Scientists have unlocked the gene responsible for a rare and debilitating genetic disorder.
Rapid-onset dystonia-parkinsonism, or RDP, is a rare genetic disorder whose sufferers share symptoms with both dystonia and Parkinson’s disease. In an article published in the July 21 issue of the neuroscience journal Neuron, a research team detailed its discovery that six unique mutations in a single gene were responsible for the occurrence of RDP.
The discovery rebuts a longtime criticism of RDP, that it is not a unique genetic disorder. The discovery also offers hope to individuals who suffer from this disorder and from related, more common, others.
“It’s particularly exciting because it opens further avenues for examining different mutations in this gene that might shed light on the cause of more common neurological disorders that have similar symptoms, such as Parkinson’s and epilepsy,” explained Dr. Laurie Ozelius, associate professor at Albert Einstein College of Medicine, and a member of the team that made the discovery.
The gene, ATP1A3, is closely related to the gene ATP1A2, itself related to a number of other neurological disorders. Patients with Dystonia, a genetic disease common to Jews of Ashkenazic descent, and Parkinson’s both share the same phenatypes as patients with RDP. This makes scientists hopeful that it may lead to breakthroughs in the other genetic disorders.
RDP is so named because of its rapid onset. A few days, or even a couple of hours, are all that is needed for someone to develop the disease. In more than half of patients, the disorder is sparked by a precipitating event. A high fever from a different illness or normal activities like running can trigger the symptoms. Each victim has slight variations on how the disease initially manifests, but many start in speech, affecting the jaw and mouth. Contortions and tremors in the muscles make speaking and forming words impossible. Others will experience foot dragging as the disease begins. The disease also strikes a broad range of ages. Individuals as young as 4 years old, and as old as 58, have developed RDP.
Because stress frequently is linked to the manifestation of RDP, some experts claimed that it was not a real genetic disorder. “Many folks didn’t appreciate that rapid-onset was real and it was often confused with psychogenic disease,” explained Dr. Allison Brashear, professor of Neurology at Indiana University School of Medicine.
Dr. William Dobyns first distinguished RDP as a disorder in 1993. He discovered the disorder when treating two siblings within a month of each other, both displaying the same symptoms. After some research, he found that other members of the family also had the rapid onset of symptoms. The disease had never been reported before 1993, and it is thought that it probably had been misdiagnosed as an unusual movement disorder, instead of the unique genetic disorder it is.
Since then, Brashear and Ozelius have worked to discover the gene responsible. In addition to the first family that Dobyns discovered in 1993, Brashear found another occurrence of the disorder in a family in New York. Since then, the scientists have collected genetic histories from six more families, making eight overall.
Brashear attributed Dobyns’s discovery to an “observant physician who took a really good history.”
Although RDP can manifest in isolated individuals, doctors stress the family connection. In the eight families, six different mutations of the same gene, ATP1A3, were discovered. While there are no other neurological diseases associated with ATP1A3, another closely related gene, ATP1A2, has been connected to both familial emipaligic migraines and infantile convulsions.
When RDP does affect individuals with no family history, which is the case in a couple of the patients studied, doctors ascribe its occurrence to a new mutation.
“The ATP1A3 gene codes for a protein that plays a role in the cellular ‘pumps’ that regulate the transit — both into and out of cells — of sodium and potassium, which are necessary for proper nerve signaling throughout the body,” explained Ozelius. “The mutations in ATP1A3 appear to compromise the encoded protein’s function and disrupt nerve signaling.”
During the family studies, Brashear took DNA samples from family members so that Ozelius could study them. “With her discovery of the mutation of ATP1A3 among the families studied, and the prevalence of RDP that we’ve observed within these families, the link between RDP and a single gene has now been firmly established,” explained Brashear.
Brashear is hopeful about the possibility that locating these mutations might have for people who suffer from RDP. “If they can figure out why people with the mutation get the disease,” Brashear said, referring to the latency of symptoms despite the presence of the mutation, “maybe they can figure out how to treat it.”
Ozelius said a cure is a long way off, but she is hopeful. “Things have been moving rapidly in scientific advances. Science has really stepped up the pace. Theoretically, we may be able to get closer quicker.”