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 the FMR1 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.