Angelman syndrome affects one in every 10,000 to 12,000 births. Prader-Willi syndrome, at one in 12,000-15,000 births, is even rarer. Rett syndrome affects one in every 12,500 female births. Clearly, one of the biggest challenges in learning more about these diseases is simply finding children to study.
UAB, however, has taken a leadership role in the Rare Diseases Clinical Research Network organized by the National Institutes of Health. The network employs institutions across the country to gather information on syndrome patients and organizes the data at a coordinating center housed at the University of South Florida. The ultimate goal, says pediatrician Alan Percy, M.D., principal investigator for the network's UAB component, is not symptomatic relief but treatment of the syndromes themselves. "While this grant is not going to provide a cure," he says, it will provide the information "to develop a treatment and make it available."
In Search of a Champion
Angelman and Prader-Willi are inherited syndromes; Rett involves a mutation in the X chromosome and affects females almost exclusively. Diagnosis is difficult because of similar symptoms among the three: Angelman and Prader-Willi are related to abnormalities in the 15th chromosome and frequently result in poor development of motor skills, though Prader-Willi also causes a virtually insatiable appetite that can result in excessive, even fatal, weight gain. Children with Angelman or Rett have low muscle tone or have "floppy" limbs and may engage in repetitive motions with their arms or hands, but Rett patients often develop normally for the first six months before regressing markedly in terms of language and motor skills.
"At least on the horizon, we're looking at small-molecule drugs that could pass into the brain and cause a mutated gene to be ‘turned back on' in a normal way," says Percy.
Particularly with Rett syndrome, pediatricians and family physicians frequently have difficulty diagnosing the disorder simply because they see it so rarely. "They're at least starting to become more familiar with it," says Percy, "but nonetheless, it's a challenge to get the message out to physicians in order to help care and advocacy organizations."
Educating insurers is another challenge, Percy says. "Many of these girls need physical appliances, wheelchairs, and orthotic devices, and we have to fight in many cases to get an insurance company or Medicaid to pay for them," he notes. "By the same token, many parents face great challenges in the school system, because it's expensive to educate children with special needs. Most states have advocacy agencies that parents can engage with... but it's still a challenge with these diseases. And it's nice to have a champion." Percy adds that a few celebrities, including actress Julia Roberts and musician Clint Black (who has a niece with the disease), have been able to bring some attention to the syndrome in recent years.
The Clinical Research Network project began in 2003; it now has nearly 600 Rett enrollees (out of a goal of 1,000) and is about a third of the way toward an Angelman target of 300 children. The Prader-Willi database has 35 out of a targeted 150-200 patients, but "they're catching up somewhat," Percy reports.
To speed up the process of enrolling Rett patients, the network is using regional clinics around the country to ease the travel burden on parents who might have trouble reaching the three institutions focusing on the syndrome, all located in the Southeast. "With teams coming from the three different sites, we can see many different girls over the course of a weekend," Percy says.
The Rett investigators at UAB, the Baylor College of Medicine, and Greenwood Genetic Center in South Carolina have already begun to mine some of their data with the help of UAB School of Medicine postdoctoral fellow Daniel Tarquino. "Daniel presented a poster at a network trainee meeting in Rockville, Maryland—there were 56 or 58 posters, so it really was a remarkable showing," Percy says. Tarquino is also sifting the data "to construct Rett syndrome-specific growth charts so that families will know where their daughters fit in relationship to the syndrome as a whole."
With additional help from parent advocacy organizations and the National Organization for Rare Diseases, Percy hopes that one day a treatment will be devised that can reverse the developmental regression of Rett patients. Stem-cell and cell-replacement therapies aren't really a practical solution, he says, but "at least on the horizon, we're looking at small-molecule drugs that could pass into the brain and cause a mutated gene to be ‘turned back on' in a normal way."