceanographic Institution and their American colleagues. Their contribution has been huge.”